HEMATOLOGY HISTORY & PE

● Hematology is the study of blood in health and disease.

● It includes problems with:
○ the red blood cells ○ lymph nodes
○ the white blood cells ○ spleen
○ platelets ○ proteins involved in bleeding and
○ blood vessels clotting (hemostasis and thrombosis)
○ bone marrow
● HPI/ROS:
○ Fatigue ○ Heavy ○ Pain in lymph
○ Weakness menstruation nodes
○ Fevers ○ Blood in stools ○ Bone pain
○ Night sweats ○ Infections ○ Tingling or loss of
○ Weight loss ○ Jaundice sensation
○ Dyspnea, Dyspnea ○ Easy bruising, ○ Skin rash
on exertion bleeding ○ Pruritus
○ Palpitations ○ Swelling of lymph
nodes
● PMH/PSH:
○ Frequent ○ Surgery to the GI ○ History of bleeding
infections tract disorder
○ Bleeding disorders ○ Transplant ○ History of clotting
○ Clotting disorders recipient – taking disorder
○ Menstrual history immunosuppressa ○ Hemophilia
and Pregnancies nts ○ von Willebrand’s
○ Blood in stools, ○ Malignancies Disease
tarry stools ○ Hematologic ○ Sickle Cell Disease
○ History of History ○ Thalassemia
radiation therapy ○ Family History ○ Leukemia,
○ Recent ○ Ethnic/family Lymphoma,
trauma/blood loss origin Multiple Myeloma
● Social History
○ Tobacco use ○ Living situation, ○ Steroids
(frequency, who is caregiver ○ Vitamins/supplem
duration, type) ○ Hematologic ents
○ Alcohol use History ○ Oral
○ Illicit drug use ○ Medication Use contraceptives,
○ Diet ○ OTC meds such as hormone
○ Sexual History NSAIDS, ASA replacement
○ Anticoagulants ○ Any allergies?
● Hematologic Physical Exam
○ General: ■ Bruising
■ Appearance ■ Scratch marks
■ Race, gender ■ Plethoric red face (could be an
■ Skin color (pale, jaundice, indication of too many RBCs)
cyanotic) ■ Wasted/cachexic

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 ■ Conversational dyspnea ■ Apical impulse or Point of
Maximal Impulse (PMI)
○ Hands and Nails: ■ Systolic murmur
■ Koilonychia (spooning of nail; ○ Abdomen
misshapen nail) ■ Palpate liver and spleen
■ Pale nail bed, clubbing ■ Surgical scars
■ Pallor of palmar creases ■ Ascites
(indication of anemia) ■ Inguinal nodes
■ Decreased sensation in hands ■ Rash
○ Arms ○ Legs
■ Scratch marks ■ Ulcers
■ Ecchymoses, purpura, petechiae ■ Ecchymoses, purpura, petechiae
■ Epitrochlear nodes ■ Edema/swelling
○ Axilla ■ Popliteal nodes
■ Nodes enlarged? ■ Decreased sensation
■ Central, lateral, pectoral, ■ Toe clubbing
infraclavicular, subscapular ■ Nail changes
○ Eyes ○ Lymph Nodes
■ Conjunctiva (pallor) ■ Symmetry: clinically significant
■ Sclera (icteric, hemorrhages) nodes classically asymmetric
■ Injected sclerae ■ Size: insignificant if < 2cm; in
○ Mouth axilla and inguinal insignificant
■ Gums (bleeding, hypertrophy) if < 3cm; in the supraclavicular
■ Tongue (glossitis) fossa > 1cm is significant
■ Ulcers ■ Consistency: soft (insignificant),
■ Tonsillar/adenoid enlargement rubbery (classically lymphoma),
○ Neck hard (classically malignancy &
■ Inspect nodes (submental, granulomatous infection)
submandibular preauricular, ■ Tender (classically infection) vs.
postauricular, occipital jugular non-tender (classically
chain, supraclavicular, malignancy)
paratracheal) ■ (Patients 2-12 years old
○ Chest/Lungs commonly present with
■ Bone pain insignificant lymph nodes in
■ Dyspnea neck secondary to frequent viral
■ Cardiac infection.)

ANEMIA
● A decrease in the number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood
● Anemias are generally due to decreased production or increased destruction of RBCs
● Classified as microcytic, normocytic, or macrocytic
○ The normal mean corpuscular volume (MCV) is 80-100 fL, with smaller cells (<80 fL) described as
microcytic and larger cells (>100 fL) as macrocytic
Red Blood Cells in a Nutshell
● Also called erythrocytes
● Most common blood cell in the body
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 ● Job = carry oxygen
● Cytoplasm is rich in hemoglobin, an iron-containing molecule that can bind oxygen and is responsible for the
blood's red color
● In humans, mature red RBC are flexible and oval biconcave disks
● Mature RBC lack a nucleus
● Cells develop in the bone marrow and circulate for about 100-120 days in the body before their components are
recycled by macrophages.
● Each circulation takes about 20 seconds

MICROCYTIC ANEMIAS
● RBCs are small and usually also hypochromic
● Iron Deficiency
● Thalassemia
● Sideroblastic Anemia
● Lead Poisoning
● Anemia of chronic disease
● Diagnosis of Microcytic Anemias
○ Once microcytosis is confirmed, start by distinguishing between iron deficiency anemia and thalassemia
○ If RBC is low (or H/H low), obtain iron studies to assess for Iron Deficiency Anemia
○ If ethnicity or family history is suggestive of thalassemia, then Hemoglobin analysis (electrophoresis)
● Iron studies:
○ Serum Iron (SI): total amount of iron in the blood
○ Transferrin: the main protein in the blood that binds and transports iron
○ TIBC: amount of transferrin available to bind and transport iron
○ Transferrin saturation: blood’s ability to bind and transport iron
○ Transferrin Saturation (%): calculated based on TIBC and SI

Iron Deficiency Anemia

● A common anemia caused by insufficient dietary intake and absorption of iron, and/or iron loss from bleeding
● S&S:
○ Pallor due to reduced oxyhemoglobin in skin or mucous membranes (conjunctivae, palmar folds)
○ Cheilitis – fissures at the corners of the mouth
○ Koilonychia – spooning of the nails
○ Atrophic glossitis with loss of tongue papillae (smooth tongue)
○ Fatigue ○ Exercise intolerance
○ Lightheadedness ○ Exertional dyspnea
○ Palpitations ○ Weakness
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 ○ Pica – desire or compulsion to eat substances not fit as food (clay, dirt, charcoal, paper products, ice);
*pagophagia (pica for ice) is quite specific for IDA
● Causes
○ Parasites - hookworms, whipworms, roundworms → inflammation as well as chronic blood
loss
○ Blood loss: menstruation, menorrhagia (heavy periods), GI bleeding (peptic ulcer, colon polyp, or
gastrointestinal cancer), GI bleeding from medications (non steroidal anti inflammatory drugs (NSAIDs)
e.g. aspirin, anticoagulants)
○ Lack of dietary iron (meat, eggs, leafy green vegetables and iron-fortified foods)
○ Inability to absorb iron (Celiac disease, inflammatory bowel disease, surgical resection)
○ Pregnancy: iron stores need to serve the mother’s increased blood volume as well as be a source of
hemoglobin for the growing fetus, and for placental development
● Diagnosis
○ CBC: low hemoglobin (Hbg) by definition makes the diagnosis of anemia, and a low hematocrit (Hct)
value is also characteristic of anemia
○ RDW: high red blood cell distribution width, reflecting an increased variability in the size of RBCs
○ Serum iron represents the amount of iron bound to transferrin (low) and the TIBC is an indirect measure
of transferrin (high)
○ Transferrin saturation (serum iron x 100 ÷ TIBC) is usually 25-50%. Iron deficiency is associated with
saturation < 18%
○ Serum ferritin correlates with total body iron stores; as iron stores are depleted, ferritin levels fall
○ Low serum ferritin, a low serum iron level, an elevated serum transferrin and a high total iron binding
capacity
○ A low serum ferritin is the most sensitive lab test for iron deficiency anemia. However, serum ferritin can
be elevated by any type of chronic inflammation and so is not always a reliable test of iron status if it is
within normal limits (e.g., this test is meaningful if abnormally low, but less meaningful if
normal).
○ A blood smear of a patient with iron deficiency looks like this:
■ hypochromic (pale and relatively colorless)
■ small RBCs
■ poikilocytosis (variation in shape)
■ anisocytosis (variation in size)
■ target cells - bullseye appearance (severe)
■ nucleated red blood cells (severe)
● Differential Diagnosis
○ 4 other conditions that need to be considered in the
DDx of hypochromic, microcytic anemia
■ Thalassemias (normal or increased serum iron and transferrin saturation)
■ Anemia of Chronic Disease (ferritin is normal or increased and TIBC is below normal)
■ Myeloproliferative disorders (iron values reveal normal stores)
■ Sideroblastic anemia
○ It is very important not to treat a patient with thalassemia with an iron supplement, as this can lead to
hemochromatosis (accumulation of iron in various organs, especially the liver)
○ Hemoglobin electrophoresis and iron studies distinguish these two conditions
● Treatment
○ Oral Iron Therapy

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 ■ 300mg elemental iron PO daily (divided in 3-4 doses)
■ Treat for 6-12 months after the correction (usually occurs after ~2 months) of anemia to achieve
adequate iron stores
■ Complication: GI distress – vomiting, nausea, constipation, abdominal pain
○ Dietary iron
■ Eating more iron-rich foods, such as beans, lentils or red meat, or taking iron supplements
○ Bioavailability
■ Decrease bioavailability: milk, coffee, tea
■ Increase bioavailability: ascorbic acid (vitamin C), heme iron (meat, fish)
■ Gluten free diet if the cause is Celiac Disease
○ Red Blood Cell Transfusion: used when anemia is symptomatic, cardiovascular instability, continued
blood loss; used to stabilize a patient
○ Parenteral Iron: IV iron can be given if a patient cannot tolerate oral therapy, needs ongoing iron; concern
regarding safety of iron dextran (anaphylaxis)
Sideroblastic Anemia
● A disease in which the bone marrow produces ringed sideroblasts rather than healthy RBCs
● The body has iron available but cannot incorporate it into Hgb, which RBCs need to transport O2 efficiently
● Sideroblasts are atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules
of iron accumulated in perinuclear mitochondria
● Ring sideroblasts - arrangement of the iron granules in a ring form around the nucleus
● Causes
○ Toxins: lead or zinc poisoning; excessive alcohol use
○ Drug-induced: isoniazid, chloramphenicol, cyclosporine, Linezolid, oral contraceptives
○ Nutritional: pyridoxine (Vitamin B6) or copper deficiency
○ Diseases: Myelodysplastic Syndrome
○ Genetic: X-linked, mitochondrial disorders
● Pathophysiology
○ Failure to completely form heme molecules, whose biosynthesis takes place partly in the
mitochondrion → deposits of iron in the mitochondria that form a ring around the
nucleus of the developing RBC
● Signs and Symptoms
○ Skin paleness, fatigue, dizziness, peripheral neuropathy, abdominal pain, enlarged spleen and liver
○ Heart disease, liver damage, and kidney failure can result from iron build up in these organs
● Diagnosis
○ Ringed sideroblasts are seen in the bone marrow
○ The anemia is moderate to severe and dimorphic with marked anisocytosis and poikilocytosis
○ Basophilic stippling (left) is marked and target cells are common
○ Pappenheimer bodies (right) are present

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 ○ The MCV is decreased (a microcytic anemia)
○ The RDW is increased
○ In excess of 40% of the developing erythrocytes are ringed sideroblasts
○ Serum iron, percentage saturation and ferritin are increased
○ The TIBC is normal to decreased
● Treatment
○ Occasionally, the anemia is so severe that support with blood transfusion is required
○ Phlebotomy (routine removal of blood) may be required in cases of iron overload
○ Vitamin supplementation (vitamin B6, folic acid, thiamine)
○ Alcohol abstinence
○ In severe cases (often inherited) of SBA, bone marrow transplant is also an option
Anemia of Chronic Disease
● Also known as anemia of chronic inflammation
● An anemia due to a chronic illness:
○ from chronic infection
○ chronic immune activation
○ malignancy
● Pathophysiology
○ In response to inflammatory cytokines, the liver produces increased amounts of hepcidin → increased
internalization of iron carrier protein (ferroportin) molecules on cell membranes
which prevents release from iron stores → access of iron to the circulation is reduced
○ Inflammatory cytokines promote white blood cell production so fewer stem cells differentiate into RBCs
● Diagnosis
○ Mild normocytic anemia (if more severe = microcytic)
○ Resembles iron deficiency anemia
○ In anemia of chronic disease without iron deficiency, ferritin levels should be normal or high, reflecting
the fact that iron is stored within cells, and ferritin is being produced as an acute phase reactant but the
cells are not releasing their iron (in IDA ferritin should be low)
○ TIBC should be low or normal in anemia of chronic disease (TIBC should be high in genuine IDA)
○ In the short term, this is a protective mechanism, allowing the body to keep more iron away from bacterial
pathogens in the body, while producing more immune cells to fight off infection
○ Almost all bacteria, like most life forms, depend on iron to live and multiply
● Treatment
○ Treat the underlying disease
○ Parenteral iron in some cases

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 ○ Possible support with blood transfusions if symptoms become severe

NORMOCYTIC ANEMIAS
● MCV is 80-100 fL
● Occurs in three conditions:
○ Acute blood loss
○ Intrinsic defect of RBC (membrane defects, abnormal hemoglobin, enzyme defects)
○ Extrinsic defect of RBC (leads to hemolysis)
Hemolytic Anemia
● Anemia due to hemolysis: the abnormal breakdown of RBCs, either in the blood vessels (intravascular hemolysis)
or elsewhere in the body (extravascular)
● Features
○ Abnormal and accelerated destruction of RBC or their precursors
○ Increased breakdown of hemoglobin, which may result in:
■ increased bilirubin level (mainly indirect) with jaundice
■ increased fecal and urinary urobilinogen
○ Bone marrow compensatory reaction:
■ Erythroid hyperplasia with accelerated production of red cells, reflected by reticulocytosis
■ Expansion of bone marrow in infants and children with severe chronic hemolysis changes in
bone configuration visible on X-ray
○ The balance between red cell destruction and marrow compensation determines the severity of anemia
● Pathophysiology
○ The spleen is the main organ that removes old and damaged RBCs from the circulation
○ In healthy individuals, RBC breakdown and removal by the spleen is matched by the production of RBC in
the bone marrow
○ If RBC breakdown is increased, the body initially compensates by producing more RBCs; however, if
breakdown of RBCs exceeds the rate that the body can make RBCs, anemia can develop
● Causes
○ Intrinsic (hereditary):
■ Defects in RBC membrane: hereditary spherocytosis, eliptocytosis → more prone to
hemolysis
■ Defects in hemoglobin production (sickle cell disease, thalassemia)
■ Defective red blood cell metabolism (G6PD deficiency)
○ Extrinsic (acquired):
■ Autoimmune diseases like autoimmune hemolytic anemia, SLE, RA
■ Hypersplenism
■ Infections, i.e. Mycoplasma pneumoniae infection (cold agglutinin disease)
■ Paroxysmal Nocturnal Hemoglobinuria (PNH)
● Signs and Symptoms
○ Pallor, fatigue, shortness of breath, jaundice, splenomegaly
○ Certain aspects of the medical history can suggest a cause for hemolysis, e.g. certain medications,
consumption of fava beans, the presence of prosthetic heart valve
● Diagnosis
○ Peripheral blood smear microscopy:
■ Schistocytes: fragments of the red blood cells
■ Some RBCs may appear smaller and rounder than usual (spherocytes)

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 ■ Reticulocytes (immature RBCs) are present in elevated numbers
■ Bite cells may be present due to Heinz body removal by the spleen in G6PD deficiency

○ The level of indirect (unconjugated) bilirubin in the blood is elevated → jaundice.

○ The level of lactate dehydrogenase (LDH) in the blood is elevated (enzyme contained in RBC)
○ Haptoglobin levels are decreased
○ If the direct Coombs test is positive, hemolysis is caused by an immune process (e.g. autoimmune
hemolytic anemia)
○ Hemosiderin in the urine indicates chronic intravascular hemolysis; urobilinogen in the urine
○ Hemoglobinuria in the morning is suggestive of paroxysmal nocturnal hemoglobinuria (PNH)
● Treatment depends on the cause:
○ Symptomatic treatment can be given by blood transfusion if there is marked anemia
○ In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary
○ Splenectomy may be helpful where extravascular hemolysis is predominant (e.g. most of the red blood
cells are being removed by the spleen)
G6PD Deficiency
● X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate
dehydrogenase, a metabolic enzyme involved in the pentose phosphate pathway, especially important in red
blood cell metabolism.
● G6PD deficiency is the most common human enzyme defect
● Will have a non-immune hemolytic anemia due to: infections, medications, fava beans.
● African, Middle Eastern and South Asian people are affected the most. A side effect of this disease is that it
confers protection against Plasmodium falciparum, the most deadly form of malaria
● Pathophysiology
○ The rate-limiting enzyme of the metabolic pathway that supplies reducing energy to cells by maintaining
the level of the co-enzyme NADPH. NADPH maintains the supply of reduced glutathione in the cells that is
used to mop up free radicals that cause oxidative damage
○ The G6PD / NADPH pathway is the only source of reduced glutathione in RBCs
○ The role of RBCs as oxygen carriers puts them at substantial risk of damage from oxidizing free radicals
except for the protective effect of G6PD/NADPH/glutathione
○ People with G6PD are at risk of hemolytic anemia in states of oxidative stress
● Signs and Symptoms
○ Most people are asymptomatic (those that are symptomatic are usually male, given the X-linked pattern
of inheritance)
○ Hemolysis can manifest as:
■ Prolonged neonatal jaundice leading to kernicterus

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 ■ Hemolytic crisis due to
● Illness (especially infections)
● Certain drugs
● Foods, most notably broad beans
● Certain chemicals
○ Very severe crises can cause acute renal failure due to the breakdown of RBCs in the circulation and
direct excretion of hemoglobin by the kidneys
● Diagnosis
○ Suspected when someone develops jaundice, anemia, and hemolysis especially after exposure to the
above triggers and especially if they are from an area where G6PD is most prevalent
○ Tests include: CBC, LFTs, LDH, Haptoglobin, Coombs test
○ Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies
NADPH produced by G6PD under UV light. When it does not fluoresce → positive.
● Treatment
○ Prevention – avoiding triggers
○ Blood transfusion
○ Dialysis if needed
○ Splenectomy

MACROCYTIC ANEMIAS
● Larger than normal RBC; elevated MCV
● Larger cells associated with insufficient number of cells and insufficient hemoglobin
● Caused by abnormalities in RBC production, altered RBC membrane composition, or ↑ number
of reticulocytes
● Causes (non-megaloblastic)
○ Drug Induced: hydroxyurea, chemotherapy, antiretroviral therapy
○ Alcohol/Liver Disease
■ Mechanism unknown; metabolic breakdown product of alcohol can affect RBCs
■ Liver disease may cause macrocytosis by effects on the lipid composition of RBC membrane
○ Hypothyroidism - mechanism unclear
○ Reticulocytosis - normal physiologic response to anemia; because reticulocytes are larger than mature
RBCs, their increasing percentage of total RBCs will raise the MCV proportionately
Megaloblastic Anemia
● Causes
○ DNA replication disorders - cells are larger because they cannot produce DNA quickly enough to divide at
the right time, so they grow too large before division
○ Due to deficiency in folate (vitamin B9) and/or cobalamin (vitamin B12)
○ Vegetarians and Vegans at greater risk of vitamin B12 deficiency
○ Inability to absorb vitamin B12 due to: autoimmune disorders, cancer, alcohol addiction, inflammatory
bowel disease, atrophic gastritis (especially in older adults)
○ Pregnancy, breastfeeding and celiac disease can lead to folate deficiency
● Signs/Symptoms: ○ Pallor
○ Fatigue
○ Dyspnea
○ Dizziness
○ Palpitations ● Signs/Symptoms of vitamin B12 Deficiency:

