Chapter 22: Disorders of Hemostasis

5 stages of Hemostasis
1.​ Vessel spasm
a.​ Vessel spasm constricts vessel reduce blood flow
b.​ Initiated by Endothelial injury
c.​ endothelium triggers local and humoral mechanisms
i.​ (Lasts minutes or hours)
d.​ Vasoconstriction Contributors
i.​ Neural reflexes
ii.​ Thromboxane A2(TXA2)--produce by activated platelet
iii.​ Prostaglandins(release form platelet)
1.​ Prostacyclin (another prostaglandin), but released from vessel
endothelium has effects in surrounding blood vessels
a.​ Produces vasodilation and inhibits platelet aggregation in
the surrounding uninjured endothelium
iv.​ Other mediators(serotonin)
v.​ Endothelin is released from vascular endothelium(most powerful)
2.​ Formation of the platelet plug
a.​ Platelet plug formation involves activation, adhesion, and aggregation of
platelets.
i.​ Platelets are attracted to a damaged blood vessel wall
ii.​ Become activated by factors in the subendothelial tissue
iii.​ Activated, change their shape form smooth disks to spiny spheres
iv.​ Expose a number of receptors on their surface
b.​ Platelet (Thrombocytes)
i.​ Produce in the bone marrow and needed for blood clotting
ii.​ Half-life 8 to 12 days
iii.​ Normal concentration 150,000 to 400,000 per microliter of blood
iv.​ Thrombocytes arise from where?
1.​ Megakaryocytes.
v.​ Platelet production is controlled by what protein?
1.​ Thrombopoietin.
vi.​ What does thrombopoietin do?
1.​ Causes proliferation and maturation of megakaryocytes.
vii.​ Sources of thrombopoietin include?
1.​ Liver, kidney, smooth muscle, bone marrow.
viii.​ Platelets are capable of producing ATP and can produce prostaglandins,
and thromboxane A2, required for their function in the hemostasis
process.
ix.​ Platelet adhesion(sticking to the vessel surface) requires a protein called
von Willebrand factor(VWF)
 1.​ VWF is produced by endothelial cells of blood vessels and
circulates in the blood as a carrier for coagulation factor VIII(factor
8)
2.​ Adhesion occurs when the platelet receptor bind with VWF at the
injure site, linking the platelet and exposed collagen
x.​ Platelets aggregate together→ requires participation of ADP, ATP,
Calcium and TXA1. → expands and becomes the primary hemostatic
platelet plug→ stabilized by activation of the coagulation processes,
which creates a fibrin mesh around the platelets.
c.​ GP llb/lla is an important glycoprotein
i.​ Binds fibrinogen and connect platelets to one another
d.​ Lack vWF can delayed clotting
e.​ Platelet inhibitors are important drugs that work at different points in the platelet
adhesion-activation-aggregation process
i.​ Cyclooxygenase-1(COX-1) inhibitors(aspirin) to reduce clot formation
1.​ Prevent clots in people with atherosclerotic vessel disease; high
risk for MI(Heart attack) or stroke
a.​ Clot formation can cause MI, stroke, or vascular occlusion
ii.​ Low-dose aspirin therapy inhibits prostaglandin synthesis(including
thromboxane A2)
iii.​ Thienopyridines(clopidogrel and ticlopidine) achieve their antiplatelet
effects by blocking ADP action in platelets→no effect on prostaglandin
synthesis
3.​ Blood coagulation or development of an insoluble fibrin clot
a.​ Coagulation cascade is a set wise process resulting in the conversion of soluble
plasma protein fibrinogen into insoluble Fibrin
b.​ Most of the coagulation factors are proteins which are made in the liver
i.​ Vitamin K is necessary synthesis
1.​ Factors II, VII, IX, X(Factors 2,7,9,10)
2.​ Prothrombin(converts to thrombin)
3.​ Protein C
4.​ Vit K deficiency or liver dysfunction→ clotting dysfunction
c.​ Two pathways (Intrinsic and extrinsic) in the coagulation process
i.​ Intrinsic(blood or vessel injury): is relative slow process(1-6 min)begins in
the circulation with activation of Factor XII(factor12)
1.​ Activated when blood comes in contact with collagen
ii.​ Extrinsic(Tissue factor) much faster(15 sec) begins with trauma to
thromboplastin(lipoprotein ) form subendothelial class
1.​ Activated when blood is exposed to tissue extracts
iii.​ The terminal step in both pathways are the same
1.​ Calcium, Factor X and V, and platelet phospholipids combine to
form prothrombin activator
2.​ Activation of prothrombin converted to thrombin (Facilitated by
factor Xa)
 3.​ This interaction cause thrombin facilitates conversion of fibrinogen
into fibrin
4.​ Formation of fibrin mesh stablizeds clot
d.​ Blood cells are trapped in fibrin mesh
e.​ They shrink and plasma squeezed out of them→silidifying clot
f.​ Regulation of Blood coagulation
i.​ Antithrombin III: is complexed with naturally occurring heparin
1.​ Inactivates coagulation factors
2.​ Neutralizes thrombin
ii.​ Protein C(Factor V Ledien): a plasma protein
1.​ Anticoagulant by inactivates factors V and VII (5 and 7)
2.​ Produced in the liver and prevent thrombosis
3.​ Protein S, amplifies action of protein C
iii.​ Plasmin: acts as an anticoagulant
1.​ Breaks down fibrin into fibrin degradation products
g.​ Anticoagulant drug: prevent thromboembolic disorder
i.​ Warfarin: decreasing prothrombin and other procoagukation factors
1.​ Interferes with Vit K component coagulation in the coagulation
cascade
ii.​ Heparin: naturally formed and released in small amounts by mast clees in
tissues surrounding capillaries
1.​ Binds to antithrobin III, reduced activation of thrombin and other
clotting factors
2.​ Suppresses the formation of fibrin
4.​ Clot retraction
a.​ Formation of the clot, begins process of healing the broken tissue
b.​ Occurs within 20-60 minutes after a clot has formed
c.​ Process of rejointing edges of broken vessel
d.​ Squeezes serum form the clot to join the edges of the broken vessel
e.​ FAILURE of clot retractions is indicative of low platelet count
5.​ Clot dissolution
a.​ Begins shortly after clot formation
b.​ Allows for blood flow to be reestablished and permanent tissue repair
c.​ Process by which a blood clot dissolves FIBRINOLYSIS
d.​ Clot dissolution is controlled by activators and inhibitors and requires a sequence
of steps
e.​ Termination of clotting, connective tissue replaces clot→ wound healing and new
tissue formation
i.​ The clot is not longer needed
ii.​ Dissolution of clot is part of clotting cascade process
iii.​ Plasminogen is (inactive protein in tissue) binds to fibrin and is
incorporated into the clot
 1.​ Its converted to plasmin by plasminogen activators and digests the
fibrin strands of the clot and certain clotting factors. (aka
fibrinolysin)
iv.​ Plasmin breaks down the fibrin mesh
f.​ Circulating plasmin is rapidly inactivated by α2-plasmin inhibitor