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 ○ Tingling/numbness in hands and feet ○ Depression
○ Muscle weakness ○ Memory loss
○ Loss of reflexes ○ Nausea, vomiting, diarrhea
○ Confusion ○ Smooth, thick, red tongue (glossitis)
● Diagnosis - Labs:
○ Decreased RBC, Hemoglobin
○ Increased MCV
○ Hypersegmented neutrophils (nuclei have six or more lobes or the presence of more than 3% of
neutrophils with at least five nuclear lobes)
○ Macrocytes, ovalocytes, anisocytosis
○ Decreased serum vitamin B12 level in vitamin B12 deficiency
○ Decreased serum folate in folic acid deficiency
○ Measurement of methylmalonic acid (MMA) and homocysteine can provide an indirect method for
partially differentiating
○ Vitamin B12 and folate deficiencies:
■ Increased homocysteine AND methylmalonic acid in vitamin B12 deficiency
■ Increased homocysteine but methylmalonic acid is NOT elevated in folate deficiency
● Treatment depends on the cause
○ Vitamin B12 Deficiency
■ Vitamin B12 supplementation (injection or oral)
■ IM: 1000 mcg weekly until corrected, then 1000mcg monthly (if cyanocobalamin) or every other
month (if hydroxocobalamin) for maintenance
■ PO: 1000-2000mcg daily
■ Increasing dietary intake of vitamin B12 (eggs, chicken, milk, fortified cereals)
○ Folic Acid Deficiency
■ Folic Acid supplementation
■ PO: 1-5mg daily x 1-4 months (if an acute cause) or indefinitely (if a chronic cause)
■ Increasing dietary intake of folic acid (leafy green vegetables, oranges, peanuts, lentils)
● Related Disorder: Pernicious anemia
○ Rare blood d/o characterized by inability to use vitamin B12
○ Mostly due to lack of gastric protein intrinsic factor without which vitamin B12 cannot be absorbed
○ Considered an autoimmune disorder and may have genetic predisposition
○ Treated with supplemental vitamin B12

HEMOGLOBINOPATHIES
● Genetic disorders of hemoglobin
● Hemoglobin molecule is composed of 2 alpha chains and 2 beta chains and 4 iron-bearing heme groups that bind
O2
● Alpha chains are coded for by two genes on chromosome 16
● Beta chains are coded by a single gene on chromosome 11
● Mutations and deletions in these genes cause hemoglobinopathies
● Thalassemias result from a quantitative change in hemoglobin molecule
● Sickle Cell Anemia results from a qualitative change in hemoglobin molecule
Thalassemia
● Genetic underproduction of α or β globin chains → deficient Hgb synthesis and RBC hemolysis
● α: more common in SE Asian and Chinese; β: more common in African and Mediterranean

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● α: mild symptoms to none
● β: symptoms begin at 4-6 months - severe anemia, growth retardation, bone deformities, fractures, jaundice
● Will present as a microcytic anemia
● Pathophysiology
○ Normally, the majority of adult hemoglobin (HbA) is composed of 4 protein chains, 2 alpha (α) and 2 beta
(β) chains arranged into a heterotetramer
○ Defect in either α or β globulin chain → abnormal RBCs
● Causes
○ Both α and β thalassemias are often inherited in an autosomal recessive fashion
○ If both parents carry a hemoglobinopathy trait → 25% risk with each pregnancy for
an affected child
○ Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait
● Thalassemia Minor
○ The hemoglobin genes are inherited during conception
○ People with a thalassemia trait in one gene are known as carriers or are said to have thalassemia minor
○ The only way to know if someone carries the thalassemia trait is with hemoglobin electrophoresis which
can identify the gene
○ Carriers of thalassemia minor are usually asymptomatic and may become anemic or slightly anemic
● Thalassemia Intermedia
○ Anemia is not so severe as to necessitate regular transfusions
○ Clinical phenotype ranges between the severe, transfusion-dependent thalassemia major and the
asymptomatic carrier state
● Thalassemia Major
○ Occurs when a child inherits two mutated genes, one from each parent
○ Usually develop the symptoms of severe anemia within the first year of life
○ Lack the ability to produce normal adult hemoglobin and experience chronic fatigue
○ They may also fail to thrive (FTT)
○ Two major consequences: severe anemia and expansion of the bone marrow in the body’s effort to
produce more red blood cells poor growth, impaired physical activities, facial and other bone deformities,
fragile bones and enlargement of the liver and spleen
○ If left untreated, it will lead to death within the first decade of life. The only treatment to combat severe
anemia is regular blood transfusions and iron chelation therapy
● Complications
○ Overload of iron - from the disease itself or from frequent blood transfusions. Results in damage to the
heart, liver and endocrine system
○ Infection: increased risk of infection. This is especially true if the spleen has been removed.
○ Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen,
especially in the face and skull. Also makes bones thin and brittle, increasing the risk of broken bones.
○ Enlarged spleen: due to removal of destroyed RBCs; can make anemia worse
○ Heart problems: congestive heart failure and arrhythmias may be associated with severe thalassemia
● Management
○ Mild thalassemia: people with thalassemia do not require medical or follow-up care after the initial
diagnosis is made but should be warned that their condition can be misdiagnosed for the common iron
deficiency anemia. They should avoid routine use of iron supplements; yet iron deficiency can develop
during pregnancy or from chronic bleeding

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 ○ Severe thalassemia: requires medical treatment. A blood transfusion regimen was the first measure
effective in prolonging life.
○ Multiple blood transfusions can result in iron overload. The iron overload related to thalassemia may be
treated via chelation therapy with: deferoxamine, deferiprone, deferasirox. Results in improved life
expectancy in those with thalassemia major.
○ Bone marrow transplantation may offer the possibility of a cure in young people who have an HLA-
matched donor
Sickle Cell Anemia
● Sickle Cell Trait
○ A person has one abnormal allele of the hemoglobin beta gene (heterozygous), does not display severe
symptoms of sickle cell disease that occur in a person with two copies of that allele (homozygous)
○ Most common in West Africa and in South and Central America
○ Asymptomatic
○ Heterozygotes: protected from malaria (P. falciparum)
● Sickle Cell Disease
○ Caused by a point mutation in the β-globin chain of hemoglobin, causing the hydrophilic amino acid
glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The β-globin
gene is found on chromosome 11
○ The association of two wild-type α-globin subunits with two mutant β-globin subunits forms hemoglobin
S (HbS)
○ Sickle cell hemoglobin (HgbS) and hemoglobin C with sickling (HgbSC) are the two most common forms
○ Under low-oxygen conditions, the absence of a polar amino acid at position six of the β-globin chain
promotes the non-covalent polymerisation of hemoglobin, which distorts red blood cells into a sickle
shape and decreases their elasticity
○ The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease
○ Rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel
occlusion and ischemia
○ The actual anemia of the illness is caused by hemolysis (destruction of RBC) because of their misshape
● Epidemiology
○ Highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India
and the Middle-East
○ 3/4 of sickle cell cases occur in Africa
○ The prevalence of the disease in the United States is approximately 1 in 5,000, mostly affecting
Americans of Sub-Saharan African descent, according to the National Institutes of Health
● Diagnosis
○ In HbSS, the CBC reveals hemoglobin levels in the range of 6–8 g/dL with a high reticulocyte count (as
the bone marrow compensates for the destruction of sickle cells by producing more red blood cells)
○ Abnormal hemoglobin forms can be detected on hemoglobin electrophoresis. HgbS and HgbSC—the two
most common forms—can be identified from there
○ Newborn screening: blood sample is collected via heel stick in the and initial testing is performed using
thin-layer isoelectric focusing (IEF) analysis and later confirmed with High Performance Liquid
Chromatography (HPLC)
○ IEF and HPLC – high sensitivity and specificity for SCD
● Presentations
○ Hemolysis: acute accelerated drops in hemoglobin level; red blood cells break down at a faster rate
■ This is particularly common in patients with co-existent G6PD deficiency

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 ■ Management is supportive, sometimes with blood transfusions
○ Vasoocclusion: sickle cells get clogged in capillaries → painful ischemia, necrosis,
organ damage
■ Acute episodes or “crises” occur for one of many reasons and usually last 5-7 days
■ Treated with analgesics (often IV opioids)
■ Note: many patients develop a tolerance to opioids and may require more aggressive treatment
■ Hydration if needed
■ Supplemental O2 if needed
■ Monitor for embolic disease, e.g. stroke, pulmonary embolism
○ Acute Chest Syndrome: vasoocclusive crisis of the pulmonary vasculature fever, cough, sputum,
excruciating pain, dyspnea, hypoxia
■ Often precipitated by a lung infection
■ Appears as an infiltrate on chest x-ray
■ Because it presents like a pneumonia, must cover for PNA with broad spectrum antibiotics
■ Aggressive pain treatment with opioids
■ Incentive spirometry, bronchodilators (if wheezing), supplemental O2 (if hypoxic)
■ Hydration (if dehydrated)
■ Exchange transfusion (removes sickled cells)
■ ***Leading cause of death in patients with SCD***
○ Splenic sequestration: because of its narrow vessels and role in clearing damaged RBCs,
the spleen is usually infarcted by late childhood. Autosplenectomy → risk of
infections with encapsulated organisms.
■ Acute, painful enlargements of the spleen, caused by intrasplenic trapping of RBCs and resulting
in a precipitous fall in hemoglobin levels with the potential for hypovolemic shock
■ Sequestration crises = emergency
■ If not treated, patients may die within 1–2 hours due to circulatory failure
■ Fluid resuscitate if patient is in shock
■ PRBC transfusion to goal Hgb 6-8 g/dL
○ Aplastic crises: acute worsening of the patient's baseline anemia → pallor,
tachycardia, and fatigue
■ Normally triggered by parvovirus B19, which directly affects erythropoiesis by invading the red
cell precursors and multiplying in them and destroying them
■ In healthy individuals, this is of little consequence, but the shortened RBC life in sickle-cell anemia
results in an abrupt, life-threatening situation
■ Reticulocyte counts drop dramatically during the disease (and the rapid turnover of red cells
leads to the drop in hemoglobin)
■ This crisis takes one week to resolve
■ Most managed supportively; some need blood transfusion if Hgb drops > 2g/dL from baseline
● Complications
○ Overwhelming post-(auto)splenectomy infection (OPSI); especially with encapsulated organisms:
Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Pseudomonas aeruginosa
○ Stroke
○ Cholelithiasis – due to elevated bilirubin
○ Avascular Necrosis (often see joint replacements of humeral heads)
○ Priapism or infarction of the penis – emergent urologic intervention needed
○ Osteomyelitis (bacterial bone infection) esp w/ Salmonella or Staphylococcus aureus
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 ○ Opioid tolerance
○ Leg ulcers
○ Pulmonary Hypertension
○ Chronic Renal Failure
○ During pregnancy: intrauterine growth retardation, spontaneous abortion, and pre-eclampsia
○ Background retinopathy, proliferative retinopathy, vitreous hemorrhages and retinal detachments,
resulting in blindness
● Treatment
○ Mainstay of management = Hydroxyurea: medication that stimulates fetal hemoglobin to replace
Hemoglobin S reduce sickling. RBC lifespan is increased; RBC hydration is improved; hemolysis is
reduced; and adhesion of cells to the vascular endothelium is decreased. Blood flow through the
microcirculation improves and vasoocclusive events are less likely to occur.
○ Prophylactic antibiotics (penicillin) in children < 5 years of age
○ Immunizations: all routine childhood vaccinations including, Streptococcus pneumoniae, seasonal
influenza, Neisseria meningitidis, Haemophilus influenzae type B, and hepatitis B virus)
○ Management of vasoocclusive pain crises and Acute Chest crises
○ Folate supplementation at 1mg daily
○ Blood transfusions
○ Hematopoietic cell transplantation (HCT) is only curative option
● Prognosis: About 90% of patients survive to age 20, and close to 50% survive beyond the fifth decade
Aplastic Anemia
● The bone marrow and the blood stem cells that reside there are damaged
● Causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells
(leukopenia), and platelets (thrombocytopenia)
● Aplastic: inability of the stem cells to generate the mature blood cells
● Causes
○ Occurs most commonly in the teens and twenties and also among the elderly
○ Can be caused by exposure to chemicals, drugs, radiation, infection, immune disease, and heredity; in
about half the cases, the cause is unknown
○ Short-lived aplastic anemia can also be a result of parvovirus infection. Parvovirus causes complete
cessation of red blood cell production.
● Signs and Symptoms
○ Anemia: malaise, pallor, palpitations
○ Thrombocytopenia: bruising, bleeding, petechiae
○ Leukopenia: increased risk of infection
● Diagnosis
○ Needs to be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia
resulting in decrease of all formed elements. In contrast, pure red cell aplasia is characterized by
reduction in red cells only.
○ The diagnosis can only be confirmed on bone marrow examination by bone marrow biopsy
○ Usually, 30-70% of the marrow is blood stem cells, but in Aplastic Anemia, these cells are missing or
replaced with fat cells
● Treatment
○ Aplastic anemia is treated with immunosuppressive drugs, typically either anti-lymphocyte globulin or
anti-thymocyte globulin, combined with corticosteroids and cyclosporine, with a response rate of about
70%; this indicates that aplastic anemia has an auto-immune component.

14
 ○ Stem cell transplant is also used, especially for patients < 30 years old

HEMATOLOGY LABS
● Blood Basics
○ Four main components of Whole Blood: Plasma, Red Blood Cells, White Blood Cells, and Platelets
○ Made up of: 55% plasma and 45% blood cells
○ What is plasma?
■ Liquid component of blood, made up of water, sugar, fat, protein, and salts
■ Transports blood cells as well as nutrients, waste, antibodies, hormones, proteins
● Complete Blood Cell Count (CBC)
○ CBC is the number of blood elements in relation to volume
○ Lavender top tube
■ Contains EDTA as an anticoagulant
■ After tube is filled, invert tube several times to prevent coagulation
○ CBC: How it is used
■ Very commonly ordered lab
■ Screen for a wide range of diseases/conditions
■ Narrow the differential diagnoses
■ Help to guide the diagnosis of conditions such as: anemia, infection, inflammation, bleeding
disorder, leukemia, lymphoma, etc.
■ Monitor for effectiveness of treatment
● Red Blood Cell Information
○ Red Blood Cell Count
■ Number of RBCs per microliter (µL)
● Reference range varies by lab
● Mirrors changes in Hemoglobin/Hematocrit
■ RBCs
● most abundant cells
● contain hemoglobin binds oxygen delivers oxygen to tissues
● produced in the bone marrow
● production stimulated by Erythropoietin, a hormone produced by the kidneys
● no nucleus*
● life span 120 days
○ Hemoglobin and Hematocrit
■ Hemoglobin (Hgb)
● iron-containing protein found in RBCs
● enables RBCs to bind oxygen
● measured in grams per deciliter (100ml)
■ Hematocrit (Hct)
● ratio of the volume of RBCs to the volume of whole blood
● expressed as a percentage (e.g. Hct 40%: 40 mL of RBCs per 100 mL of blood)
■ Both are based on whole blood and therefore, are dependent on plasma volume
■ What does this mean?
● If a patient is dehydrated, the Hgb and Hct will appear higher (“hemoconcentrated”)
● If a patient is fluid overloaded, they will appear lower (“hemodiluted”)
● Rule of threes – checks for artifacts

15
 ● Hct = 3X Hgb
● Hgb = 3X RBC count
○ Mean Corpuscular Volume (MCV) a.k.a. Mean cell volume
■ Measures average volume of the RBC
■ Calculated value derived from the Hct and RBC count
■ Classifies anemia as: normocytic, microcytic, or macrocytic
■ Measured in femtoliters (femto is 10^-15)
■ Normocytic = 80-100 fL
■ Microcytic = < 80 fL
■ Macrocytic = > 100 fL
○ Mean Corpuscular Hemoglobin (MCH)
■ Average mass of hemoglobin per RBC
■ Calculated value (mass of Hgb divided by number of RBCs in a volume of blood)
■ Reference range: 27-34 pg (picograms)
■ Usefulness? Small cells have less Hgb, large cells more, so MCH variation tracks along with MCV.
Adds little information independent of the MCV.
○ Mean Corpuscular Hemoglobin Concentration (MCHC)
■ Measure of the concentration of hemoglobin in a given volume of packed RBCs
■ Calculated by dividing the hemoglobin by the hematocrit
■ Expressed as %, reference range 32-36%
■ Very few conditions cause elevated MCHC - electronic counter problem, spherocytosis
■ Decreased MCHC: iron deficiency anemia, sideroblastic anemia, chronic disease anemia
○ Red Cell Distribution Width (RDW)
■ Measure of the variation of RBC volume (size)
■ Reference Range 11.5-14.5%
■ Higher values = more variation in size
■ Lower values = less variation in size
■ Elevated RDW = RBCs of unequal size = anisocytosis (image
→ )
■ High RDW:
● Iron Deficiency Anemia: high RDW with low MCV
● Folate and vitamin B12 deficiency anemia: high RDW and high MCV
● Mixed Deficiency (Iron + B12/folate) anemia: high RDW with MCV being high, low or often
normal range
● Recent Hemorrhage: high RDW with normal MCV
■ Anemia w/ Normal RDW: suspect Thalassemia
● Peripheral Smear Examination of RBCs
○ Complements RBC indices and RDW
○ Size
○ Morphology
■ Shape and staining characteristics
■ Should not see nucleated RBCs
○ Peripheral Smear Abnormalities
■ Microcytosis, macrocytosis: small, large RBC
■ Anisocytosis: unequal size
■ Poikilocytosis: unusual shape

16
 ■ Hypochromasia: staining less intensely; RBCs are pale due to insufficient hemoglobin; seen in
thalassemia and iron deficiency
■ Hyperchromasia: RBCs are darker in color; may be due to dehydration or presence of spherocytes
■ Polychromasia: variation in Hgb content; blue-staining RBCs indicate they are immature and
released early from the bone marrow
■ Sickle cells: crescent shaped
■ Spherocytes: found in hereditary spherocytosis or due to an immune hemolytic anemia
■ Elliptocytes: seen in hereditary elliptocytosis and various anemias; myelofibrosis
■ Target cells: bullseye; seen with abnormal inherited forms of hemoglobin (hemoglobinopathies),
thalassemia, and various anemias
■ Teardrop cells (dacrocytes): seen in myelofibrosis and thalassemia
■ Rouleaux: stack of coins; seen in MM or Waldenstrom macroglobulinemia
■ Acanthocytes: spur, thorn, spiculated cells; seen in people who have had their spleen removed;
chronic alcoholism, hemolytic anemia, or thalassemia
○ Red Blood Cell Inclusions
■ Basophilic stippling
● Small, dark blue, dot like structures scattered through cell
● Nuclear remnants seen in lead poisoning, nutritional deficiencies, myelofibrosis
■ Howell-Jolly bodies
● Blue black inclusions, larger than basophilic stippling and usually one per RBC
● Seen in severe anemia, especially hemolytic anemia and after splenectomy
● Red Cell Reference Ranges

● White Blood Cell (WBC) Information

○ Total WBC count
■ Reference range: 4,500 – 10,000 cells/µL
■ Done on an electronic counter
○ Differential or “Diff”
■ Measures the percentage of each type of WBC
■ Most facilities check by automated method and if abnormal, checked manually
○ WBC Differential

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○ Two Major Types of Leukocytes