Key Differences
Feature Platelet Component (Primary Coagulation Process (Secondary
Hemostasis) Hemostasis)

Main Forms a temporary platelet plug Reinforces the plug with a fibrin mesh
Function

Key Players Platelets, vWF, collagen Clotting factors (II, VII, IX, X, etc.),
fibrinogen

Time Frame Immediate (seconds to minutes) Slower (minutes)

End Platelet plug Stable fibrin clot

Product

Disorders of hemostasis
●​ Thrombosis(Excessive clotting):The inappropriate formation of clots within the vascular
system
●​ Bleeding(Insufficient clotting ):Failure of blood to clot in response to appropriate stimulus

Hypercoagulability States高凝状态:
●​ Hypercoagulability represents and exaggerated form of hemostasis that predisposes to
thrombosis and blood vessel occlusion (BLOCKAGE/ blood clot)
○​ Two Forms of Hypercoagulability states
■​ Condition that increases platelet function
■​ Condition that cause accelerated activity of the coagulation system
●​ Arterial Thrombi: are usually due to turbulence and composed largely of platelet
aggregates
○​ Reducing risk of arterial thrombi→ ANTI PLATELET MEDICATION
●​ Venous Thrombi are usually to stasis(stoppage) of flow and composed largely of platelet
aggregates
○​ Reducing risk of Venous Thrombosis→ ANTICOAGULANT
MEDICATION(Heparin, warfarin)

Conditions Associated with Hypercoagulability States

●​ Increased Platelet Function
 ○​ Atherosclerosis
○​ Diabetes mellitus
○​ Smoking
○​ Elvated blood lipid and cholesterol levels
○​ Increased platelet levels
●​ Accelarated Activity of the Clotting System
○​ Pregnancy and the puerperium
○​ Use of oral contraceptives
○​ Postrurgical state
○​ Immobility
○​ Congestive heart failure
○​ Malignant disease

Hypercoagulabilty Associated with Increased Platelet Function

●​ Hypercoagulability because of increased platelet function results in platelet adhesion,
formation of platelet clots, and disruption of blood flow.
○​ Causes of increase platelet function are:
■​ Disturbances in flow
●​ Atherosclerotic plaques (buildup of fats, cholesterol in and on
artery wall) disturb blood flow causing endothelia damage and
promoting platelet adherence.
■​ Endothelial damage
●​ Smoking, elevated levels of blood lipids and cholesterol,
hemodynamic stress (response to standing).
●​ Diabetes mellitus predisposes to vessel damage, platelet
adherence, and eventual thrombosis
■​ Increased sensitivity of platelets to factors that cause adhesiveness and
aggregation.

Thrombocytosis
●​ Elevations in platelet count above > 1,000,000/µL (seldom exceeds).
●​ Thrombosis can occur as a reactive process (secondary) or as an essential process
(primary)

●​ Etiology and Pathogensis

○​ Thrombopoietin is the key hormone that regulates the process of platelet
formation from megakaryocytes
○​ Megakaryocytes and platelets have receptors for thrombopoietin.
 ○​ Thrombopoietin is carried in the plasma; platelet production is normally controlled
by negative feedback mechanism related to platelet count.
Primary thrombocytosis is a disorder of the bone marrow, which it over produces platelets
○​ Abnormalities in the body→higher than needed levels of circulation
thrombopoietin
■​ Since thrombopoietin triggers platelet formation from megakaryocytes,
and excess → over production
Inherited Disorder
●​ A common hereditary thrombophilia, factor V Leiden, causes activated protein C
resistance.
●​ Hypercoagulability is associated with increased risk of VTE.
●​ High morbidity and mortality are associated with VTE.
●​ VTE, which includes pulmonary embolism and deep vein thrombosis is mostly acquired,
not genetic
Secondary thrombocytosis is due to disease states that stimulate thrombopoietin production
○​ → increased megakaryocyte proliferation and platelet production.
○​ In this case, platelet count seldom exceeds 1,000,000/μL.
○​ Common underlying causes of secondary thrombocytosis include tissue damage
from surgery, infection, cancer, and chronic inflammatory conditions such as
rheumatoid arthritis and Crohn disease.
○​ Usually, there are no signs other than those of the underlying condition
Acquired Disorder
●​ Venous stasis: Stasis of blood flow causes accumulation of activated platelets and
clotting factors
●​ Venous stasis can be due to bed rest/immobility, reduction in cardiac output, cancer,
elevated estrogen, smoking, obesity, oral contraceptives.
●​ Malignancy: People with a malignancy develop VTE more often than those without a
malignancy
●​ Approximately 20% to 25% of those presenting with primary VTE will be found to have
an occult malignancy
●​ Heart failure also contributes to venous congestion and thrombosis.
●​ Clotting factors are also increased during normal pregnancy; can predispose to venous
thrombosis.

Venous thromboembolism prevention

●​ low-molecular-weight heparin, unfractionated heparin, and compression stockings and/or
intermittent pneumatic stockings.

●​ Thrombocytosis may occur as part of other myeloproliferative disorders, such as

polycythemia vera (excess RBC) and myelogenous leukemia (excess WBC)
●​ Common clinical manifestations of essential thrombocytosis are thrombosis and
hemorrhage.
 ○​ Dysfunction of the platelets produced contributes to the major clinical features of
bleeding and thrombosis.
○​ Thrombotic events include:
■​ Deep vein thrombosis
■​ Pulmonary embolism
■​ Portal and Hepatic Vein Thrombosis
○​ Some patients experience erythromelalgia a painful throbbing and burning of the
fingers caused by occlusion of the arterioles by platelet aggregates.
○​ The disorder is characterized by long asymptomatic periods punctuated by
occasional thrombotic episodesand hemorrhage crisiso
○​ ** INCREASES THE RISK OF CLOT OR THROMBUS FORMATION IN
ARTERIAL/VENOUS CIRCULATION
○​ Treatment
■​ Platelet-lowering drugs (hydroxyurea) in high-risk cases.
■​ Aspirin in adjunctive therapy

Bleeding Disorder (impaired)

●​ Bleeding because of platelet disorders reflects a decrease in platelet number because
of:
○​ Decreased production
○​ Increased destruction
○​ Impaired function of platelets
●​ Spontaneous bleeding from platelet disorders most often involves small vessels of the
mucous membranes and skin.
○​ Common sites of bleeding: Mucous membranes of the nose, mouth, GI tract and
uterine cavity.
●​ Cutaneous bleeding is seen as pinpoint hemorrhages (petechiae) and purple areas of
bruising (purpura) in a dependent area where the capillary pressure is higher.
●​ Petechiae are seen almost exclusively in conditions of platelet deficiency NOT platelet
dysfunction

Thrombocytopenia
●​ Decrease in the number of circulating platelets to a level less than < 150,000/µL; can
result from a decrease in platelet production, increased sequestration of platelets in the
spleen, or decreased platelet
●​ Thrombocytopenia is an important cause of generalized bleeding. The greater the
decrease in platelet count the greater the risk of bleeding.
●​ Depletion of platelets must be relatively severe before spontaneous bleeding occurs
●​ Decreased platelet production because of loss of bone marrow function occurs in
aplastic anemia.
●​ HIV Infection or cytomegalovirus may suppress the production of megakaryocytes, the
platelet precursors.
●​ Thrombocytopenia can result from reduced platelet survival
●​ Caused by a variety of immune and nonimmune mechanisms.
 ●​ Platelet destruction may be caused by antiplatelet antibodies.
●​ The antibodies target the platelet membrane glycoproteins GPIIb/IIIa and GPIb/IX.
●​ Nonimmune destruction of platelets results from mechanical injury because of prosthetic
heart valves or from narrowed blood vessels
●​ DIC: acute disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic
purpura (TTP), excessive platelet consumption leads to a deficiency.
Drug-Induced Thrombocytopenia
• Some drugs, such as aspirin, atorvastatin, and some antibiotics, may cause drug-induced
immune thrombocytopenia (DITP).
• Induce an antigen–antibody response and formation of immune complexes that cause platelet
destruction.
• In people with drug-associated thrombocytopenia, there is a rapid fall in the platelet count
within 7 days of starting or 2-3 days or resuming drug
• The platelet count rises rapidly after the drug is discontinued.