○ Lymphocytes: T-cells, B-cells, Natural Killer Cells

■ Adaptive Immune Response
● T-cells: cell mediated immunity
● B-cells: humoral immunity
■ Innate Immune Response
● NK cells: defends against viruses, tumors
● Reactive Lymphocytes: Usually associated with viruses such as Epstein-Barr virus,
Cytomegalovirus, Toxoplasma gondi, Syphilis, Group B Streptococci, Hepatitis C
○ Neutrophils
■ Normal Neutrophils (segmented)
■ Band Neutrophils
■ Hypersegmented Neutrophils - megaloblastic anemia, chemo, long-term chronic infection

○ Leukocytosis ↑
■ Disease in the bone marrow (e.g. leukemia)
■ Infection
■ Immune system disorder
■ Reaction to a drug
○ Leukopenia ↓
■ Severe infection that use up WBC faster than they are produced
■ Drugs, such as antibiotics
■ Autoimmune disease that destroy WBC
■ Cancer
■ Viral infections that disrupt work of the bone marrow
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 ○ “Left Shift”
■ presence of increased proportions of younger, less well differentiated neutrophils or neutrophil
precursors in the blood
■ early or premature release of myeloid cells from the bone marrow
■ generally indicates infection (bacterial), inflammation, or necrosis
■ Promyelocytes → myelocytes → metamyelocytes bands
○ Leukemoid Reaction
■ Non-leukemic WBC count >50,000
■ Physiologic response to stress or infection
■ ↑early neutrophil precursors (in leukemia, you would see immature forms)
■ Benign condition
■ Causes: infections (C. difficile, infectious mononucleosis, tuberculosis, pertussis); certain drugs;
organ necrosis; asplenia
○ Neutropenia: abnormally low neutrophil count as a result of decreased production or increased
destruction
■ Absolute Neutrophil Count (ANC) = (% neutrophils + % bands) x WBC
■ Neutropenia: ANC < 1000
■ Severe Neutropenia: ANC < 500
■ Profound Neutropenia: < 100
● Platelets
○ Main function: contribute to hemostasis
○ Adhere to injury site Clump together Release chemicals to stimulate more aggregation
○ On a blood smear, appear as dark purple spots, about 20% the diameter of RBCs
○ Normal Range: 150,000-400,000/µL
■ ↑ = thrombocytosis
■ ↓ = thrombocytopenia
○ Mean Platelet Volume (MPV)
■ Measures average volume (size) of platelets
■ Normal range: 7.5 – 11.5 fL
○ Small or normal sized platelets + thrombocytopenia → failure of production
○ Large platelets + thrombocytopenia → peripheral destruction/consumption
○ Normal size platelets + thrombocytosis → reactive (infection/inflammation)
○ Large platelets + thrombocytosis → myeloproliferative disorder/neoplasm
● Hemoglobin Electrophoresis
○ Used to measure and identify the different types of Hemoglobin
○ Types of Hemoglobin
■ Hemoglobin F: found in fetuses and newborns; replaced with Hgb A after birth
■ Hemoglobin A: Most common Hgb found in healthy children and adults
■ Hemoglobin C, D, E, M, and S: Abnormal
○ Detects conditions such as:
■ Sickle Cell Anemia: caused by Hgb S and HgbSC
■ Thalassemias: too much abnormal Hgb and too little Hgb A
○ How is it done? electrical current is passed through a blood sample, Hgb separates into different bands
○ In infants and children, a normal, healthy level of hemoglobin is:
■ hemoglobin F (newborn): 50 to 80 percent
■ hemoglobin F (6 months): 8 percent
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 ■ hemoglobin F (6 months+): 0.8 to two percent
○ In adults, healthy levels are:
■ hemoglobin A: 95 to 98 percent
■ hemoglobin A2: 2 to 3 percent
■ hemoglobin F: 0.8 to two percent
■ hemoglobin S: 0 percent
■ hemoglobin C: 0 percent
● Nucleated Red Blood Cells (NRBC)
○ Very immature RBC
○ Normal in infants for a short time after birth
○ Very abnormal in adults
○ Seen when there is a severe demand for RBCs or when the bone marrow is severely damaged by: tumor
or fibrosis
○ Also seen in: severe anemia, thalassemia, miliary TB, chronic hypoxemia
○ Can be incorrectly counted and reflected as WBC
● Reticulocyte Count
○ Reticulocytes: immature RBCs
○ “Retics”
○ Measures percentage of reticulocytes in the blood
○ Indicates bone marrow activity
○ Used in conjunction with RBC, Hgb, HCT
○ Rises in: blood loss or RBC destruction (hemolytic anemia)
● Erythrocyte Sedimentation Rate (ESR)
○ aka “Sed Rate”
○ Rate at which RBCs sediment in a period of one hour
○ Non-specific measure of inflammation
○ When inflammation is present → ↑fibrinogen in the blood → RBCs stick together → form stacks
(“rouleaux”) which settle faster
○ Used in diagnoses of conditions such as: temporal arteritis, polymyalgia rheumatica, lupus, IBD
○ Rarely used alone, often used along with C-Reactive Protein
● C-Reactive Protein (CRP)
○ Protein synthesized in the liver found in blood plasma that rises in response to inflammation
○ Non-specific test used to detect inflammation: cannot detect where inflammation is or what is causing it
○ Along with signs and symptoms, may detect or monitor acute conditions such as: sepsis or fugal
infections, pelvic inflammatory disease
○ Chronic conditions such as: arthritis, lupus, vasculitis
○ Measures the same thing as ESR but is more sensitive (increases sooner)
● Bone Marrow Aspiration and Biopsy
○ Procedures used to collect and evaluate bone marrow cells and structure
○ Bone marrow = site of stem cell development and differentiation
○ Bone marrow biopsy: collects a cylindrical core sample that preserves the marrow's structure
○ Bone marrow aspiration: collects a sample of the fluid that contains cells so that they can be examined
under a microscope and/or evaluated with other tests
○ Common tests for biopsy: cellularity, different cell lines present in adequate numbers, any abnormal
infiltrates or changes to the stroma
○ Common tests for aspirate: myeloid/erythroid ratio, differential, any abnormal cells

20
 ○ Additional tests: immunophenotyping by flow cytometry; chromosome analysis and/or FISH analysis;
molecular tests (e.g. JAK2 mutation, BCR-ABL)
○ Collected from: iliac crest
○ Area cleaned and local anesthetic applied
○ For an aspiration, a syringe is attached to the needle to collect a small amount of marrow
○ For a bone marrow biopsy, a special needle is used that allows the collection of a solid core (a cylindrical
sample) of marrow

COAGULATION LABS
● Review – 5 phases of blood clotting
○ Vessel spasm - reduces blood flow
○ Formation of platelet plug
○ Formation of fibrin clot - Coagulation factors become activated on platelet surface and
convert fibrinogen to fibrin → cements
○ Clot retraction - Pulls edges of blood vessel together
○ Clot dissolution (fibrinolysis)
● Disorders of Coagulation
○ Disease states that result in bleeding or obstructive clotting
○ Failure of blood to clot in response to an appropriate stimulus such as bleeding
○ Inappropriate blood clotting – thrombosis
○ Clot-forming proteins are balanced by clot-breaking proteins which break up a clot after the bleeding site
heals
■ If there is an imbalance, inappropriate bleeding or clotting occurs
● Too Much Bleeding
○ Causes of disorders of coagulation
■ Endothelial injury → failure of the platelet plug
● Too few platelets (thrombocytopenia)
● Von Willebrand’s disease or other cause of defective platelet function
■ Failure of blood coagulation - problem in intrinsic or extrinsic pathway
● Platelet Count
○ Main function: contribute to hemostasis
○ Adhere to injury site → clump together → release chemicals to stimulate more aggregation
○ Normal Range: 150,000-400,000/µL
○ Mean Platelet Volume (MPV)
■ Measures average volume (size) of platelets
■ Normal range: 7.5 – 11.5 fL
● Von Willebrand’s Disease (vWD)
○ vWD = most common hereditary coagulation abnormality (1 in 100); occurs equally in men and women
○ Normally, vWF binds factor VIII, a key clotting protein + platelets in vessel walls → platelet plug
○ Deficiency of von Willebrand factor → decrease in factor VIII levels
■ can check factor VIII levels
■ amount of vWF in a vWF antigen assay
■ functionality of vWF with a glycoprotein (GP)Ib binding assay, a collagen binding assay, or a
ristocetin cofactor activity (RiCof) or ristocetin induced platelet agglutination (RIPA) assays
○ Different types of vWD with varying degrees of bleeding
■ Type 1 = most common; asymptomatic or mild symptoms (nose bleeds, heavy menstrual flow)
21
 ■ Type 3 = greatest bleeding
● Coagulation Factors
○ Coagulation factor tests measure the function of proteins essential for clot formation
○ When someone has unexplained bleeding, one cause could be a low level of a coagulation factor
○ There are 9 coagulation factors. When one or more is produced in too low a quantity or fail to function,
bleeding can occur
● Coagulation Pathways
○ Intrinsic pathway: occurs in vascular system
○ Extrinsic pathway: occurs in tissues
○ Terminal steps in both pathways are the same: activation of factor X and thrombin-induced formation of
fibrin (material that stabilizes the clot)
● Coagulation Tests & Their Use
○ Screening Tests: based on measurements of time required to form fibrin strands by using either optical or
electrical laboratory devices. Unusual prolongation of such a test may represent:
■ Abnormally low factor concentration
■ Presence of biologically inactive factor(s)
■ Presence of inhibitors
○ Prothrombin time (PT) & International Normalized Ratio (INR)
■ Measures the number of seconds it takes for a clot to form in a blood sample after reagents are
added; measured in seconds
■ International Normalized Ratio (INR) is a calculation based on the results of a PT
■ Often performed with a Partial Thromboplastin Time (PTT)
■ Together they assess the amount and function of coagulation factors
■ PT, INR, and PTT are commonly referred to as “coags”
■ PT evaluates how well the coagulation factors in the extrinsic/common pathways work together
■ PT includes: Factors I (Fibrinogen), II (Prothrombin), V, VII, and X (factors II, VII, IX, and X are
vitamin K dependent)
■ Because reagents vary and therefore normal ranges vary, the WHO developed and recommends
using the INR for people receiving warfarin (Coumadin)
■ PT and INR are generally reported together; INR should only be used for patients taking warfarin
○ Partial Thromboplastin Time (PTT)
■ Also known as Activated Partial Thromboplastin Time (aPTT)
■ Measures the number of seconds it takes for a clot to form in a sample of blood after reagents
are added
■ PTT evaluates the protein factors that are a part of the intrinsic and common pathways
■ PTT evaluated coagulation factors I (fibrinogen), II (prothrombin), V, VIII, IX, X, XI, XII
■ Uses of PTT include:
● Identify coagulation factor deficiency or dysfunction
● Detect nonspecific autoantibodies (e.g. lupus anticoagulant); performed as part of
clotting disorder panel
● Monitoring heparin anticoagulant therapy. Heparin is given to prevent or treat blood clots
and it prolongs PTT; must be closely monitored
● Pre-surgery screening
○ Partial Thromboplastin Time (PTT): Mixing Study
■ When a PTT is prolonged, a second PTT test is done by mixing the person’s plasma with pooled
normal plasma (collected from normal donors)

22
 ■ If PTT returns to normal → suggests deficiency in one or more coagulation factors (assays for
fibrinogen and factors II, V, VII, and X can be performed)
■ If PTT remains prolonged problem may be due to an autoantibody
○ Acquired Causes of PT and PTT Prolongations
■ Liver disease: PT affected earlier and more than PTT
■ Vitamin K deficiency: PT affected earlier and more than PTT
■ Warfarin (Coumadin): PT affected earlier and more than PTT
■ Disseminated Intravascular Coagulation (DIC): PT affected earlier and more than PTT
■ Lupus anticoagulants: may or may not prolong PTT; PT rarely prolonged
■ Heparin: prolongs PTT; PT usually normal
○ Hereditary Causes of PT and PTT Prolongations
■ Deficiency of factor VII: PTT is normal
■ Deficiency of fibrinogen or factors II, V, or X: PTT may also be prolonged
○ Example
■ 1/15/07 Reference Range
■ PT 15.9 11.5-14.5 sec
■ INR 1.33
■ PTT 40.9 23.3 – 34.5 sec
○ Therapeutic ranges for INR*:
○ Prophylaxis and treatment of venous thrombosis: INR 2.0-3.0
○ Mechanical Prosthetic valves: INR 2.5-3.5
○ *INR values are only valid for patients on stable oral anticoagulants
● Bleeding Time
○ Done to assess platelet function
○ Induce bleeding and measure the time it takes to stop bleeding
○ Ivy method: incision on ventral side of arm, BP cuff to 40 mmHg, time from incision is made until all
bleeding has stopped; every 30 seconds filter paper is used to draw off blood; normal 3-10 minutes
○ Duke method: patient pricked with needle/lancet on earlobe or fingertip; wipe blood away every 30
seconds; normal 2-5 minutes
○ Bleeding time is affected by platelet function, vascular disorders, and von Willebrand Disease
○ Diseases that cause prolonged bleeding: thrombocytopenia, DIC, hypofibrinogenemia
○ Medications: Aspirin and cyclooxygenase inhibitors can prolong bleeding time
● Thrombin Time (TT)
○ Thrombin is an enzyme that acts on the clotting factor fibrinogen to form fibrin
○ TT is used to investigate bleeding disorder or inappropriate clot formation, particularly to evaluate the
level and function of fibrinogen
○ Functional fibrinogen assay test now largely replaces TT for evaluation of fibrinogen
○ TT is very sensitive to heparin
○ Prolonged TT may indicate
■ Contamination with heparin
■ Decreased fibrinogen level or abnormally functioning fibrinogen (e.g. Disseminated
Intravascular Coagulation or DIC)
● Functional Fibrinogen Assay
○ Fibrinogen is a coagulation factor that is produced in the liver and released into circulation
○ Two tests to evaluate:
■ Fibrinogen activity test – evaluates fibrinogen function

23
 ■ Fibrinogen antigen test – measures amount of fibrinogen
● D-Dimer
○ D-dimer: a protein fragment produced when a blood clot breaks down
○ Once area of injury heals and clot is no longer needed plasmin breaks down clot
○ These fragments are called Fibrin Degradation Products (FDP)
○ One of the final fibrin degradation products is the D-dimer
○ D-dimer rises when there’s significant formation or breakdown of clots in the body
○ Used to help rule out thrombotic episodes (DVT, PE) or to help dx conditions related to thrombosis (DIC)
○ Normal or negative D-dimer means: most likely, the patient does not have an acute condition causing clot
formation/breakdown
○ Positive D-dimer means: there may be significant clot formation/breakdown in the body but does not
specify where or the cause
○ Elevated D-dimer does not always mean there is a clot because other conditions can cause an elevated
D-dimer: surgery, trauma, infection, cancer, liver disease, pregnancy
○ Use with Caution
■ Best used for patients with low to intermediate risk for thrombosis and/or embolism
■ Not used in hospitalized patients (likely to be elevated anyway)
■ If negative, it is highly unlikely that a clot is present
■ If positive, cannot predict whether or not a clot is present and FURTHER TESTING IS REQUIRED
■ It is a sensitive test but lacks specificity
● Vitamin K Deficiency
○ Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to
glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z
○ Adding the gamma-carboxyl group Vitamin K is itself oxidized
○ Another enzyme, Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form
○ VKORC is pharmacologically important as a target of anticoagulant drug warfarin (Coumadin)
○ This drug creates a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of
clotting factors
○ Vitamin K deficiency from malabsorption or impaired vitamin K metabolism in liver failure formation of
proteins which are partially or totally non-gamma carboxylated, affecting the coagulation factors' ability to
bind to phospholipid bleeding
● Liver Disease
○ Liver disease can affect hemostasis in several ways:
■ impaired coagulation factor synthesis
■ synthesis of dysfunctional coagulation factors
■ increased consumption of coagulation factors
■ altered clearance of activated coagulation factors
○ PT affected earlier and more profoundly than PTT
● Too Much Clotting
○ Protein C and Protein S
○ Factor V Leiden
○ Plasminogen
○ Antithrombin III
○ Lupus anticoagulants
● Protein C and Protein S
○ Used to investigate a possible hypercoagulable disorder and/or to diagnose a cause of a blood clot

24
 ○ Normally, Protein S combines with Protein C to control clot formation
○ However, if deficient or malfunctioning excessive clotting
○ When is it ordered?
■ unexplained blood clots, especially in patients < 50 y.o.
■ family history of blood clots
■ blood clots in an unusual location (other than legs/lungs)
■ multiple miscarriages
○ Should not be ordered for at least 10 days after an episode
○ Should not be ordered when patient is on warfarin
○ A test that shows decreased activity/quantity of Protein C or Protein S should be repeated
○ Elevated: not associated with medical problems
○ Normal: adequate clotting
○ Low: coagulation process isn’t sufficiently regulated and increased risk of developing a clot
● Factor V Leiden
○ Genetic mutation associated with increased risk of developing inappropriate blood clots
○ Most common inherited predisposition to abnormal clotting in the U.S. in Caucasians
○ Homozygous much higher clot risk than heterozygous
○ Often performed with prothrombin 20210 (PT 20210)
○ Factor V is normally inactivated by Protein C to prevent the blood clot from growing too large
○ Factor V Leiden mutation can lead to an altered factor V protein that resists inactivation by Protein C →
clotting more active than usual → DVT/VTE
○ Order Factor V Leiden test when:
■ first DVT or VTE before the age of 50
■ blood clot in an unusual part of the body
■ personal history or family history of recurrent DVT/VTE
■ first VTE not related to oral contraceptives, pregnancy, or hormone replacement therapy
■ unexplained miscarriages, especially in 2nd or 3rd trimesters
● Plasminogen
○ Plasminogen is a glycoprotein synthesized in the liver, and it circulates in the blood
○ Plasminogen is the precursor of plasmin, which lyses fibrin clots to fibrin degradation products (FDP) and
D-dimer; the conversion to active protease is mediated by tissue-type (tPA) and urokinase-type (uPA)
plasminogen activators
○ Generated plasmin is quickly inactivated by its main inhibitor alpha2-antiplasmin
○ No clear association between plasminogen deficiency and thrombosis
○ Should be included with other labs in the work-up of thromboembolic disease
● Antithrombin III
○ Protein produced by the liver that helps regulate blood clot formation
○ Inhibits action of thrombin, factors Xa, IXa, and XIa
○ Inherited antithrombin deficiencies are rare; heterozygous (clots start around the age of 20-30 years);
homozygous (clotting problems soon after birth)
○ Acquired antithrombin deficiencies occur at any age; associated with liver disease, DIC, cancer, nephrotic
syndrome
○ Testing measures the quantity and function of antithrombin
○ Order in conjunction with Protein S, Protein C, Lupus Anticoagulant when investigating inappropriate
clotting
○ Deficiency in antithrombin increased risk of clotting

25
 ● Lupus Anticoagulants
○ Lupus anticoagulants (LA) are autoantibodies produced by the immune system that mistakenly attack
certain components of the body's own cells
○ They specifically target phospholipids as well as the proteins associated with phospholipids that are
found in the cell membranes.
○ These autoantibodies interfere with the blood clotting and ↑ a person's risk of developing a blood clot
○ Tested in the work-up of inappropriate thrombosis
○ Not used for the diagnosis of lupus