Heparin-Induced Thrombocytopenia
• Heparin-induced thrombocytopenia (HIT) is associated with the anticoagulant drug heparin.
• Ten percent of people treated with heparin develop a mild, transient thrombocytopenia within 2
to 5 days of starting the drug
• Small % of these experience life-threatening thromboembolic events 1 to 2 weeks after the
start of therapy
• HIT is caused by an immune reaction directed against heparin and against platelet factors
• Binding of antibody to platelet factor while destroying some, activates the rest of the platelets,
leading to thrombosis.
• Treatment: immediate discontinuation of heparin therapy and the use of alternative
anticoagulants to prevent thrombosis recurrence.
• Low molecular weight heparins: lower incidence than older, high molecular weight heparins

immune Thrombocytopenic Purpura

• ITP is due to platelet antibody formation and excess destruction of platelets.
• Primary ITP is an autoimmune disease in which platelets are directly destroyed or inhibited in
production by the immune system.
• Incidence is highest in females aged 30 to 59 and in persons older than 60 years
• Autoimmune disorders and chronic infections such as Helicobacter pylori, hepatitis C virus,
and HIV contribute to secondary forms of ITP.

Clinical Manifestations.
• bruising, bleeding from gums, epistaxis (i.e., nosebleed), melena, and abnormal menstrual
bleeding in those with moderately reduced platelet counts.
• Because the spleen is the site of platelet destruction, splenic enlargement may occur.
• The condition may be discovered incidentally or as a result of signs of bleeding, often into the
skin (i.e., purpura and petechiae) or oral mucosa.
Diagnosis and Treatment.
• Diagnosis of ITP is usually based on severe thrombocytopenia (platelet counts <20,000 to
30,000/μL) and exclusion of other causes.
• Tests for the platelet-bound anordertibodies are available but lack specificity (e.g., they react
with platelet antibodies from other sources).
• The decision to treat ITP is based on the platelet count and the degree of bleeding. Many
people with ITP do well without treatment. Corticosteroids
are usually used as initial therapy. Other effective initial treatments include intravenous
immunoglobulin. However, this treatment is expensive, and
the beneficial effect lasts only 1 to 2 weeks.

Clotting defects
• Deficiencies can arise because of defective synthesis, inherited disease, or increased
consumption of the clotting factors
• Hereditary disorders
• Hemophilia A
• Hemophilia B
• Von Willebrand disease
• Any genetic disruption of the production of clotting factor

Disseminated Intravascular Coagulation (DIC):

●​ DIC is a life threatening complication (usually of serious illness i.e. sepsis) that occurs
when the normal clotting system behaves abnormally
●​ Begins when tissue factor (thromboplastin) is produced and exposed to blood
●​ Thromboplastin triggers the coagulation cascade, which also includes the fibrinolytic
pathway (to break up clots when no longer needed)
●​ Activation of the fibrinolytic pathway causes the release of tissue plasminogen activator
(t-PA) to be released by the endothelial cells
●​ T-PA degrades the fibrin in clot

●​ In normal situations injury→ tissue factor → activation of clotting factors and clotting
cascade → travel to site of injury and cause clotting, to stop bleeding
●​ In DIC the clotting process and the clotting factors are abnormally active.
●​ This results in numerous small blood clots forming in the blood vessels, which can
occlude the vessel and → ischemia and further injury

●​ The supply of clotting factors is limited, they have to be produced

●​ As this process continues, eventually all the clotting factors available become depleted
●​ This can → serious bleeding from even a minor injury

Etiology unclear, but typical triggers occur in three ways:

●​ Endothelial cell injury
●​ Massive tissue destruction
●​ Severe inflammation
Conditions associated with DIC
​ Sepsis and septic shock
​ Pregnancy and obstetric conditions
​ Cancers
​ Infections
​ Shock
​ Trauma or surgery

Chapter 23
Characteristics of RBCs

●​ Biconcave Disc Shape

●​ Lack of Nucleus and Organelles: Mature RBCs do not have a nucleus, mitochondria, or
other organelles, maximizing space for hemoglobin.
●​ Facilitated by hemoglobin; Hemoglobin is a protein containing iron that facilitates the
transport of oxygen in red blood cells.
○​ Oxygen is poorly soluble in plasma, therefore ~ 95% to 98% of it is carried by
being bound to hemoglobin.
●​ lifespan: 120 days.
●​ Produced in the bone marrow through a process called erythropoiesis, regulated by the
hormone erythropoietin (produced in the kidneys).
●​ Old or damaged RBCs are removed by the spleen and liver.
●​ Oxygen and Carbon Dioxide Transport
●​ The RBC membrane is flexible and durable, allowing cells to change shape while passing
through tiny capillaries.
●​ RBCs help maintain acid-base balance by converting carbon dioxide into bicarbonate
(HCO₃⁻), a key buffer in blood.
●​ RBCs rely on anaerobic glycolysis for ATP production since they lack mitochondria.