PLATELET DISORDERS AND COAGULOPATHIES

● Hemostasis
○ The body’s ability to stop bleeding
○ Opposite of hemostasis = hemorrhage
○ The players
■ Vascular endothelial cells
■ Platelets
■ Coagulation (clotting) factors
● Vasoconstriction
○ Occurs immediately after injury
○ Endothelium-derived vasoconstrictor endothelin is secreted
○ Vasoconstriction is transient so bleeding would resume if primary hemostasis were not activated
● Primary Hemostasis (forming platelet plug)
○ Platelets are activated and adhere to exposed endothelial matrix
○ Mediated by von Willebrand factor: binds to surface receptors (glycoprotein 1b) on platelets and
endothelium
○ Then, platelet glycoprotein VI interacts directly with collagen in the exposed vessel wall
○ Platelets undergo activation → release granules
○ Stimulation by ADP, epinephrine, collagen → activation of platelet membrane phospholipase A2 (PLA2)
○ PLA2 cleaves phospholipids → liberates arachadonic acid → cyclic endoperoxide → thromboxane A2
(TxA2)
○ TxA2 releases granules
○ ADP, calcium, ATP, serotonin, vWF, and platelet factor 4 are actively secreted from platelet granules
○ ADP especially important - makes platelets sticky
○ Platelets aggregate with each other through fibrinogen
○ Just as the vWF:GPIb interaction is important for platelet aggregation, the fibrinogen:GPIIb-IIIa interaction
is critical for platelet aggregation

26
● Secondary Hemostasis (coagulation
cascade)
○ Goal: form a stable fibrin clot
○ Extrinsic (tissue factor): major
role in releasing thrombin
(converts fibrin fibrinogen).
Measured by Prothrombin
Time (PT).
○ Intrinsic (contact activation):
minor role in initiating clot
formation. Measured by Partial
Thromboplastin Time (PTT)
■ Both pathways interact
to activate the Final
Common Pathway
○ Factor X → Thrombin → Fibrin
● Coagulation Factors
○ I Fibrinogen (Ia=Fibrin)
○ II Prothrombin
(IIa=Thrombin)
○ III Tissue Factor
○ IV Calcium ions
○ V Labile Factor
○ VII Stable Factor
○ VIII Antihemophilic Factor
○ IX Christmas Factor
○ X Stuart Prower Factor
○ XI Plasma Thromboplastin Antecedent
○ XII Hageman Factor
○ XIII Fibrin Stabilizing Factor
● Regulation of Hemostasis
○ After injury, the endothelium becomes “activated” → presents procoagulant factors for hemostasis →
anticoagulant factors to restrict propagation of the clot
○ Procoagulant factors (TF and phosphatidylserine): membrane bound and localized to the site of injury;
provide a surface for the coagulation cascade
○ Anticoagulant factors: secreted by endothelium and are soluble in the blood
○ Thus, the endothelium maintains a balance of pro-/anti-coagulant factors
○ 5 mechanisms that limit hemostasis to the site of the injury
■ Prostacyclin (PGI2): synthesis of cAMP; prevents platelets from adhering and maintains vascular
patency
■ Antithrombin III: inactivates thrombin and other factors (IXa, Xa, Xia, XIIa)
■ Protein S & C: vit-K dependent proteins; slow coagulation cascade by inactivating Va and VIIIa
■ Tissue Factor Pathway Inhibitor (TFPI): limits the action of TF; the coagulation cascade starts
when factor VIIa complexes with TF at the site of injury
■ Plasmin: cleaves fibrin into FDP

27
 ○ Several mechanisms keep the clotting process in check. (e.g. to prevent vascular complications such as
DVT, PE, arterial occlusion):
■ Proteins C & S: degrade factors Va and VIIIa
■ Antithrombin (III): degrades IXa, Xa, XIa, XIIa
■ Tissue Factor Pathway Inhibitor: Limits TF
■ Plasmin: Cleaves fibrin to FDP
■ Prostacyclin: leads to synthesis of cAMP, inhibiting granule release from platelets
○ Clots are eventually resorbed in a process called fibrinolysis (occurs via action of plasmin)
● Primary Hemostasis Disorder (Platelet Dysfunction)
○ Prolonged Bleeding Time
○ Petechiae/Purpura
● Secondary Hemostasis Disorder (Coagulation Factor Deficiency)
○ Delayed deep bleeding
○ Hemarthrosis (bleeding into joints)
○ Muscle hematomas
● Lab Tests Used to Evaluate Bleeding/Thrombotic Disorders
○ Common:
■ CBC ● Monitor heparin tx
■ PT (INR) ■ Chemistry:
● Extrinsic system ● BMP
● Monitor warfarin tx ● LFT (bilirubin)
■ aPTT ● LDH
● Intrinsic
○ Less Routine:
■ FDP (d-dimer)
● DVT/PE, DIC
■ Fibrinogen
● DIC
■ Bleeding Time
● Platelet disorders (vWD)
● DIC
■ Mixing study
● Differentiates factor deficiency from factor inhibitor (eg: Lupus AC)
● Correction of PTT when mixed with normal blood = factor deficiency
● Failure to correct = inhibitor
■ Coagulation Factor Assays
● Determine individual factor deficiencies
● Disorders of Hemostasis (Bleeding Problems)
○ Thrombocytopenias
■ ITP
■ TTP-HUS
■ Various
○ Platelet dysfunction/clotting factor deficiency
■ vWd
■ Liver Disease
■ Vitamin K deficiency

28
 ■ Hemophilias A/B
■ Hypoprothrombinemia (very rare)
THROMBOCYTOPENIAS
Immune Thrombocytopenic Purpura (ITP)
● Isolated low platelet count with normal bone marrow
● Diagnosis of exclusion
● Acute: children; happens after an infection and self resolves
● Chronic: adults; lasts longer than 6 months without specific cause
● Epidemiology
○ Autoimmune disorder: caused by IgG antibodies to platelet membrane glycoproteins
○ Coating platelets with IgG → opsonization and phagocytosis by splenic macrophages and Kupffer cells in
the liver
● Signs/Symptoms:
○ Platelets < 20,000
■ Spontaneous bruising (purpura) and petechiae (tiny bruises) especially on the extremities
■ Bleeding from nostrils/gums
■ Menorrhagia
○ Platelets < 10,000
■ Hematomas in the mouth or other mucous membranes
○ Platelets < 5,000
■ Subarachnoid or intracerebral hemorrhage
■ Lower GI bleeding
■ Internal bleeding from blunt trauma
● Diagnosis
○ CBC: Isolated thrombocytopenia
○ Peripheral smear: normal morphology (platelets may be enlarged)
○ Normal bone marrow biopsy
○ Normal coags
○ Rule out secondary causes, e.g. leukemia, medications, lupus, cirrhosis, HIV, hepatitis C
● Treatment – only if significant bleeding
○ Steroids
○ Splenectomy
○ IVIg – transient benefit; expensive; reserved for emergencies or pre-op
○ Platelet transfusion only in an emergency
Thrombotic Thrombocytopenic Purpura (TTP)
● Rare disorder causing microscopic clots to form in small blood vessels
● Epidemiology: 4-5 cases/million/year; W>M; 1/25,000 pregnancies
○ Normally, ADAMTS13 cleaves large vWF into smaller units
○ In TTP, ADAMTS13 is inhibited → vWF not cleaved → ↑ platelet
adhesion
○ RBCs passing through → sheer stress → intravascular hemolysis →
anemia and schistocytes (a.k.a. Helmet cells, image right)
○ Reduced blood flow → end organ damage
● Idiopathic: nhibition of ADAMTS13 by antibodies
● Secondary: poorly understood, ADAMTS13 is usually normal
○ Cancer

29
 ○ Bone Marrow Transplant
○ Pregnancy
○ Medications (Acyclovir, Quinine, Immunosuppressants, Platelet inhibitors)
○ HIV
● Signs/Symptoms:
○ Classic 5 features (“pentad”) indicate TTP*
■ Thrombocytopenia bruising, bleeding
■ Microangiopathic hemolytic anemia (anemia, jaundice, and RBC fragmentation)
■ Neurologic symptoms
■ Renal failure
■ Fever
○ *Most patients with TTP do NOT have the classic pentad.
○ *Most common presentation is petechiae with neurological dysfunction (HA/confusion/sz/coma)
○ *The patient will appear acutely ill
● Diagnosis:
○ Anemia with reticulocytosis
○ Hemolysis (elevated LDH & indirect bilirubin)
○ Fragmented RBCs (shistocytes “helmet cells”)
○ Severe thrombocytopenia
○ Coags normal (unless secondary DIC is present)
○ Renal insufficiency might be present
● Treatment
○ Emergent plasmapheresis is first line treatment, continued daily until remission
○ Plasmapheresis: exchange transfusion removes patient’s blood plasma through apheresis and replaces
with donor plasma (FFP or cryo)
○ Splenectomy if no response to therapy or if recurrent
Hemolytic-Uremic Syndrome (HUS)
● Syndrome along the spectrum of TTP, characterized by microangiopathic hemolytic anemia, thrombocytopenia
and renal failure
● Children: self-limited disease. Usually occurs after diarrheal illness (salmonella, shigella, E. coli 157:H7)
● Adults: high rate of CRI or death in untreated cases. Usually in setting of estrogen use or postpartum state.
● ***Remember***
○ TTP - more neurological signs/symptoms
○ HUS - more renal failure
● Signs/Symptoms:
○ Bloody diarrhea
○ 5-10 days later - oliguria, hematuria, renal failure, thrombocytopenia, anemia, bleeding
● Labs:
○ Elevated LDH, indirect bilirubin (hemolytic anemia)
○ Thrombocytopenia
○ Elevated BUN/Creatinine (renal failure)
○ Normal coags
● Ddx:
○ Positive Shiga-toxin/EHEC test confirms an etiological cause for STEC-HUS
○ Severe ADAMTS13 deficiency (≤5% of normal ADAMTS13 levels) confirms a diagnosis of
TTP

30
 ● Treatment
○ STEC-HUS: supportive care (fluids/electrolytes, BP control, nutrition)
○ Non STEC-HUS: plasmapheresis until remission
Various Causes of Thrombocytopenia
● Malnutrition: folate/B12 deficiency
● Heme disorders: MDS, Leukemia
● Sepsis: bacterial, viral illness (dengue fever, HIV)
● Liver failure
● Paroxsysmal Nocturnal Hemoglobunuria (PNH)
● Antiphospholipid Syndrome (APLS)
● Medications
○ GI meds: H2 blockers, PPI
○ Antiepileptics: Valproic Acid
○ Immunologics: Methotrexate, Interferon
○ Chemotherapy
PLATELET DYSFUNCTION AND CLOTTING FACTOR DEFICIENCIES
von Willebrand Disease (vWD)
● Genetic disorder caused by missing/defective von Willebrand factor (VWF)
● VWF binds factor VIII, a key clotting protein, and platelets which helps to form the platelet plug
● vWF produced by megakaryocytes and in endothelial cells in multimers of various sizes. Only large multimers are
functional in platelet adhesion.
● von Willebrand Disease (vWD)
● Deficiency of vWF → defective platelet adhesion to subendothelial matrix
○ Type I: (80% cases) quantitative decrease in vWF
○ Type IIa: only small multimers are produced
○ Type IIb: rapid clearance of large vWF multimers
○ Type III: (rare) vWF nearly absent
● The most common inherited bleeding disorder (autosomal dominant); affects 1% of the US population
● Signs/Symptoms:
○ Epistaxis
○ Easy bruising
○ Excessive bleeding
○ Menorrhagia
○ Hemorrhage after childbirth
● Labs: ● Specific Labs:
○ PT unaffected ○ von Willebrand factor (vWF) antigen
○ PTT unaffected or prolonged ○ Ristocetin cofactor activity
○ Platelet count unaffected ○ Factor VIII clotting activity
○ Bleeding time prolonged ○ von Willebrand factor multimers
○ Platelet function test (PFA-100)
● Treatment
○ Most cases are mild, so usually no treatment unless surgery or trauma
○ Desmopressin (DDAVP): synthetic hormone, similar to vasopressin, that controls bleeding by stimulating
the release of more von Willebrand factor stored in endothelial cells - thereby enhancing factor VIII levels.
DDAVP is usually effective in people with type 1 and some subtypes of type 2 disease.

31
 ○ Replacement therapies: infusions of prepared doses of concentrated blood-clotting factors containing
vWF and factor VIII. Used if DDAVP not effective or if vWD is more severe.
○ Contraceptives: controlling heavy bleeding during menstrual periods. Estrogen present in OCPs can boost
levels of von Willebrand factor and factor VIII activity.
○ Anti-fibrinolytic or clot-stabilizing medications: medications, such as aminocaproic acid (Amicar) and
tranexamic acid (Cyklokapron; Lysteda, others) can slow down the breakdown of clotting factors. This
can help keep a clot in place once it has formed, putting a stop to bleeding.
○ Fibrin sealants: applied like a glue using syringes, are placed directly on a cut to curtail bleeding
Hemophilias A & B
● Hemophilia A – Factor VIII deficiency
● Hemophilia B – Factor IX deficiency (Christmas Disease)
● X-linked recessive inheritance (only males affected)
● Most common severe bleeding disorder
● Hemophilia A is the most common inherited bleeding disorder after vWD
● S/S:
○ Spontaneous hemarthroses (knees, ankles, elbows)
○ Muscle hematomas
● Labs:
○ Prolonged PTT, other coags normal
○ Factor assays demonstrate low Factor VIII or IX
● Treatment:
○ Factor VIII or IX concentrate infusions
○ DDAVP may be used perioperatively in Hemophilia A (not B)
○ Avoid ASA
Liver Disease and Coagulopathy
● The liver has the central role in synthesis of almost all coagulation factors and some inhibitors of coagulation and
fibrinolysis
● Hepatocellular necrosis → impaired synthesis of many coagulation factors and their inhibitors
● Produces a prolongation in prothrombin time (PT) which is widely used to monitor severity of hepatic injury
● Significant platelet dysfunction (with both quantitative and qualitative platelet defects)
● Progressive thrombocytopenia with loss of larger and more active platelet is almost universal
● S/S:
○ Most patients have clinically apparent liver disease by this point
○ Bleeding at any site
● Labs:
○ PT affected early on, but with time both the PT and PTT may be affected (PT > PTT)
○ Fibrinogen levels normal
○ Platelets usually normal (may be low due to low levels of thrombopoietin, hypersplenism, or bone marrow
suppression by alcohol)
● Treatment:
○ Fresh Frozen Plasma (FFP) is treatment of choice for bleeding
○ Limited by tendency toward volume overload
Vitamin K Deficiency
● Vitamin K controls the formation of coagulation factors II (prothrombin), VII, IX and X in the liver
● Other Vitamin K dependent factors: protein C, protein S (both anticoagulants) and protein Z
● Where do we get Vitamin K?

32
 ○ Green, leafy vegetables
○ Synthesis by intestinal bacteria
● Causes of Vitamin K Deficiency
○ Poor diet
○ Malabsorption
○ Broad-spectrum antibiotics (suppress colonic flora)
○ Warfarin (Coumadin)
● Signs/symptoms: bruising, petechiae, hematomas
● Labs: PT is prolonged, PTT is normal, bleeding time is unaffected, platelet count is unaffected
● Treatment: Vitamin K administration (oral or SC or IV)
ABNORMALLY INCREASED TENDENCIES TOWARD BLOOD CLOTTING (COAGULATION)
● Thromboembolic Disease
○ **Virchow’s Triad** Three factors that contribute to thrombosis:
■ Endothelial injury
■ Hypercoagulable state
■ Stasis of blood
● Hypercoagulable States
○ Genetic/Inherited
■ Factor V Leiden (the most common)
■ Prothrombin gene mutation
■ Deficiencies of natural proteins that prevent clotting (such as antithrombin, protein C and S)
■ Elevated levels of fibrinogen or dysfunctional fibrinogen (dysfibrinogenemia)
○ Acquired
■ Cancer ■ Pregnancy
■ Recent trauma or surgery ■ Supplemental estrogen use,
■ Central venous catheter including OCP
■ Obesity ■ HRT
■ Prolonged bed rest or immobility
■ Myeloproliferative neoplasms such as polycythemia vera or essential thrombocytosis
■ Antiphospholipid antibody syndrome
Factor V Leiden
● Genetic mutation associated with increased risk of developing inappropriate blood clots
● Most common inherited predisposition to abnormal clotting in the U.S. in Caucasians
● Homozygous much higher clot risk than heterozygous
● Often performed with prothrombin 20210 (PT 20210)
● Factor V is normally inactivated by Protein C to prevent the blood clot from growing too large
● Factor V Leiden mutation can lead to an altered factor V protein that resists inactivation by Protein C → clotting
more active than usual → DVT/VTE
● Order Factor V Leiden test when:
○ first DVT or VTE before the age of 50
○ blood clot in an unusual part of the body
○ personal history or family history of recurrent DVT/VTE
○ first VTE not related to oral contraceptives, pregnancy, or hormone replacement therapy
○ unexplained miscarriages, especially in 2nd or 3rd trimesters
Essential Thrombocytosis
● A chronic myeloproliferative neoplasm characterized by increased platelets in circulating blood

33
 ● Proliferation of platelet precursors (megakaryocytes) in the bone marrow → overproduction of platelets
● Commonly diagnosed around age 60
● More common in women
● Can develop into AML or myelofibrosis (rare)
● Signs/Symptoms:
○ Most are asymptomatic
○ Small vessel disturbance (headache, visual disturbances, burning/redness/pain in hands and feet)
○ Thrombotic (stroke, TIA, DVT, PE)
○ Bleeding (GI, GU, bruising, menorrhagia)
● Diagnosis:
○ CBC: Thrombocytosis (may be >2,000,000)
○ Leukocytosis
○ Blood smear
○ Janus Kinase 2 (JAK2) mutation present in ~50%
○ Bone Marrow Biopsy
● Treatment*:
○ Low-dose aspirin
○ Platelet lowering medications (Hydroxyurea, Anagrelide, Interferon)
○ Plateletpheresis
Other Causes of Thrombocytosis
● Reactive Thrombocytosis (infection) - platelets rarely over 1,000,000
● Trauma
● Inflammatory Disorders: RA, UC, chronic infection
● Polycythemia vera - elevated H/H and RBC mass
Polycythemia Vera
● Chronic myeloproliferative neoplasm
● Accumulation of phenotypically normal RBCs, granulocytes, and platelets without a physiologic stimulus
● Somatic mutation in the Janus kinase 2 (JAK2) gene is found in 95% of cases
● The most common myeloproliferative neoplasm
● Occurs in 2 per 100,000 people
● Slight male predominance but females predominate within the reproductive range
● Clinical Features
○ Massive splenomegaly
○ Elevated hemoglobin or hematocrit on CBC
○ Aquagenic pruritus - very specific for polycythemia vera
○ Uncontrolled erythrocytosis vertigo, tinnitus, headache, visual disturbances
○ Venous or arterial thrombosis
● Diagnosis
○ Elevated red cell mass
○ Normal arterial oxygen saturation
○ Splenomegaly
○ If no splenomegaly: leukocytosis and thrombocytosis
○ Erythropoietin level: if elevated, suggests hypoxic cause of erythrocytosis
● A Word About Erythropoietin
○ Erythropoiesis is regulated by the glycoprotein hormone erythropoietin
○ Produced in the kidney (primarily) and liver