o Hemoglobin structure: alpha and beta chains, # of oxygen molecules that can attach

●​ Hemoglobin is a tetrameric protein composed of:

●​ Two α (alpha) chains
●​ Two β (beta) chains
●​ Each chain contains a heme group, with iron (Fe²⁺) at the center, allowing oxygen
binding.
●​ Each hemoglobin molecule can bind four oxygen (O₂) molecules due to its four heme
groups.

Hemoglobin Synthesis Requires Iron

●​ Iron (Fe²⁺) is essential for heme synthesis.

 ●​ Without sufficient iron, hemoglobin production decreases, leading to conditions like
iron-deficiency anemia.

Sources of Iron in the Body

●​ Recycled Iron from RBCs

●​ Old or damaged RBCs are broken down by macrophages in the spleen, liver, and bone
marrow.
●​ Iron from degraded hemoglobin is recycled and stored for future RBC production.

Iron Absorption from the Gut

●​ Iron from food is absorbed in the small intestine; duodenum

●​ Absorption is regulated by hepcidin, a hormone that controls iron release into the
bloodstream.
●​ Heme iron (from animal sources) is absorbed more efficiently than non-heme iron (from
plant sources).

Ferritin and Its Clinical Significance

●​ Ferritin is the primary intracellular iron storage protein.

●​ It stores iron in a soluble and non-toxic form for later use in hemoglobin synthesis.
●​ Ferritin levels indicate iron status:

Low ferritin → Iron deficiency (common in anemia)

High ferritin → Iron overload (e.g., hemochromatosis) or inflammation (ferritin is also an

acute-phase reactant)

Iron absorbed→Becomes transferrin→Travels in blood to liver→stored as ferrtin

o Erythropoiesis

o Site of RBC formation:Red bone marrow

o Function of erythropoietin:Erythropoietin is released and triggers marrow to

cause RBC to mature

o Trigger for erythropoietin production

●​ Kidney senses low tissue oxygen tension

o Site of erythropoietin production: 90% Kidney; 10% liver

o Reticulocyte (what is it, what do elevated counts mean):

Erythropoietin is released and triggers marrow to cause RBC to mature

 They are released from marrow as reticulocytes, which go on to mature into RBC

Most maturing red cells enter the blood as reticulocytes.

The reticulocyte count is an index of how rapidly new RBC are being produced
by the marron

o RBC lifespan: 120 days

o RBC destruction: liver/ spleen

●​ Rate of red cell destruction (1% per day) normally is equal to the rate of red cell
production
●​ The degradation products (iron and amino acids) are recycled
●​ The majority of the heme unit→ bilirubin, (pigment of bile) which is insoluble in
plasma and attaches to plasma proteins for transport.
●​ Bilirubin is removed from the blood by the liver and conjugated with glucuronide
to render it water soluble so that it can be excreted in the bile.
●​ Serum levels of conjugated and unconjugated bilirubin can be measured and are
reported as direct and indirect, respectively.
●​ If red cell destruction and consequent bilirubin production are excessive,
unconjugated bilirubin accumulates in the blood.
●​ The heme molecule itself is converted to bilirubin and transported to the liver.
○​ It is removed and rendered water soluble for elimination in the bile

o Site of RBC destruction and recycling

o Conversion of heme to bilirubin

Heme → Biliverdin → Unconjugated (Indirect) Bilirubin

§ Unconjugated (indirect):Unconjugated bilirubin is lipid-soluble and not

water-soluble, so it binds to albumin for transport to the liver.