34
 ○ Its level is constant as long as tissue oxygenation is adequate
○ Hypoxia is the only physiological stimulus that increases the number of cells producing erythropoietin
○ The plasma erythropoietin level is a useful diagnostic test because an elevated level excludes
polycythemia vera as the cause for erythrocytosis
● Diagnosis
○ Only 3 conditions cause a microcytic erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis, and
polycythemia vera
○ With β-thalassemia, the RDW is normal and with hypoxic erythrocytosis and PV, it is elevated
○ A peripheral smear will be almost unreadable due to the marked elevation in RBCs
○ WBCs and platelets will appear normal but if also elevated, the diagnosis is assured
● Complications
○ Relate directly to increased blood viscosity; indirectly to the increased turnover of RBC, WBC, platelets
○ Increase in uric acid and cytokine production
○ Erythromelalgia – unknown etiology; manifests as erythema, warmth, and pain of (usually) the lower
extremities
○ Intravascular thrombosis: liver, heart, brain, lungs
● Treatment
○ Maintain hemoglobin < 14mg/dl in men and < 12mg/dl in women to avoid thrombosis
○ Phlebotomy to reduce red cell mass and viscosity – first line treatment
○ Antihistamines for pruritis
○ Pain medication for erythromelalgia
○ Hydroxyurea, IFN-α
○ Ruxolitinib (Jakafi): if inadequate response to hydroxyurea
Secondary Polycythemia
● Caused by either natural or artificial increases in the production of erythropoietin, hence an increased production
of erythrocytes
● Resolves when the underlying condition is treated
● Secondary polycythemia in which the production of erythropoietin increases appropriately is called physiologic
polycythemia
● Physiologic Polycythemia
○ Altitude
○ Hypoxic diseases (e.g. COPD, OSA)
● Not a result of physiologic adaptation
○ Neoplasm (renal cell carcinoma, liver)
○ Erythropoietin supplementation
Hypercoagulable States
● Antiphospholipid Syndrome (APLS)
○ Autoimmune hypercoagulable state
○ Antibodies (IgM, IgG) to antiphospholipids
○ Provokes thrombosis in both arteries and veins
○ Diagnosis:
■ One clinical event and two positive blood tests spaced three months apart
■ lupus anticoagulant, anti-cardiolipin and anti-β2-glycoprotein-I
○ Treatment: aspirin to inhibit platelet activation and/or warfarin as an anticoagulant
● Pregnancy-related complications (miscarriage, stillbirth, preterm delivery, severe preeclampsia)
● Primary: in absence of other disease, or-

35
 ● Secondary: with other autoimmune disease, e.g. lupus
● Hypercoagulable States
DISORDERS INVOLVING BOTH THROMBOCYTOPENIA AND THROMBOSIS
Disseminated Intravascular Coagulation (DIC)
● Pathological process characterized by widespread activation of clotting cascade → blood clots in small vessels
● In addition, coagulation process consumes clotting factors and platelets → severe bleeding
● Does not occur by itself but rather a complicating factor of an underlying condition (e.g. sepsis)
● Tissue ischemia + bleeding → ↑death
● Pathophysiology
○ Release of Tissue Factor (TF)
○ Upon exposure to blood/platelets, TF binds to activated VIIa → forms tenase complex → activates IX and
X to IXa and Xa → common pathway → formation of thrombin and fibrin
● Normal
○ Activation of the coagulation cascade → thrombin → converts fibrinogen to fibrin
○ The stable fibrin clot is the final product of hemostasis
○ Fibrinolytic system then functions to break down fibrinogen and fibrin
○ Activation of the fibrinolytic system plasmin (in the presence of thrombin), which is responsible for the
lysis of fibrin clots
○ The breakdown of fibrinogen and fibrin → polypeptides called fibrin degradation products (FDPs) or fibrin
split products (FSPs)
○ In homeostasis, presence of plasmin is critical. It is the central proteolytic enzyme of coagulation and is
also necessary for the breakdown of clots, or fibrinolysis
● DIC
○ One critical mediator of DIC is the release of tissue factor (TF); present on the surface of many cell types
○ TF is not normally in contact with the general circulation, but is exposed to the circulation after vascular
damage
○ Upon exposure to blood and platelets, TF binds with activated factor VIIa, forming the extrinsic tenase
complex.
○ This complex further activates factor IX and X to IXa and Xa, respectively, leading to the common
coagulation pathway and the subsequent formation of thrombin and fibrin
○ Circulating thrombin results from the excess activation of the coagulation cascade
○ Excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation
○ Excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular
thrombosis.
○ Lodging of clots in the microcirculation, in large vessels, and in organs is what leads to the ischemia,
impaired organ perfusion, and end-organ damage
○ Coagulation inhibitors are also consumed in this process → more clotting
○ Thrombocytopenia; platelets trapped and consumed
○ Excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis
● Normally, thrombin → coagulation is confined to a localized area
● DIC: Circulating excess thrombin leads to hypofibrinogenemia, thrombocytopenia, depletion of coagulation
factors and fibrinolysis → bleeding and thrombosis
● S/S:
○ Occurs in critically ill patients
○ Sepsis (especially gram negative bacteremia)
○ Bleeding more common than thrombosis
36
 ■ Bleeding (oozing from venipuncture sites)
■ Thrombosis (ischemia/gangrene of digits)
● Diagnosis:
○ Prolonged PT and PTT reflect the underlying consumption and impaired synthesis of the coagulation
cascade
○ Low fibrinogen level consistent with the consumptive process of DIC
○ Rapidly declining platelet count
○ High levels of fibrin degradation products, including D-dimer, are found owing to the intense fibrinolytic
activity stimulated by the presence of fibrin in the circulation
○ Peripheral blood smear may show schistocytes due to shear stress from thrombi
● Treatment:
○ Treat the underlying illness (e.g. sepsis)
○ Transfusion of platelets to maintain above 30-50,000/mL
○ Replacement of fibrinogen (cryoprecipitate)
○ Heparin (may be contraindicated in some cases)
○ Successful treatment is indicated by rising fibrinogen level
○ Platelet rise may lag by approximately 1 week
Heparin Induced Thrombocytopenia (HIT) and Thrombosis (HITT)
● Occurs when a patient being treated with heparin (UFH/LMWH) develops antibodies to heparin; usually IgG
● Usually occurs 5-14 days after starting heparin
● Begins earlier in patients on heparin within the past 3 months
● S/S:
○ Extension of known blood clot (DVT/PE or arterial thrombosis) or new clot in different location.
○ Thrombocytopenia (not usually profound)
● Labs:
○ Falling platelets
○ + HIT antibody
● Treatment:
○ Stop heparin
○ Warfarin contraindicated (high risk of skin necrosis; “warfarin necrosis”)
○ Anticoagulation is still required: argatroban, lepirudin, danaparoid (Heparin alternatives)

Common Antiplatelet Drugs

Common Anticoagulants

37
Thrombolytics (Fibrinolytics)

Preoperative Screening for Bleeding Disorders

● History
○ Prolonged bleeding/swollen mouth after biting tongue, lip or cheek?
○ Large bruises (silver dollar) with no recollection of injury?
○ Has bleeding ever restarted the day after tooth extraction?
○ Bleeding problems with past surgeries?
○ Blood relatives with bleeding problems or bleeding after surgery?
● Physical Exam
○ Skin: petechiae/purpura/jaundice
○ Stigmata of liver disease (cirrhosis)
■ Encephalopathy/asterixis
■ Skin: Jaundice/Spider angiomata/Caput medusae/Palmar erythema
■ Hemorrhoids
○ Organomegaly: liver, spleen
○ Lymphadenopathy
○ Mucous membranes
○ Musculoskeletal: joint effusions, muscle hematomas

LEUKEMIA
Two Types:
1. Acute Leukemia’s
○ Acute Myelogenous Leukemia (AML)
○ Acute Promyelocytic Leukemia (APL or APML)
○ Acute Lymphocytic Leukemia (ALL)
2. Chronic Leukemia’s
○ Chronic Myelogenous Leukemia (CML)
○ Chronic Lymphocytic Leukemia (CLL)

38
Acute Myelogenous Leukemia
● Cancer of the myeloid line of blood cells, characterized by the rapid growth of
abnormal/immature cells that accumulate in the bone marrow and interfere with the
production of normal blood cells; increased blasts in the bone marrow and periphery→
decreased RBCs, platelets, and neutrophils
● AML is the most common acute leukemia affecting adults and its incidence increases with age
○ median age 65 years
Risk Factors
● Increasing age
● Previous treatment with chemotherapy (alkylating agents and topoisomerase II inhibitors)
● Exposure to radiation
● Exposure to chemicals (benzene, toluene)
● Tobacco
● Acquired hematopoietic diseases: Myelodysplastic syndrome, Myeloproliferative neoplasm
● Genetic disorders: Down and Klinefelter (XXY) Syndromes
Signs and Symptoms
● caused by the replacement of normal bone marrow with leukemic cells→ a drop in red blood
cells, platelets, and normal white blood cells
○ Shortness of breath
○ Easy bruising
○ Unusual bleeding (nosebleeds, bleeding from the gums)
○ ↑ risk of infection
○ Lethargy and fatigue
○ Pancytopenia: anemia, thrombocytopenia, neutropenia. Splenomegaly, gingival hyperplasia (monocytic),
bone pain. Megakaryoblastic MC in children <5y with Down Syndrome.
○ 士 Leukostasis (WBC >100,000/μL): occluded microcirculation → local
hypoxemia and hemorrhage → headache, blurred vision, TIA/CVA, dyspnea,
hypoxia
○ DIC (especially with APML; M3)
■ condition in which blood clots form throughout the body's small blood
vessels.the increased clotting uses up platelets and clotting factors in
the blood,With fewer platelets and clotting factors in the blood,
serious bleeding can occur.
○ Leukemia infiltration of the skin, gingiva (especially with M4 and M5)
FAB Classification of AML→ M3: APML or APL (promyelocytic); associated with DIC; very good
response to ATRA + chemotherapy, freq 10%

39
Diagnostic Evaluation:
● CBC/blood smear, Coagulation profile, Chemistry panel (LDH, uric acid)
● Bone marrow aspirate and biopsy (needed for definitive diagnosis)
○ Morphology: + granules +/- Auer rods
○ Cytochemistry: + myeloperoxidase and/or nonspecific esterase
● Flow cytometry: detect and measure physical and chemical characteristics of a population of cells or particles
● Immunophenotyping: cells from a lymph node, blood or bone marrow are examined to determine what type of
cells are present
● Cytogenetics: testing samples of tissue, blood, or bone marrow in a laboratory to look for changes in
chromosomes
● Lumbar Puncture (select cases)
Treatment:
● Induction chemotherapy with “7+3” regimen. Cytarabine x 7 days + anthracycline (idarubicin, mitazantrone, or
daunarubicin) x 3 days
○ The goal of the induction phase is to reach a complete remission.
● Check for Complete Response (CR): normal peripheral counts and < 5% blasts in bone marrow (day 14)
● Must ALWAYS follow-up induction chemotherapy with consolidation chemotherapy
○ If + CR, then consolidation chemo +/- stem cell transplant
○ If – CR, then re-induction chemotherapy
AML: Treatment Exception
● M3: Acute Promyelocytic Leukemia (APML)
○ t(15;17)
○ It is associated with Disseminated Intravascular Coagulation (DIC) ***
○ Can be treated with All-trans-retinoic acid (ATRA), Arsenic trioxide (Trisenox) and chemotherapy
○ Induction, then consolidation + prolonged maintenance
○ Most favorable prognosis of all acute leukemias because of its response to ATRA (70-80% cure rate)
Prognosis
● CR is achieved in 70-80% of patients < 60 y.o. and 40-50% of patients > 60 y.o.
● Overall survival depends on prognostic factors: ranges from ~50% for pts < 60 y.o. without poor prognostic
factors to < 10% in pts > 60 y.o. with poor prognostic factors
● Poor prognostic factors: age > 60, unfavorable cytogenetics (e.g. monosomy, deletion of chromosome 5 or 7,
FLT3 mutation), poor performance status, pre-existing MDS/MPN, arising from
the treatment of another cancer (e.g. breast)

Acute Lymphocytic Leukemia (ALL) a.k.a. Acute Lymphoblastic Leukemia

Most common type of cancer in children
● Cancer of the WBC characterized by excess lymphoblasts
● Morphology: NO granules (granules seen only in myeloid lineage)
● Cytochemistry: + terminal deoxynucleotidyl transferase (TdT) in 95% of ALL
● Cytogenetics: t(9;22) = Philadelphia Chromosome in ~25% of people with ALL
● Immunohistochemistry: 3 major phenotypes – Precursor B-cell, Precursor T-cell,
and B-cell
● ~ 4,000 cases per year; median age 10 years; bimodal with second peak in the elderly
● Unclear etiology but can include previous cancer therapy, exposure to radiation, genetic disorders, most cases are
not inherited
Signs and Symptoms:

40
 ● Generalized weakness and fatigue
● Frequent or unexplained fever and infection
● Weight loss and/or loss of appetite
● Excessive and unexplained bruising
● Bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the
marrow cavity)
● Shortness of breath
● Enlarged lymph nodes, liver and/or spleen→ Lymphadenopathy & Hepatosplenomegaly
● Pitting edema in the lower limbs and/or abdomen
● Petechiae
● Tumor Lysis Syndrome
● CNS involvement: headache, stiff neck, visual changes, vomiting
Diagnostic Evaluation:
● CBC/blood smear, Coagulation profile, Chemistry panel (LDH, uric acid)
● Bone marrow aspirate and biopsy (needed for definitive diagnosis)
○ hypercellular with >20% blasts
● Lumbar Puncture for CSF analysis
○ Pts tend to relapse in the CSF
● Flow cytometry: detect and measure physical and chemical characteristics of a population of cells or particles
● Immunophenotyping: cells from a lymph node, blood or bone marrow are examined to determine what type of
cells are present
● Cytogenetic analysis: testing samples of tissue, blood, or bone marrow in a laboratory to look for changes in
chromosomes
● Imaging
Treatment:
● Induction therapy: eradicate leukemia cells
● Consolidation therapy: destroy any remaining cancer cells
● Maintenance therapy: prevent leukemia cells from re-growing (low doses over a long period)
● Targeted drug therapy
● Prophylaxis (chemo) to the spinal cord
● Stem cell transplant (usually reserved for relapsed disease)
● CAR T-cell therapy for relapsed disease or no response to chemo
● Immunotherapy: T cells taken from patient and genetically engineered with a virus. Infused back into patient and
recognize and kill cancer cells that express a specific antigen.
CNS Prophylaxis:
● Prevents early CNS relapse and is mandatory in children with ALL after a CR is induced. The CNS is the initial site
of relapse in more than ½ of patients unless prophylaxis is given.
○ Agent: IT MTX→ intrathecal Methotrexate
Prognosis
● CR achieved in > 90% of children and 80% of adults
● Cure achieved in 50-70% of patients with good prognostic factors vs. 10-30% with poor prognostic factors
● Good prognostic factors: younger age, WBC < 30,000 for B-cell ALL and < 100.000 for T-cell ALL, Hyperdiploid B-
ALL, certain chromosomal changes (e.g. hyperdiploidy, t(10;14), no spread to CNS

Chronic Myelogenous Leukemia (CML)

● Myeloproliferative disorder with overproduction of myeloid cells that can differentiate

41
 ● The rate of transformation to acute leukemia and then presence of chromosomal markers distinguish CML from
other myeloproliferative disorders
○ CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes
(neutrophils, eosinophils, and basophils) and their precursors is the main finding.
● ~4300 new cases per year; median age about 50 years; 20% of adult leukemias; incidence in men slightly higher
than women
● Increased risk with prior radiation and ionizing radiation; no clear relation to cytotoxic drugs
● Cytogenetic: Philadelphia Chromosome t(9;22)
○ Arises from the translocation of the C-ABL gene from the long arm of chromosome 9 to the long arm of
chromosome 22 --> BCR-ABL
○ PH negative CML: prognosis is poorer; usually child or elderly; leukocyte and platelet counts lower; BM
shows more immaturity
○ PH in acute leukemias: can be found in acute leukemias; 25% of adults with ALL and 2% with AML present
with the PH chromosome.
Clinical Manifestations:
● Triphasic clinical course; 85% present in the chronic phase
○ Chronic phase: often asymptomatic but common features include: malaise, weight loss, night sweats,
abdominal fullness (splenomegaly 50%). Readily controlled by chemotherapy.
○ Accelerated phase: refractory leukocytosis and worsening symptoms fever, weight loss, splenomegaly,
bone pain
○ Blastic phase: acute leukemia severe constitutional symptoms, infection, bleeding, and possible
leukostasis; can be either AML or ALL; often refractory to treatment
Diagnostic Evaluation
● Peripheral smear: leukocytosis (often WBC > 100,000), left-shifted with all stages of myeloid maturation; anemia,
thrombocytopenia, basophilia
● Bone marrow: hypercellular, increased myeloid to erythroid ratio
○ Chronic: < 10% blasts (peripheral or BM)
○ Accelerated: 10-20% blasts
○ Blastic: > 30% blasts
Treatment
● Imatinib: a selective inhibitor of the BCR-Abl tyrosine kinase; active in chronic, accelerated, and blastic phases;
consider for all patients in chronic phase
● Imatinib resistance associated with BCR-Abl mutation or amplification
● Allogeneic SCT: consider for patients with an available donor who present in accelerated or blastic phase and
who can undergo transplant
Prognosis
● Chronic phase CML treated with TKI: 89% overall survival, 7% progression to blast phase at 5 years
● Accelerated phase CML treated with TKI: ~ 50% overall survival at 4 years
Poor prognostic factors: increased age, high platelet count, increased spleen size, high percentage of blasts
Survival
● Median survival times are: 3.5 years in high risk group, 5 years in intermediate risk group, and > 8 years in low risk
group.
● Median survival for PH negative CML is 9-15 months.
● Survival after blast crisis is usually 2-4 months.