If red cell destruction and consequent bilirubin production are excessive,

unconjugated bilirubin accumulates in the blood.

accumulation of unconjugated bilirubin→ yellow discoloration of the skin,

called jaundice.

Liver Converts to Conjugated (Direct) Bilirubin

§ Conjugated (direct) bilirubin: The liver conjugates bilirubin with

glucuronic acid, making it water-soluble.
 Conjugated bilirubin is then excreted into bile and eventually eliminated
through feces and urine.

o Normal hemoglobin range female and male:

●​ MEN 14-16.5g/dL
●​ Women 12-15g/dL

o Normal hematocrit range female and male

●​ Men 40%-50%
●​ Women 37%-47%

o Blood types, A, B, O

o The blood type refers to the antigen on the person’s blood cell

o Person has an antibody against the other type of antigen

o Type A has A antigen and anti-B antibody

o Type B has B antigen and anti-A antibody

Blood types, antigens, antibodies

o If blood with an antigen is given to someone with the antibody to that antigen, there will
be an immune response
o Ex: If type A blood (donor has A antigen) is given to type B recipient (has B antigen and
anti-A antibody, there will be an immune response and antibody will attack antigen

o S/S of transfusion reactions

Manifestations of reaction:

• Sensation of heat along the vein where the blood is being infused

• Flushing of the face

• Urticaria, headache, pain in the lumbar area

• Chills, fever, constricting pain in the chest

• Cramping pain in the abdomen

• Nausea, vomiting

• Tachycardia, hypotension, and dyspnea

o Anemia

Definition

• An abnormally low number of circulating red blood cells or level of hemoglobin, or both

• Results in diminished oxygen-carrying capacity

Causes include

• Excessive loss or destruction of red blood cells

• Deficient red blood cell production because of a lack of nutritional elements

• Bone marrow dysfunction

o Causes

o Deficient or Impaired production of RBC

o Not enough, abnormal, not properly functioning

o Excessive destruction or loss of RBC

o S/S of anemia

Manifestations include : fatigue, weakness, dyspnea, and sometimes angina.

• Hypoxia of brain tissue results in headache, faintness, and dim vision.

• The redistribution of the blood from cutaneous tissues or a lack of hemoglobin causes pallor
of the skin, mucous membranes, conjunctiva, and nail beds.

• Tachycardia and palpitations may occur as the body tries to compensate with an increase in
cardiac output.

o Blood loss anemia

o Loss of cells and iron

o Anemia of deficient RBC production

o Iron deficiency anemia

o Inadequate dietary iron

o Inadequate iron for hemoglobin synthesis

o cells that are produced have too little hemoglobin

o small and pale, giving rise to microcytic hypochromic anemia

o Aplastic anemia

o Bone marrow under performance; This results in pancytopenia, a condition

characterized by low levels of all three blood cell types.

o Hemolytic anemia

o Characterized by:

o The premature destruction of red cells

o Normal cell size and color, just not enough since they have been destroyed

o Almost all types of hemolytic anemia are distinguished by normocytic and

normochromic red cells. Just not enough

o Body retains iron and other products of hemoglobin destruction

o An increase in erythropoiesis occurs due to inadequate functioning cells and

low oxygen delivery to tissues

o Hemolytic anemias: SCD, thalassemia, autoimmune hemolytic

o Sickle Cell:
 o Cause of SCD:​​Sickle cell disease is an inherited disorder in which an abnormal
hemoglobin (hemoglobin S [HbS]) leads to chronic hemolytic anemia, pain, and
organ failure.

o Cause of cell sickling: the abnormal structure of HbS results from a point
mutation in the β chain of the hemoglobin molecule, with an abnormal
substitution of a single amino acid, valine, for glutamic acid.

o Consequences of sickling:chronic hemolytic anemia and blood vessel occlusion

o Thalassemia alpha and beta

●​ Group of inherited disorders affecting hemoglobin synthesis, leading to decreased

alpha- or beta-globin chain production in HbA (adult hemoglobin).
●​ Can be heterozygous (mild form) or homozygous (severe disease).