Chronic Lymphocytic Leukemia (CLL)

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MC leukemia in adults overall
● CLL is a clonal disease of immunologically incompetent, long lived lymphocytes that express high levels of anti-
apoptotic proteins, especially BCL-2. All cases involve CD5+ lymphocytes.
● B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing
antibodies.
○ In CLL, B cells grow out of control and accumulate in the bone marrow and blood, where they crowd out
healthy blood cells
Epidemiology
● ~10,000 new cases per year; median age at diagnosis is 65
● >75% of patients are over the age of 50 at diagnosis and the majority are men
● Higher incidence in first degree relatives; no association with radiation, chemicals, drugs
Clinical Manifestations:
● Symptoms: oftentimes asymptomatic and identified when CBC reveals lymphocytosis; 10-20% present with
fatigue, malaise, night sweats, weight loss
● Signs: lymphadenopathy (80%) and hepatosplenomegaly (50%)
● Autoimmune hemolytic anemia (AIHA) or thrombocytopenia
● Aggressive transformation: ~5% develop
○ Richter’s Syndrome = transformation into high grade lymphoma
(usually DLBCL) and rapid clinical deterioration
Diagnostic Evaluation
● Peripheral Smear: lymphocytosis (>5000/uL, mature-appearing small cells), anemia
● “Smudge” cells from damage to lymphocytes from making the smear
● Bone marrow: normal or hypercellular; infiltrated with small B cell lymphocytes (> 30%)
● Lymph nodes: infiltrated with small lymphocytic or diffuse small cleaved cells
● Flow cytometry: CD5+, CD19+, CD20+, CD23+
● Cytogenetics: 11q22-23 and 17p13 are unfavorable; trisomy 21 is neutral, while 13q14 is favorable
● CLL: Staging; Rai System→ higher the # the worse the prognosis, 4=worse 0=best
● CLL: Staging; Binet System
Treatment
● Treatment is palliative→ early stage disease can be followed without treatment
● Indications for treatment: Rai stages III/IV, Binet stage C, disease related symptoms, progressive disease, AIHA,
ITP, refractory to steroids, recurrent infections
● Fludarabine is superior to alkylating agents in its associated complete response rate and duration of response
○ Prolonged treatment with Fludarabine increases risk of opportunistic infections and autoimmune
hemolysis
● Initiation – timed according to the pace of the disease
● Immune hemolysis or thrombocytopenia – treated with steroids
● Resistant Disease – treat with an alkylating agent if Fludarabine already used
● Purine analogs: Fludarabine (F), Pentostatin (P)
● Alkylating agents: Cyclophosphamide (C), CVP, CHOP
● Monoclonal antibody against CD20 (Rituximab “R”) or CD52 (alemtuzumab)
● Combination regimens most popular
● Supportive care: PCP, HSV, VZV prophylaxis; CMV monitoring for patients receiving CD52
● AIHA/ITP→ steroids
● bulky disease with compressive symptoms→ XRT
● splenomegaly with refractory cytopenias→ splenectomy

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LYMPHOMA
● Cancers that develop in the lymphatic system
● Malignant transformation of the lymphoid cell
● These malignant cells often originate in lymph nodes, presenting as an enlargement of the node
● Can also affect other organs in which case it is referred to as extranodal lymphoma
○ Extranodal sites include: skin, brain, bowels, bone, etc.
Two types:
1. Hodgkin Disease/Lymphoma (HL): characterized by Reed Sternberg cells; develops in white blood cells; tends to
arise in lymph nodes and spreads in an orderly fashion
● 8,110 estimated new cases in 2019; 1,000 deaths
● The 5-year relative survival rate for all patients diagnosed with Hodgkin lymphoma is now about 86%
2. Non-Hodgkin Lymphoma (NHL): lymphoid cancers characterized by more than 20 histologic subtypes; start in
bone marrow, spleen, thymus, or lymph nodes and spread to other parts of the body (not orderly fashion)
● About 74,200 people will be diagnosed with NHL in 2019; 19,970 people will die
● One of the most common cancers in the U.S.
● begins when a lymphocyte (usually a B cell) becomes abnormal. The abnormal cell divides to make
copies of itself. The new cells divide again and again, making more and more abnormal cells. The
abnormal cells don't die when they should. They don't protect the body from infections or other diseases.
The buildup of extra cells often forms a mass of tissue called a growth or tumor.
Hodgkin Lymphoma
● bimodal distribution (15-35 and > 50 years old); more common in men (85% of children with HL are boys)
● Pathology: affected nodes show Reed-Sternberg cells in background of non-
specific inflammatory cells
○ Classic RS cells: bi-lobed nucleus and prominent nucleoli with surrounding
clear space (“owl’s eyes”).
○ RS are clonal B cells: CD15+, CD 30+, CD20- by flow cytometry
Rye Histologic Classification of Classic HL

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Ann Arbor Staging System with Cotswolds Modifications

Risk Factors
● Sex: male
● Age: 15-40 and > 55
● Family History
● History of infectious mononucleosis or infection with Epstein-Barr virus
● Immune compromise, e.g. HIV
● Prolonged use of growth hormone
● Exposure to Agent Orange (Vietnam War)
Clinical Manifestations
● Lymphadenopathy (most common):
○ Superficial (usually axial/cervical/supraclavicular) +/- mediastinal
● lymphadenopathy or mass; nodal disease with orderly anatomic spread to adjacent nodes.
● Constitutional (B) Symptoms: fever, sweats, weight loss (>10% in 6 months)
● Pruritus: 10-15% have pruritus (due to high eosinophils)
● Abdominal pain, Splenomegaly/Hepatomegaly
● Pain after alcohol consumption (not common, only 2-3%, but very specific) → in affected nodes
● Lower back pain
Diagnosis
● Definitive diagnosis is by lymph node biopsy (usually excisional biopsy with microscopic examination)
● Blood tests are also performed to assess the function of major organs and to assess safety for chemotherapy
● Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. PET
scans are also useful in functional imaging (by using a radiolabeled glucose to image tissues of high metabolism)
● Bone marrow biopsy
● Flow cytometry: detect and measure physical and chemical characteristics of a population of cells or particles
● Immunophenotyping: cells from a lymph node, blood or bone marrow are examined to determine what type of
cells are present
● Cytogenetic analysis: testing samples of tissue, blood, or bone marrow in a laboratory to look for changes in
chromosomes
● FISH: molecular cytogenetic technique
Treatment:

45
 ● Several combinations of chemotherapy medications
● Radiation therapy
● Bone marrow transplant
● Targeted therapies
● Patients are at risk for second malignancies: acute leukemia/MDS, NHL, lung cancer, breast cancer
Prognosis
● In 1998, an international effort identified 7 prognostic factors that accurately predict the success rate of
conventional treatment in patients with locally extensive or advanced stage Hodgkin's lymphoma.
● Freedom from progression (FFP) at 5 years was directly related to the number of factors present in a patient
● The 5-year FFP for patients with zero factors is 84%. Each additional factor lowers the 5-year FFP rate by 7%, such
that the 5-year FFP for a patient with 5 or more factors is 42%.
● The adverse prognostic factors identified in the international study are:
○ Age > 45
○ Stage IV disease
○ Hemoglobin < 10.5 g/dL
○ Lymphocyte count < 600/µl or < 8%
○ Male
○ Albumin < 4.0
○ WBC > 15,000/µl

Non-Hodgkin Lymphoma (NHL)

● Divided into three types: B-cell (85% of cases), T-cell, NK-cell
● Classified by how quickly it spreads and is referred to as indolent or aggressive:
○ Indolent NHL: follicular, lymphoplasmacytic, marginal zone, MALT
○ Aggressive NHL: diffuse large B-cell, primary mediastinal large cell, anaplastic large cell, Burkitt’s,
lymphoblastic, mantle cell, T-cell lymphomas, plasmablastic
Risk Factors
● Gender: slightly more common in men
● Race: slightly more common in Caucasians
● Bacteria or viruses:Human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), Helicobacter pylori, Human T-
cell leukemia/lymphoma virus type 1 (HTLV-1)
● Medical Conditions: inherited disorders, autoimmune disease, taking immunosuppressant drugs after organ
transplant
● Age: can occur in young people but the chance of developing this disease goes up with age; most people with
non-Hodgkin lymphoma are > than 60 years old
Symptoms
● Swollen, painless lymph nodes in the neck, armpits, or groin
● Unexplained weight loss
● Fever
● Soaking night sweats
● Coughing, trouble breathing, or chest pain
● Weakness and tiredness that don't go away
● Nausea, vomiting, pain, or a feeling of fullness in the abdomen
● Severe itchiness or skin rash
● Extranodal sites common: GI, skin & CNS MC, testicular enlargement, mediastinal masses.

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 ● Burkitt Lymphoma: often presents with abdominal pain (sporadic type), jaw involvement (African type). Histology
in Burkitt shows "starry sky" appearance.
Diagnosis
● History and physical exam
● Blood tests: CBC, LFTs, renal function, LDH
● Imaging: x-ray, CT, PET, MRI
● Biopsy: remove an entire lymph node (excisional biopsy) or only part of a lymph node (incisional biopsy)
● Bone marrow aspiration and biopsy
● Flow cytometry: detect and measure physical and chemical characteristics of a population of cells or particles
● Immunophenotyping: cells from a lymph node, blood or bone marrow are examined to determine what type of
cells are present
● Cytogenetic analysis: testing samples of tissue, blood, or bone marrow in a laboratory to look for changes in
chromosomes
● FISH: molecular cytogenetic technique
Non-Hodgkin Lymphoma: Staging
● Stage I: One lymph node region is involved. If the cancer is in one organ outside the lymph node such as the skin,
lung, brain, etc., this is called extranodal or E non-Hodgkin’s lymphoma
● Stage II (locally advanced disease): The cancer is in two or more lymph regions on one side of the diaphragm. If
the cancer is in one lymph node region plus a nearby organ, it is considered E disease.
● Stage III (advanced disease): Non-Hodgkin’s lymphoma involves lymph nodes above and below the diaphragm or
one node area and one organ on the opposite sides of the diaphragm.
● Non-Hodgkin Lymphoma: Staging
● Stage IV (widespread disease): The lymphoma is outside the lymph nodes and spleen and has spread to one or
more organs such as bone, bone marrow, skin, and other organs.
● Other classifications:
○ A: no weight loss, drenching night sweats, or fevers
○ B: weight loss, drenching night sweats, or fevers
○ S: cancer is found in the spleen
○ E: extranodal
○ Recurrent: cancer that has recurred after treatment
Treatment
● Depends on: Stage, Phenotype, Histology, Symptoms, Performance status (is your patient active or bedbound?),
Comorbidities
● Indolent:
○ Stages I and II:
■ Radiation alone for local disease
■ Monoclonal antibody and/or chemotherapy
■ Watchful waiting
○ Stages II, III, and IV:
○ Monoclonal antibody with or without chemotherapy
○ Chemotherapy with or without steroids
○ Combination chemotherapy
● Aggressive:
○ Monoclonal antibody and combination chemotherapy
○ + involved field radiation therapy
○ Combination chemotherapy

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 ○ CNS prophylaxis in some cases
○ intrathecal or systemic high-dose methotrexate if paranasal sinus, testicular, breast, periorbital, or bone
marrow involved
● Relapse: salvage chemo, high-dose chemo plus BMT if second relapse
● Treatment: Non-Hodgkin Lymphoma
● Highly aggressive: Burkitt
○ Treat with short bursts of intensive chemotherapy
○ All patients receive CNS prophylaxis
○ Tumor lysis syndrome prophylaxis
● Indolent Recurrent:
○ Chemotherapy
○ Monoclonal antibody
○ Radiation therapy for palliation
○ Stem cell transplant
● Aggressive Recurrent:
○ Chemotherapy
○ Monoclonal antibody with combination chemotherapy followed by stem cell transplant
○ Radiation therapy for palliation
○ CAR-T cell therapy:
○ Immunotherapy: T cells taken from patient and genetically engineered with a virus. Infused back into
patient and recognize and kill cancer cells that express a specific antigen.
Prognosis:
● Indolent: lower response to chemotherapy but a long median survival (but probably cannot be cured)
● Aggressive: higher chance of cure but overall worse prognosis
HIV-Associated NHL
● HIV + imparts 60-100x relative risk
● NHL is an AIDS-defining malignancy along with Kaposi’s sarcoma, cervical cancer, and anal cancer
● Concurrent HAART and chemotherapy likely provides survival benefit
Survival
● Indolent Lymphomas – rarely curable
● Aggressive and Highly Aggressive – 80-90% of patients with stage I or early stage II disease and 30-40% with
stage III or IV disease may be curable
● Mantle Cell Lymphoma – rapid and steady decline; 2.5 year median survival
Double Hit Lymphoma
● Characterized by the presence of concurrent MYC and BCL2 gene rearrangements
● With standard therapy, patients with DHL have worse prognosis
● Many treatment options such as DA-R-EPOCH, R-hyperCVAD, R-CODOX-M/IVAC

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MULTIPLE MYELOMA
● Plasma cells are white blood cells that make antibodies
● Malignant proliferation of plasma cells producing a monoclonal immunoglobulin = “M component” This clone of
plasma cells proliferates in the bone marrow interferes with normal cells and causes skeletal destruction
● Without effective therapy, patients die within a median of 6 months
Epidemiology
● Accounts for 1% of all cancers and 10% of all hematologic malignancies in the US
● Annual incidence in US: 4 to 5 per 100,000
● Incidence in African Americans and blacks from Africa is 2-3 times that in caucasians
● Median age at diagnosis: 66 years
Pathophysiology
● B lymphocytes start in the bone marrow and then lymph nodes. When they are activated to secrete antibodies
plasma cells.Loss of control of the proliferation of B cells and the secretion of antibodies due to damaged
chromosomes and genes. Often, a promoter gene translocates to a chromosome where it stimulates an antibody
gene to overproduce
● A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome 14, locus q32)
and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11) is frequently observed
● This mutation results in dysregulation of the oncogene proliferation of a plasma cell clone and genomic
instability that leads to further mutations and translocations.
● Production of cytokines (especially IL-6) by the plasma cells causes much of their localized damage
● Angiogenesis is increased
● The produced antibodies are deposited in various organs renal failure, neuropathy, and various other myeloma-
associated symptoms
Clinical Presentation: CRAB
● HyperCalcemia: due to binding of the monoclonal protein with calcium
● Renal Disease: serum creatinine is increased; renal impairment is due to: light chain cast nephropathy and/or
Hypercalcemia
● Anemia: decreased BM production of RBC or kidney damage
● Bone pain: usually in the back and chest; worse with movement; most common symptom in MM

49
 ● Neurologic disease: usually radiculopathy; caused by compression of the nerve by a paravertebral plasmacytoma
or collapse of the bone itself; Spinal Cord Compression occurs in 5% of patients
● Infection: due to immune dysfunction (impaired lymphocyte function, suppression of normal plasma cell function,
hypogammaglobulinemia)
Work up:
● Suspect MM when: presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate
(ESR), lytic bone lesions, elevated beta-2 microglobulin, and/or a high serum protein (especially raised globulins or
immunoglobulin)
● protein electrophoresis to look for: paraprotein (monoclonal protein, or M protein) band
● Urine electrophoresis for Bence Jones protein which is a urinary paraprotein composed of free light chains
● Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease
● The paraprotein is an abnormal immunoglobulin produced by the tumor clone → IgG (MC) then Iga & IgM
● Very rarely, the myeloma is nonsecretory (not producing immunoglobulins)
Pathologic Features
● Monoclonal proteins:
○ Presence in the serum or urine
○ Secreted by malignant plasma cells
○ Detected by protein electrophoresis of the serum (SPEP) or 24-hour
urine (UPEP)
○ Single narrow peak in the gamma, beta, or alpha2 region
● Peripheral smear: rouleaux formation “stack of coins”, leukopenia,
thrombocytopenia
● Bone marrow biopsy: aspirate and biopsy are key to diagnosis; 10% or more plasma cells in the vast majority of
people with MM
● Cytogenetics: there is no single cytogenetic abnormality that is typical or diagnostic of MM; however the
presence of trisomies by FISH is a predictor of good response whereas
abnormal markers in the absence of trisomies define high risk MM
● Radiographic Studies
○ Skeletal Survey: Punched out lytic lesions (60%), Diffuse osteopenia
(20%), Fractures (20%)
■ Most often involve: vertebral bodies, skull, thoracic cage, pelvis,
proximal humeri, and femora
Diagnosis
● Complete H and P
● CBC with differential and smear
● Chemistry screen
● SPEP/UPEP
● Immunofixation: shows component is monocolonal and identifies Ig type IgG (50%), IgA (20%), IgD (2%), IgM
(0.5%), light chain only (20%), nonsecretors (< 5%)
● Serum free light chain assay: important for diagnosis and to follow treatment response
● Bone marrow biopsy and aspiration
MM: Variants

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Diagnostic Criteria
● International Myeloma Working Group agreed on diagnostic criteria for multiple myeloma and variants
● Symptomatic Multiple Myeloma:
○ Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues
(plasmacytoma)
● Any one or more of the following evidence of end-organ damage felt related to the plasma cell disorder
(commonly referred to by the acronym "CRAB"):
● Any one or more of the following biomarkers of malignancy (MDEs)*:
○ 60% or greater clonal plasma cells on bone marrow examination
○ Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the
involved light chain is at least 100mg/L (a patient's involved free light chain either kappa or lambda is the
one that is above the normal reference range; the uninvolved free light chain is the one that is typically in,
or below, the normal range)
○ More than one focal lesion on MRI that is at least 5mm or greater in size
○ *The presence of at least one of these markers is considered sufficient for a diagnosis of multiple
myeloma, regardless of the presence or absence of symptoms or CRAB features
Diagnosis and Staging
● Protein electrophoresis and immunofixation:
● Serum protein electrophoresis (SPEP): quantitates M component; positive in ~ 80% of patients
● Urine protein electrophoresis (UPEP): detects the 20% of patients who secrete only light chains (Bence Jones
proteins), which are filtered rapidly from the blood
○ Bence Jones Proteins→ small proteins (light chains of immunoglobulin) found in the urine
○ made by plasma cells
○ The amount of Bence Jones proteins in the urine indicates how much tumor is present
Revised International Staging System (RISS)
● The RISS is based on 4 factors: albumin, β2M, LDH, and specific cytogenetics
○ Stage I: β2 microglobulin (β2M) < 3.5 mg/L, albumin >/= 3.5 g/dl, normal LDH, low risk cytogenetics
○ Stage II: Not stage I or III
○ Stage III: β2M >= 5.5 mg/L, high risk cyto, high LDH
Survival Rates: stage 1= 62mon, 2=44mon, 3= 29mon
Treatment
● Once the diagnosis is verified, the choice of initial therapy is affected by two main factors:
1. Risk stratification: Standard risk & High risk
2. Eligibility to undergo autologous stem cell transplant
○ Determining Transplant Eligibility
■ Autologous stem cell transplant results in superior event-free overall survival rates when
compared with combination chemotherapy

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 ■ Autologous transplant is a standard treatment for patients with multiple myeloma, however it
doesn’t cure the cancer, and eventually the myeloma returns
■ Allogeneic transplants are not considered standard treatment for myeloma
● Proteosome inhibitors: Bortezomib (Velcade), Carfilzomib (Kyprolis), Ixazomib (Ninlaro)
● Immunomodulating agents: Thalidomide, Lenalidomide (Revlamid), Pomalidomide (Pomalyst)
● Histone deacetylase inhibitors: Panobinostat (Farydak)
● Monoclonal antibodies: Daratumumab (Darzalex), Elotuzumab (Empliciti)
● Traditional Chemotherapy
● Corticosteroids: active against myeloma cells
● Bone marrow transplant
● Radiation therapy (mostly palliative, e.g. for bone pain)

MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS

Myelodysplastic Syndromes (MDS)
● Collection of malignancies caused by poorly formed or dysfunctional blood cells
● Immature blood cells in the bone marrow do not mature or become healthy cells
● Immature cells crowd out healthy cells
● 4.4-4.6 cases per 100,000 people
● More common in men and Caucasians
Risk Factors
● Can arise de novo, as a secondary malignancy after treatment with chemo or radiation, or (rarely) after
environmental exposures
● Most (~90%) have no identifiable cause
● Cytogenetic abnormalities (e.g. deletion of chromosomes 5 or 7 or trisomy 8)
● Environmental causes: tobacco, ionizing radiation, organic chemicals (benzene), pesticides, fertilizers, etc.
Complications
● Anemia
● Recurrent infections
● Bleeding
● Increased risk of cancer
Clinical Presentation
● Occurs in older patients (> 60 years)
● Median age at diagnosis: 70 years
● Anemia, fatigue, pallor, Bleeding, bruising, petechiae, Frequent infections
Diagnostics
● History and Physical Exam
● Complete Blood Count (CBC) with Differential
● Blood chemistries
● Bone marrow aspiration and biopsy
● Cytogenetics
● Immunocytochemistry, immunophenotyping, flow cytometry, fluorescence in situ hybridization (FISH)
Pathologic and Prognostic Scoring
● classified by: features of cellular morphology, etiology, and clinical presentation
● Largely based on: percentage of myeloblasts, type and degree of myeloid dysplasia, and the presence of ring
sideroblasts
● French American British (FAB) and World Health Organization (WHO)

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 ● Prognostic scoring systems: International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System
(WPSS), MD Anderson Cancer Center
● MDS: Pathologic and Prognostic Scoring
○ Refractory anemia (RA)
○ Refractory anemia with ring sideroblasts (RARS)
○ Refractory anemia with excess blasts (RAEB)
○ Refractory cytopenia with multilineage dysplasia (RCMD)
○ Refractory cytopenia with unilineage dysplasia (RCUD)
○ Unclassifiable myelodysplastic syndrome (MDS-U)
○ Myelodysplastic syndrome associated with an isolated del(5q)
○ Therapy-related myeloid neoplasms
○ Chronic myelomonocytic leukemia (CMML)
Treatment
● Standard therapy: supportive care, drug therapy, stem cell transplant
● Supportive Care
○ Transfusions
○ Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa (Epogen) or darbepoetin alfa (Aranesp)
○ Medications such as azacitidine (Vidaza) and decitabine (Dacogen) that stimulate blood cells to mature
○ Antibiotics
● Drug therapy
○ Lenalidomide (Revlamid): lower risk, transfusion-dependent MDS patients with del(5q)
○ Immunosuppressive therapy with ATG
○ Chemotherapy: higher risk patients with excess blasts
● Stem Cell Transplant
○ High dose chemotherapy is given (wipes out immune system and residual disease)
○ Donor cells are infused and proliferate

Myeloproliferative Neoplasms (MPN)

1. Polycythemia Vera
● Chronic myeloproliferative neoplasm
● Accumulation of phenotypically normal RBCs, granulocytes (neutrophils, eosinophils, basophils), and
platelets without a physiologic stimulus
● Somatic mutation in the Janus kinase 2 (JAK2) gene is found in 95% of cases
● The most common of the myeloproliferative disorders
○ Occurs in 2 per 100,000 people
○ Slight male predominance but females predominate within the reproductive age range
● Clinical Features
○ Massive splenomegaly
○ Elevated hemoglobin or hematocrit on CBC
○ Aquagenic pruritus
○ Uncontrolled erythrocytosis vertigo, tinnitus, headache, visual disturbances
○ Venous or arterial thrombosis
○ Elevated red cell mass
○ Normal arterial oxygen saturation
○ Splenomegaly
■ If no splenomegaly: leukocytosis and thrombocytosis

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 ○ Erythropoietin level: if elevated suggests hypoxic cause of erythrocytosis
○ Erythropoiesis is regulated by the glycoprotein hormone erythropoietin
○ Produced in the kidney (primarily) and liver
○ It’s level is constant as long as tissue oxygenation is adequate
○ Hypoxia is the only physiologic stimulus that increases the number of cells producing
erythropoietin
○ The plasma erythropoietin level is a useful diagnostic test because an elevated level excludes
polycythemia vera as the cause for the erythrocytosis
● Diagnosis
○ Only 3 conditions cause a microcytic erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis,
and polycythemia vera
○ With β-thalassemia, the RDW is normal and with hypoxic erythrocytosis and PV, it is elevated
○ A peripheral smear will be almost unreadable due to the marked elevation in RBCs
○ WBC and platelets will appear normal, but if also elevated, the diagnosis is assured
● Complications
○ Relate directly to increased blood viscosity and indirectly to the increased turn over of RBC, WBC,
and platelets
○ Increase in uric acid and cytokine production
○ Erythromelalgia – unknown etiology; manifests as erythema, warmth, and pain of (usually) the
lower extremities
○ Intravascular thrombosis: liver, heart, brain, or lungs
● Treatment
○ Maintain Hgb < 14mg/dl in men and Hgb < 12mg/dl in women to avoid thrombosis
○ Phlebotomy to reduce red cell mass and viscosity
○ Antihistamines for pruritus
○ Salicylates to treat erythromelalgia
○ Hydroxyurea, IFN-α
○ Ruxolitinib (Jakafi): if inadequate response to hydroxyurea
Secondary Polycythemia
● Caused by either natural or artificial increases in the production of erythropoietin, hence an increased
production of erythrocytes
● Resolves when the underlying condition is treated
● Secondary polycythemia in which the production of erythropoietin increases appropriately is called
physiologic polycythemia
● Physiologic Polycythemia
○ Altitude
○ Hypoxic disease associated (COPD, OSA)
■ Not a result of physiologic adaptation
○ Neoplasm (renal cell carcinoma, liver)
○ High testosterone due to anabolic steroids, erythropoietin supplementation
2. Essential Thrombocytosis
● Chronic myeloproliferative neoplasm characterized by increased platelets in circulating blood
● Proliferation of platelet precursors (megakaryocytes) in the bone marrow→
overproduction of platelets
● Commonly diagnosed around age 60
● More common in women

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 ● Can develop into AML or myelofibrosis (rare)
● Signs/Symptoms:
○ Most are asymptomatic
○ Small vessel disturbance (headache, visual disturbances, burning/redness/pain in hands and
feet)
○ Thrombotic (stroke, TIA, DVT, PE)
● Diagnosis:
○ CBC: Thrombocytosis (may be >2,000,000), Leukocytosis
○ Blood smear
○ Genetic testing: JAK2 mutation present in ~50%
○ Bone Marrow Biopsy
● Treatment*:
○ Low-dose aspirin
○ Platelet lowering medications (Hydroxyurea, Anagrelide, Interferon)
○ Plateletpheresis
● Other Causes of Thrombocytosis
○ Reactive Thrombocytosis (infection) → Platelets rarely over 1,000,000
○ Trauma
○ Inflammatory Disorders: RA, UC, chronic infection
○ Polycythemia vera: Elevated H/H and RBC mass
3. Primary Myelofibrosis
● Excessive scar tissue in the bone marrow impairs it’s ability to produce normal blood cells, leading to anemia,
weakness, fatigue, and hepatomegaly and splenomegaly
● Genetic mutation→ abnormal stem cells→ produce more mature cells that grow quickly→ fibrosis and chronic
inflammation
● End result: lack of RBC, abundance of WBC, variable PLT
● Can arise de novo (primary myelofibrosis), as a progression of polycythemia vera or essential thrombocytosis, or
due to chemical or radiation exposure
● Most people are diagnosed between age 60-70
● Clinical Presentation
○ Usually develops slowly
○ Symptoms are caused by abnormal numbers of blood cells or chronic inflammation
○ Fatigue, weakness, SOB
○ Early satiety, abdominal fullness, LUQ pain, weight loss
○ Fever, night sweats
○ Susceptibility to infection
○ Easy bruising or bleeding
● Complications
○ Portal hypertension: increased blood flow from enlarged spleen
○ Pain: due to splenomegaly
○ Formation of blood cells outside of the bone marrow (extramedullary hematopoiesis)
○ Bleeding due to thrombocytopenia
○ Bone and joint pain: hardening of bone marrow and inflammation of connective tissue
○ Acute Leukemia
● Treatment
○ Treatments that target gene mutations

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 ■ Ruxolitinib (Jakafi)
● Treatments for anemia
○ Blood transfusions
○ Androgen therapy: may promote red blood cell production
○ Thalidomide, Lenalidomide (Revlamid), Pomalidomide (Pomalyst): may improve blood cell counts by
antiinflammatory and immunomodulatory effects
● Treatments for splenomegaly
○ Splenectomy, Chemotherapy, Radiation
● Stem Cell Transplant: only treatment that has potential to cure

OVERVIEW OF CANCER
● Cancer is not just one disease, but a large group of almost 100 diseases. Its two main characteristics are
uncontrolled growth of the cells in the human body and the ability of these cells to migrate from the original site
and spread to distant sites.
● If the spread is not controlled, cancer can result in death.
● Definitions
○ Carcinoma - cancer that begins in the skin or in tissues that line or cover internal organs; most common
(e.g. squamous cell carcinoma of the bladder)
○ Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or
supportive tissue (e.g. osteosarcoma)
○ Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes large
numbers of abnormal blood cells to be produced and enter the blood
○ Cancer
○ Lymphoma and myeloma - cancers that begin in the cells of the immune system
○ Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord
○ Germ cell tumors: derived from pluripotent cells, most often presenting in the testicle or ovary
○ Blastoma: derived from immature “precursor” cells or embryonic tissue
● Causes
○ Environmental/Lifestyle ○ Infectious
■ Chemical (benzene) ■ Viruses (HPV, HIV, HCV, HBV,
■ Radiation (UV, ionizing, non- EBV, HTLV)
ionizing) ■ Bacteria (H. pylori)
■ Tobacco ○ Hereditary
■ Alcohol ■ Germline genetic defects
● Epidemiology in the U.S.
○ In 2019: An estimated 1.7 million new cases of invasive cancer will be diagnosed in the United States
○ In 2019: 606,880 cancer deaths
○ Second leading cause of death in the U.S. after heart disease
○ Accounts for 1 in 4 deaths
● Neoplasia
○ The process of abnormal and uncontrolled growth of cells. The product is a neoplasm (tumor)
○ Can be benign, potentially malignant (pre-cancer), or malignant (cancer)
○ Benign neoplasms: uterine fibroids and melanocytic nevi (skin moles). They are circumscribed and
localized and do not transform into cancer.
○ Potentially malignant neoplasms: carcinoma in situ. They do not invade and destroy but given enough
time, will transform into a cancer

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 ○ Malignant neoplasms = cancer. They invade and destroy the surrounding tissue, may form metastases
and eventually kill the host.
○ Secondary neoplasm: refers to any of a class of cancerous tumor that is either a metastatic offshoot of a
primary tumor, or an apparently unrelated tumor that increases in frequency following certain cancer
treatments such as chemotherapy or radiation therapy. (e.g. Leukemia after treatment for Breast Cancer)
● The Cell Cycle
○ M phase: replicated chromosomes are packaged into two new nuclei and cytoplasm is divided between
two daughter cells
○ Interphase
○ G1: cell determines readiness to commit to DNA synthesis
○ S: DNA synthesis; genetic material is replicated
○ G2: errors are corrected
○ The hallmark of cancer is the deregulation of the mechanisms controlling cell cycle progression.
● Drivers of Cancer
○ The affected genes are divided into three broad categories:
■ 1. Proto-oncogenes are genes which promote cell growth and reproduction
■ 2. Tumor suppressor genes (e.g. BRCA, p53) are genes which inhibit cell division and survival
■ 3. DNA repair genes are genes that code for proteins that repair errors
● Malignant transformation can occur through:
○ The formation of novel oncogenes
○ The inappropriate over-expression of normal oncogenes
○ The under-expression or disabling of tumor suppressor genes
○ Typically, changes in many genes are required to transform a normal cell into a cancer cell.
● Mutations
○ Point mutations in tumor suppressor genes nonfunctional proteins
○ Large deletions - large chromosomal regions are deleted leading to loss of genes within those regions
○ Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal
locus, usually containing one or more oncogenes and adjacent genetic material.
○ Translocation occurs when two separate chromosomal regions become abnormally fused, often at a
characteristic location. A well-known example of this is the Philadelphia Chromosome, or translocation of
chromosomes 9 and 22, which occurs in some forms of leukemia, and results in production of the BCR-
abl fusion protein, an oncogenic tyrosine kinase.
● Tumor Angiogenesis
○ The growth of primary and metastatic tumors requires the recruitment of neighboring blood vessels and
vascular endothelial cells (EC)
○ Angiogenic switch: the ability of the tumor to promote the formation of new capillaries from pre-existing
host vessels
○ Stimuli include hypoxia, inflammation, genetic lesions in oncogenes or tumor suppressors that alter
tumor cell gene expression
○ A complex process:
■ Endothelial cells sprout from host vessels in response to VEGF, bFGF, Ang2 and other
proangiogenic stimuli.
■ Stimulated by: VEGF/VEGFR2, Ang2/Tie2, and integrin/extracellular matrix interactions.
■ Bone marrow derived circulating endothelial precursors (CEPs) migrate to the tumor in response
to VEGF and differentiate into ECs.

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 ■ Vessel formation is haphazard – tortuous, dilated, leaky and branch in random ways → uneven
blood flow, hypoxia, acidosis, and high intratumoral pressures that inhibit delivery of therapeutic
agents.
● Metastasis
○ Metastatic cancer is cancer that has spread from the place where it first started to another place in the
body. A tumor formed by metastatic cancer cells is called a metastatic tumor or a metastasis. The
process by which cancer cells spread to other parts of the body is also called metastasis.
○ The most common sites of cancer metastasis are the lungs, bones, and liver.
○ Common cancer sites and sites of metastasis:
■ Breast → lungs, liver, bones
■ Colon→ liver, peritoneum, lungs
■ Kidney → lungs, liver, bone
■ Lung → adrenal glands, liver, brain
■ Prostate → bones, lungs, liver
○ Local Invasion: Cancer cells invade nearby normal tissues.
○ Intravasation: Cancer cells invade and move through the basal membranes of nearby lymph vessels or
blood vessels
○ Circulation: Cancer cells move through the lymphatic system/bloodstream to other parts of the body.
○ Arrest and extravasation: Cancer cells arrest, or stop moving, in capillaries at a distant location. They then
invade the walls of the capillaries and migrate into the surrounding tissue.
○ Proliferation: Cancer cells multiply at the distant location to form small tumors known as
micrometastases.
○ Angiogenesis: Micrometastases stimulate the growth of new blood vessels to obtain a blood supply for
oxygen and nutrients needed for growth.
● Clinical Application
○ The patient is a 65 year-old man with PMH significant for hypertension and non-small cell lung cancer,
which was diagnosed 2 months ago. He is undergoing chemotherapy, which he has been tolerating well.
He presented to the ER after his wife notices that he has been having difficulty finding words and also
noted an incidence of “shaking” which lasted about 1-2 minutes and then resolved.
○ What are we thinking with this information?
■ Side effect of chemo?
■ Possible stroke or TIA given his history of HTN
■ New neurologic finding, like dementia or seizure disorder
■ Metastatic disease
● Staging
○ Used to determine the extent of disease
○ Clinical staging: based on physical exam, radiographs, CT, PET scans
○ Pathologic staging: includes histologic examination of tissues removed during a surgical procedure (e.g.
lymph node biopsy, thoracotomy, laparotomy)
● TMN
○ The most widely used system for staging
○ Categorizes the tumor based on anatomy:
■ T = size of primary lesion (T1-4)
■ N = presence of nodal involvement (N0 or N1)
■ M = presence of metastatic disease (M0 or M1)
○ Then this information is used to designate a Stage (I-IV)

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 ○ There is a chart to determine the stage based on T and N numbers, but +metastases →
always stage IV
● Exceptions
○ Dukes classification for colorectal cancers
○ International Federation of Gynecologists and Obstetricians (FIGO) for gynecologic cancers
○ Ann Arbor classification for Hodgkins Disease
○ Hematopoietic tumors (leukemia, myeloma, lymphoma)
● Performance Status
○ The second most important determinate of treatment outcome after tumor burden is the patient’s
physiologic reserve.

● Karnofsky Performance Index ≤ 30 - consider whether treatment of cancer will benefit the
patient
● Summary
○ Cancer is characterized by uncontrolled cell growth and ability to metastasize
○ Caused by environmental, lifestyle, infectious, and hereditary factors
○ Hallmark of cancer: deregulation of mechanisms controlling cell cycle progression
○ Cancer of the lung and bronchus is the number one cause of cancer death in men and women in the USA
○ Staging and performance status is used to determine prognosis and treatment plan

APPROACH TO THE PATIENT WITH CANCER

● Diagnosis
○ Diagnosis of cancer relies most heavily on tissue biopsy
○ In rare settings (thyroid nodules) fine needle aspiration is acceptable
○ Tissue is evaluated for histology of the tumor, its grade, its invasiveness, expression of cell surface
markers, intracellular proteins, or molecular markers
● Tumor Markers
○ Substances produced by tumor cells and other cells in response to cancer or certain benign conditions
○ Found in blood, urine, and tissue

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 ○ Different tumor markers are found in different types of cancer and levels of some tumor markers can be
elevated in more than one type of cancer
○ Tumor markers are not elevated in all people with cancer
○ They are used in detection, diagnosis, and management of some types of cancer
○ Although abnormal tumor markers may suggest cancer, this alone is not enough to diagnose cancer
○ AFP, CA-125, CA 19-9, HCG, CEA, PSA
● Can tumor markers be used for screening?
○ PSA is often used to screen for prostate cancer, but this is controversial
■ In 80% of cases, PSA is elevated due to BPH – leads to unnecessary biopsies
○ CA-125 is used as a screen for women with increased risk of ovarian cancer but it is not sensitive nor
specific enough to really do so
○ More often tumor markers are used to monitor response to therapy
■ Should be trending down with treatment
■ Periodically check level following treatment to see if it is stable or beginning to rise again (early
indication of recurrence)
● Treatment Plan
○ Determine extent of the disease
○ Staging
○ Predilection of tumors to spread to adjacent or distant organs
○ Performance Status
○ Biologic features of the tumor
● Treatment
○ Goal of treatment is to eradicate the cancer
○ If this cannot be done, then goal shifts to palliation, symptom relief, and quality of life
○ Remember: “There is nothing more we can do” is never really the case.
○ Curative: Serving or tending to cure. Of or relating to the cure of disease.
○ Palliate: to reduce the violence of (a disease); to ease (symptoms) without curing the underlying disease
○ Four broad types:
○ Surgery
○ Radiation therapy
○ Chemotherapy (including hormonal therapy)
○ Immunotherapy
○ Surgery and radiation = local treatments
○ Chemotherapy and biologic therapy = systemic treatments
● Adjuvant therapy
○ Treatment that is given in addition to the primary (initial) treatment. Adjuvant treatment is an addition
designed to help reach the ultimate goal.
○ Adjuvant therapy for cancer usually refers to surgery followed by chemotherapy or radiotherapy to help
decrease the risk of the cancer recurring.
○ Neoadjuvant therapy: hemotherapy and/or radiation therapy are given first to try and reduce the size of
the tumor and then surgery is attempted (e.g. in bulky testicular cancer and stage III breast cancer)
● Radiosensitization: the use of chemotherapy or other agents that increase the sensitivity of tissue to the effects
or radiation therapy, usually by inhibiting cellular repair or increasing the percentage of cells in mitotic phases of
the growth cycle.
● Cancer Treatment
○ Traditional: surgery, radiation, chemotherapy, combined modalities

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 ○ Hormonal: tamoxifen (breast cancer), arimidex, femara (breast cancer), lupron (prostate cancer)
○ Biologic Response Modifiers: monoclonal antibodies, cytokines, vaccines, tyrosine kinase inhibitors
Surgery
● Prevention
○ Premalignant lesions (skin, colon, cervix)
○ Those at increased risk of cancer from underlying disease (colectomy in those with ulcerative colitis), the
presence of a genetic lesion (bilateral mastectomy or oophorectomy for familial breast or ovarian), or a
developmental anomaly (orchiectomy in those with undescended testis)
● Diagnosis
○ Goal is to obtain as much tissue as safely possible.
○ Pathologists inspect the tumor for pattern of growth, degree of cellular atypia, invasiveness, morphologic
features, genetic abnormalities and protein expression patterns
● Staging
○ Pathologic staging defines the extent of involvement by documenting the histologic presence of tumor in
tissue biopsies (e.g. axillary lymph node sampling in breast cancer)
● Types of biopsies
○ Excisional biopsy – the entire tumor mass is removed with a small margin of normal tissue surrounding it
○ Incisional biopsy – wedge of tissue is removed
○ Core needle biopsy – when endoscope or fluoroscope is used for biopsy; considerably less tissue is
obtained
○ Fine needle aspiration – obtains only a suspension of cells within the mass (useful for thyroid nodule)
● Treatment
○ Surgery is the most effective means of curing cancer.
○ Goal: excise the tumor completely with adequate normal margins, touching the tumor as little as possible
to minimize spread, and minimizing operative risk
○ Even when not curative, surgery can help by:
■ - Locally controlling the tumor
■ - Preserving organ function
■ - Debulking to allow therapy to work better
● Palliation
○ Surgery may provide relief of otherwise intractable pain or neurologic dysfunction.
○ Cord compression
○ Chest tubes for pleural effusions
○ Bypassing GI tract, urinary tract or biliary tree
○ Stabilization of weight-bearing bones
● Rehabilitation - reconstructive surgery
Acute Complications of Chemotherapy: ***
● Myelosuppression
○ Neutropenia
■ Neutrophils usually make up 50-70% of WBC. They are the primary defense against infection.
■ Neutropenia occurs when the absolute neutrophil count (ANC) falls below a certain number
■ ANC is calculated: (% neutrophils + % bands) x WBC
■ Classified as: Neutropenia ANC < 1000; Severe Neutropenia ANC< 500; Profound Neutropenia
ANC < 100
■ Growth factors (G-CSF or GM-CSF) are given after chemo to reduce the duration of neutropenia

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 ○ Thrombocytopenia (low platelets) ----->
■ More common in hematologic
malignancies than with solid tumors
■ Symptoms: bruising, petechiae, purpura,
nosebleeds, bleeding gums, fatigue,
weakness
■ Transfuse to keep platelets > 10-20,000
or if signs of bleeding
○ Anemia (low red blood cells)
■ Symptoms: fatigue, weakness, dyspnea,
palpitations
■ Transfuse pRBCs to keep Hemoglobin >
7 in pts without CV history/risk factors or > 8 or if cardiac or symptomatic
● Chemotherapy Induced Nausea and Vomiting (CINV)
○ Most common side effect of chemotherapy is nausea with or without vomiting
○ Antineoplastic agents vary in their capacity to cause nausea/vomiting. Highly ematogenic (cisplatin) or
moderately ematogeneic (doxorubicin).
○ Overall, > 35% of patients experience acute nausea and 13% of patients experience acute vomiting
○ Highly ematogenic regimens: 60% experience delayed nausea and 50% experience delayed emesis
○ Delayed (or late) N/V: occurs > 24 hours after chemo. Associated with cisplatin, cyclophosphamide, and
others given at high doses over 2 or more consecutive days
○ Emesis: reflex caused by stimulation of the vomiting center in the medulla. In addition a conditioned
reflex may contribute to anticipatory nausea and vomiting.
○ Can arise from: GI tract, chemoreceptor trigger zone (CTZ), vestibular apparatus, cerebral cortex
○ Activation of CTZ is driven by the neurotransmitters serotonin and substance P
● Antiemetics (most commonly used are highlighted)
○ Differ in locus of action; combine agents from different classes; prophylactic administration
○ 5-HT3 Antagonists
■ dolasetron, granisetron, ondansetron (Zofran)
■ palonosetron (Aloxi): delayed N/V
○ Neurokinin 1 Receptor Antagonists - given for delayed N/V
■ arepitant (Emend); oral
■ fosaprepitant (Emend); IV
○ Corticosteroids
■ Dexamethasone - augments the action of other antiemetics; given before and during treatment
■ Methylprednisone
○ Miscellaneous Agents
■ Metoclopramide (Reglan) – gastric motility agent
■ Prochlorperazine (Compazine) - antidopaminergic
■ Cannabinoids – increases appetite and decreases nausea
■ Benzodiazepines
■ Antihistamines
● Alopecia
○ Loss of hair from the head or body
○ Anthracyclines, alkylating agents, and topoisomerase inhibitors cause near total alopecia
○ Scalp cooling for prevention

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 ○ Psychological support
○ Cosmetic resources (many insurances will cover wigs and head wraps)
● Mucositis
○ Inflammation of the mucous membranes lining the digestive tract from the mouth on down to the anus.
Mucositis is a common side effect of chemotherapy and of radiotherapy that involves any part of the
digestive tract.
○ Mucositis affects the rapidly dividing mucosal cells lining the mouth, throat, stomach, and intestines.
These cells normally have a short life span. The therapy can destroy the cells quickly and they are not
replaced right away.
○ Mucositis due to chemotherapy typically begins 3 to 5 days after the start of therapy, peaks at 7 to 10
days, and slowly subsides over the next week.
○ Mucositis due to radiation usually appears toward the end of the second week of treatment, plateaus
during the fourth week of radiation, and may persist for 2 to 3 weeks after treatment is over.
○ Mucositis is a consequence of cytotoxic (cell-killing) therapy. The major complications of mucositis are
pain, infections, and (less commonly) bleeding. Good mouth care is essential.
○ It is extremely painful, can interfere with eating, drinking, taking meds, and may require pain medication
for 1-2 weeks until the tissues recover.
■ Convert medications to IV (also for patients with n/v)
Radiation Therapy
● Radiation damages DNA in the target tissue.
● Teletherapy – beams of radiation generated at a distance and aimed at the tumor within patient
● Brachytherapy – encapsulated radiation implanted directly in or adjacent to the tumor
● Systemic therapy – radionucleotides targeted to a site of tumor
● A component of curative therapy in patients with Hodgkin’s Lymphoma, breast cancer, head and neck cancer,
prostate cancer, and gynecological cancer.
● Palliation of symptoms: relief of bone pain from metastatic disease, control of brain metastases, reversal of
spinal cord compression.
● Gamma Knife Radiosurgery
○ aka stereotactic radiosurgery
○ Beams of highly focused gamma rays to treat small to medium sized lesions in the brain
○ Provides very intense and precisely focused beams of radiation
○ One session treatment
○ Minimal effect on surrounding tissue
○ Steps: head frame placement, tumor location (CT/MRI), radiation dose planning, radiation treatment
● Toxicity***
○ Systemic effects: fatigue, anorexia, nausea, vomiting
○ Male testis, female ovary and bone marrow are most sensitive.
○ Heart, skeletal muscle and nerves are more resistant
○ Vascular endothelium is most sensitive → mucositis, skin erythema
○ Chronic Toxicity
■ Head and neck: thyroid failure, cataracts, salivary gland failure
■ Mediastinum: fatal myocardial infarction, pulmonary fibrosis, radiation enteritis
■ Secondary solid tumors: women < 30 y.o. with radiation to the mediastinum have a >100 fold
increase in the incidence of breast cancer

ONCOLOGIC EMERGENCIES

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 ● Objectives
○ Identify patients at risk for having oncologic emergencies
○ Describe signs and symptoms of common oncologic emergencies
○ Identify how to treat and manage common oncologic emergencies
● Definition: complications resulting from a cancer itself, a paraneoplastic syndrome, or from treatment of the
cancer, that require immediate attention and reversal, if possible.
○ Inpatient treatment is a must, and often these conditions require intervention in an intensive care setting
● Can occur at any time in the course of the disease
○ Can be first indication of disease
○ During active treatment
○ First sign of recurrence
● Not strictly confined to period of diagnosis and active treatment
● Prompt identification and intervention can prolong life and improve quality of life
● Types
○ Metabolic: Tumor Lysis Syndrome, Hypercalcemia, Hyponatremia, Hypoglycemia
○ Cardiovascular: Pericardial Effusion and Tamponade, Superior Vena Cava Syndrome
○ Infectious: Neutropenic Fever
○ Neurologic: Malignant Spinal Cord Compression, Increased Intracranial Pressure
○ Hematologic: Hyperviscosity Syndrome, Leukostasis, Disseminated Intravascular Coagulation (DIC)
○ Respiratory: Malignant Airway Obstruction
Hypercalcemia
● Experienced by up to 30% of patients with cancer
● Among hospitalized patients with hypercalcemia, malignancy is most common cause
● Breast, lung, and renal cell carcinomas; multiple myeloma, T-cell leukemia/lymphoma
● Prostate cancer, though it often metastasizes to bones, rarely causes hypercalcemia
● Pathophysiology
○ Caused by: increased osteoclastic activity induced bone resorption, decreased renal excretion, or
increased gut absorption
○ Two categories: local bone metastases induced osteoclastic activity and humoral hypercalcemia of
malignancy (HHM)
○ HHM is caused by systemic release of parathyroid hormone-related peptide (PTHrP), which does not
require the presence of bone metastases. PTHrP causes bone resorption and renal retention of Ca++,
much like parathyroid hormone (PTH).
○ Local bone metastases induced osteoclastic activity causes bone resorption increasing levels of Ca++ in
blood
● Presentation
○ Symptoms tend to be nonspecific; “bones, stones, moans, groans”
○ Bone pain usually related to discrete metastases
○ Nephrolithiasis can occur
○ Abdominal pain from impaired intestinal motility, pancreatitis, constipation, nausea, anorexia
○ Changes in mental status from lethargy to coma
○ Shortened QT interval → arrhythmias
● Diagnosis
○ Ionized calcium is most reliable
○ If total Ca++ is used, correct for albumin
○ Rate of increase more significant than magnitude

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 ○ Measurement of PTHrP not proven to affect outcomes
● Treatment
○ Hydration is the cornerstone to management, then +/- loop diuretics to promote calciuresis
○ Bisphosphonates block osteoclastic bone resorption: Ca++ declines within 48-96 hours and nadirs at 1
week (Zolendronic acid or Pamidronate)
○ Calcitonin (IM or subcutaneous) provides more rapid lowering (12-24 hours) but effect is short lived;
nasal administration not effective. Not to be used as a single agent (maybe adjunct).
○ Steroids can help mediate the release of cytokines and prostaglandins that stimulate osteoclasts
○ Hemodialysis may be necessary
○ Denosumab can be used in certain settings (if patient is refractory)
● Case: GG (6/19/18)
○ 75 yo M with PMH HTN, BPH, CLL (previously on ibrutinib), recurrent hypercalcemia admitted for
confusion, cough, tonsillar swelling, hypoxia.
○ VS: T 36.9C, HR 82, BP 166/79 RR 20 SpO2 94% RA
○ 6/19: Normal Saline at 175 ml/hr and Pamidronate 90mg x 1
○ 6/20: Transferred to ICU for hypercapneic respiratory failure. Normal Saline at 225 ml/hr; I/O = 7626/1460
(+6100ml)
○ 6/21: Normal Saline 300 ml/hour with UOP goal ~100 ml/hr; I/O = 8430/4100 (+4330ml)
○ 6/22: Discontinue normal saline. Start Lasix 40mg IV. I/O = 2744/4370 (-1600ml)
■ Intravascular volume
restored, then diuretic
given
○ Calcium from 6/19-6/24:
Malignant Spinal Cord Compression (MSCC)
● Most common location: thoracic spine, then lumbosacral, then cervical
● Single most important prognostic factor for regaining ambulation after treatment of MSCC is pretreatment
neurologic status
● Pathophysiology
○ Compressive indentation, displacement, or encasement of the thecal sac that surrounds the spinal cord
or cauda equina by cancer
○ Posterior extension of a vertebral body mass, anterior extension or a mass from the dorsal elements, or
mass invading vertebral foramen
○ Majority of cases occur when metastatic tumor reaches vertebral body and erodes into epidural space
● Presentation
○ Most common presenting symptom is back pain
○ Back pain may worsen gradually and precedes neurologic symptoms by weeks to months
○ Neurologic symptoms: motor weakness, sensory impairment, autonomic dysfunction
○ Cauda equina syndrome: urinary retention, overflow incontinence, decreased sensation (buttocks,
posterior thighs, perineal regions)
○ Physical exam may reveal: tenderness to percussion over the affected spinal region, hyperreflexia,
spasticity, loss of sensation
○ Late findings: weakness, Babinski, decreased anal sphincter tone
● Diagnosis - gold standard for diagnosis is MRI of the total spine and should include entire thecal sac
● Treatment
○ Steroids are an integral component of initial therapy
○ Begin empirically if MSCC suspected

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 ○ Usually Dexamethasone 10mg or 16mg IV bolus followed by 4mg Q 6 hrs (16mg daily in divided doses)
○ If evidence of MSCC on imaging, consults to neurosurgery and radiation oncology
● Case: CR (01/21/2018)
○ 66y F with no PMH transferred in for newly found thoracic epidural metastasis
○ Patient was in usual state of health until 2 weeks ago when she developed numbness in her upper legs
○ Four days ago: numbness progressed to weakness/gait instability when she fell out of her sitting chair
and was unable to stand up
○ Three days ago: admitted to OSH and found to have dorsal thoracic epidural metastasis, L > R from T3-7,
worst at T4-5 with loss of CSF signal and severe cord deformation, with extension of met into pedicles at
4-5 and out laterally into paraspinal region
○ Two days ago: requiring max assistance despite dexamethasone 4mg every 6 hours
○ Transferred to our ER. Neurosurgery consulted.
○ Continued to report LE weakness and imbalance, sensory disturbance below T4 level, but no
bowel/bladder dysfunction
○ Exam: Awake, Alert, Oriented x3, Attends, Follows commands
○ Babinski left, Brisk patella, T4 sensory level, Intact proprioception, No clonus
○ Emergent OR for spinal decompression
Febrile Neutropenia (FN)
● Neutropenia is determined by the Absolute Neutrophil
Count (ANC) = the sum of circulating segmented and
band neutrophils [ANC = (%neutrophils + %bands) x
(WBC)/(100)]
● Decline in ANC due to cancer’s direct effect on
hematopoiesis or due to side effects of therapy
● The Infectious Disease Society of America defines fever in neutropenic patients as a
single temperature measurement (oral or TM) of ≥ 38.3°C (101°F) or a temperature of >
38°C (100.4°F) for > 1 hour
● Timing
○ Depends on the chemo agent(s) but neutrophil nadir occurs 5-10 days after the last dose of chemo
○ Regimens used to treat leukemias and lymphomas tend to cause a longer lasting and more profound
neutropenia
○ Most often, WBC recovery occurs 5 days after this nadir
● Pathophysiology
○ Few cases of FN will yield a causative organism
○ Gram positive cocci (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae,
Streptococcus pyogenes, Streptococci viridans, Enterococcus faecalis and faecium)
■ Seeing more often due to more pts having indwelling catheters
○ Gram negative bacilli (Escherichi coli, Klebsiella species, Pseudomonas aeruginosa)
○ Fungal: Candida, Aspergillus, Zygomycetes
● Presentation/Diagnosis
○ Fever may be the sole manifestation of infection
○ Detailed history (ROS, antibiotic prophylaxis, history of prior infections, co-morbidities)
○ Physical exam: skin, catheter sites, oral cavity, lungs, abdomen, GU, perianal; avoid DRE and meds PR
○ Labs: CBC with diff, CMP, UA, blood/urine cultures
● Diagnosis

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 ○ Micro: two sets of blood cultures; if catheter is present, set of cultures from each lumen (ideally) plus
peripheral
○ If catheter cultures become positive at least 120 minutes before peripheral cultures, it strongly suggests
the catheter is the source
○ Sputum, stool, CSF cultures only if clinical suspicion of infection
○ Imaging: CXR (usually show nonspecific findings); +/- CT
● Management
○ FN should be treated as a medical emergency
○ Broad spectrum empiric antibiotics should be administered within 60 minutes (TTA)
○ Cover gram positive and gram negative organisms
○ Monotherapy with: Cefepime, a carbapenem, or piperacillin-tazobactam; all offer antipseudomonal
activity
○ Add Vancomycin for skin/soft tissue infections, mucosal damage, pneumonia, suspicion of infected
line/device
○ Continue antibiotics until ANC > 500
○ Catheter infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, fungi, or mycobacteria
warrant catheter removal followed by a minimum of 14 days of antimicrobials
● Supportive Care
○ For rigors or shivering, Meperidine can be given at low doses and for a short period of time; e.g. 12.5-
50mg Q 15-20 minutes until symptoms are controlled
○ Acetaminophen can be given once the patient spikes a fever. Acetaminophen is avoided in general in
neutropenic patients as it can mask a fever
● Case: JG
○ 42 y/o M with relapsed, refractory AML s/p multiple therapies currently on hydroxyurea presents to the ER
with two isolated fevers at home. He reports fatigue, intermittent cough, chronic abdominal pain and no
BM x 2 days. Remainder of ROS negative.
○ VS: T 37.5C, HR 108, BP 105/68, RR 20 SpO2 98% on RA
○ Labs: WBC 24.45, 42% blasts
○ Draw blood cultures (PICC), urine culture, respiratory PCR
○ Start empiric Vancomycin and piperacillin-tazobactam
○ CT C/A/P (chest/abd/pelvis)
○ Admit
Tumor Lysis Syndrome
● Pathophysiology
○ Occurs when cancer cells release their contents into the bloodstream either spontaneously or after
antineoplastic therapy electrolytes and nucleic acids into circulation
○ Hyperuricemia → crystalization in renal tubules → obstruction
○ Hyperkalemia → arrhythmias
○ Hyperphosphatemia → hypocalcemia → tetany, seizures
○ Leads to end organ effects on myocardium, kidneys, and CNS
○ More common in rapidly proliferating hematologic malignancies, e.g. ALL, AML, and Burkitt lymphoma
● Diagnosis
○ Clinical Tumor Lysis Syndrome
■ Creatinine ≥ 1.5x the upper limit of normal
■ Cardiac arrhythmias or sudden death
■ Seizure

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 ○ Laboratory Tumor Lysis Syndrome
■ Uric acid ≥ 8 mg/dL or 25% increase from baseline
■ Potassium ≥ 6.5 mg/dL or 25% increase from baseline
■ Phosphorus ≥ 6.5 mg/dL or 25% increase from baseline
■ Calcium ≤ 7 mg/dL or 25% decrease from baseline
■ Check labs every 6 hours
● Keys to Management
○ Appropriate prophylaxis
○ Vigilant monitoring of electrolytes in patients undergoing chemotherapy
○ Initiation of more active treatment measures when it becomes necessary
● Treatment
○ Prophylaxis with Allopurinol, which inhibits xanthine oxidase → decreases uric acid production
○ Allopurinol given up to 48 hours before treatment and maintain good hydration status
○ Rasburicase, a recombinant urate oxidase, converts uric acid into water-soluble allantoin
■ Treatment once the uric acid has gone up
○ Alkalization of the urine recommended in the past however not routinely done due to the prevalence of
hyperphosphatemia and the increased formation of calcium phosphate crystals
○ Treat hyperkalemia with loop diuretics, insulin/glucose, albuterol
○ Hyperphosphatemia is managed with a low phos diet and/or a short term oral phosphate binder
○ Calcium gluconate can be given to stabilize myocyte membranes
○ Dialysis may be required to treat refractory, life-threatening electrolyte derangements
● Case: SZ (07/18/2018)
○ 74F w/ AML (FLT3, NPM1 negative and complex karyotype) s/p Vyxeos with course complicated by GI
bleed, probable fungal PNA, and recurrent fevers admitted with neutropenic fever, anemia and
thrombocytopenia and concern for relapsed disease
○ Labs compared to 6 weeks before: uric acid 2.9 → 8.8, LDH 265 → 1073, WBC 3.43 →
42.88
○ Increase normal saline rate
○ Start Allopurinol - can still give even though uric acid is already forming
○ Check G6PD to ensure it is okay to give Rasburicase
○ Monitor labs every 8 hours; adjust as indicated
Summary
● Oncologic emergencies require prompt identification and intervention
● Can improve quantity and/or quality of life
● Hypercalcemia is managed with aggressive hydration and bisphosphonate therapy
● When spinal cord compression is suspected, steroids should be started immediately
● Febrile neutropenia requires prompt blood cultures and initiation of empiric antibiotics
● The keys to managing tumor lysis syndrome are prevention, vigilant monitoring of electrolytes, and intervention
when needed

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1. contraindications in the management of vWD
2. The sites of production of blood cells
3. Know examples of the various types of anemia
4. know the features of sickle cell disease. Be able to diagnosis based on presentation
5. The manifestations of Vit B12 deficiency
6. manifestations of G6PD deficiency
7. clotting factors and their associations with the vitamins
8. the handling of iron by the body: storage, transport, etc
9. demographics of sickle cell disease
10. presentation of iron deficiency anemia
11. presentation of folate deficiency anemia
12. distinguish between folate and B12 deficiency anemia
13. factor XI deficiency
14. be able to make the diagnosis of a bleeding disorder based in PT, PTT, bleeding time, etc
15. the manifestations of multiple myeloma
16. distinguish among the WBC disorders; CML, CML, etc
17. diagnosis of Vit B12 deficiency based on presentation
18. diagnosis of vWD deficiency based on presentation
19. The hemophilias
20. Factor XI deficiency
21. The work up of a patient with lymph node abnormalities
22. features if iron deficiency anemia
23. hodgkin’s vs non-hodgkin’s lymphoma. know the characteristic features
24. polycythemia vera
25. distinguish among ALL, AML, CLL, CML
26. management of hodgkin’s lymphoma
27. ITP
28. management of DVT
29. features of Vit K deficiency
30. management of multiple myeloma
31. know the characteristic findings of the various blood disorders (smear findings)
32. Features of pernicious anemia
33. presentation and management of autoimmune anemia
34. aplastic anemia
35. management of AML
36. diagnostic work of WBC disorders
37. significant SE of chemo and radiation
38. burrkit’s lymphoma

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