o Cause:

o Manifestation

o Disorder of RBC maturation

o B12 deficiency or folate deficiency Megaloblastic anemia

o B12 needed for blood cell DNA synthesis and maturation

o Cells abnormally large

o Pernicious anemia (B12 deficiency)

o Deficiency of intrinsic factor (produced by gastric cells)

o Required for B12 exit gut and enter bloodstream

o Folic acid deficiency anemia

o Impaired DNA synthesis and maturation megaloblastic

o Aplastic anemia

o Bone marrow suppression

Ÿ Polycythemia: abnormally high total red blood cell mass

Ÿ Hematocrit greater than 54% in men and greater than 47% in women.

Ÿ Hct > 50% can cause cardiac dysfunction and vascular obstruction; > 60%: can lead to
hypoxia
 Ÿ Absolute polycythemia: rise in hematocrit because of an increase in total red cell mass

Ÿ Primary or Secondary

Ÿ Primary polycythemia, or polycythemia vera:

Ÿ Neoplastic disease (excess proliferation) of the pluripotent cells of the bone marrow

à absolute increase in total red blood cell mass

o and also elevated WBC and platelets

Ÿ Problem is increased blood viscosity due to high # RBC

Ÿ can interfere with cardiac output and blood flow.

Ÿ Venous stasis dusky redness, of the lips, fingernails, and mucous membranes.

Ÿ Phlebotomy to reduce blood viscosity.

Ÿ Secondary

o Increase in erythropoietin, as a compensatory response to hypoxia.

o Ex living at high altitudes, chronic heart and lung disease, smoking.

o To reduce excess production of RBC, correct hypoxia

Chapter 24 review sheet

●​ Types of WBC

●​ Origin & Maturation of B and T Cells

All blood cells originate from hematopoietic stem cells (HSCs) in the bone marrow.
Lymphoid progenitor cells differentiate into B cells, T cells, and Natural Killer (NK) cells.
B Cells:
Mature in the bone marrow.
Responsible for humoral immunity (antibody production).
T Cells:
Mature in the thymus.
Responsible for cell-mediated immunity.
Subtypes include Helper T cells (CD4) and Cytotoxic T cells (CD8).

Ÿ Myeloid line WBC: Myeloid line → RBC, platelets, mast cells, granulocytes and
Monocytes
WBC from the myeloid line (granulocytes and monocyte/macrophage) form in the marrow
from the common myeloid progenitor
• RBCs and platelets are formed in the myeloid line
• Myeloid progenitor cells → erythroblast → erythrocyte (RBC)
• Myeloid progenitor → Megakaryocyte → Platelet (aka thrombocyte)

Ÿ Lymphoid line WBC:Lymphoid line→ Natural killer cells (part of innate immunity); B and
T lymphocytes
Ÿ Substances required for RBC formation: B12, Folate, Iron
Ÿ Reticulocyte and significance of elevated reticulocyte count
Ÿ Conditions of deficient WBC production
o Leukopenia: Deficiency od leukocytes
o Neutropenia: Deficiency of neutrophils
●​ Neutrophils constitute the majority of blood leukocytes and play a
critical role in host–defense mechanisms against infection. They
migrate to sites of infection and engulf, digest, and destroy
microorganisms. Thus, a decrease in the number of neutrophils
(neutropenia) places a person at risk for infection
o Aplastic anemia:Anemia, thrombocytopenia, and low WBC/ All counts are low
Ÿ Normal WBC range: 5000-10,000
Ÿ Leukocytosis: WBC> 10,000
Ÿ Neutropenia definition # of cells (<1,500 cells/mL)
Ÿ Manifestations of neutropenia
●​ Varies depending on severity/cause and reflects level of immunodeficiency
●​ Initial s/s include malaise, chills, and fever
●​ Respiratory tract most common site of infection
●​ Mouth ulcerations, along with ulcers of skin, vagina, and GI tract
Ÿ Infectious mononucleosis:Self-limited lymphoproliferative disorder
o Cause:Epstein Barr Virus, a member of the herpes virus family; transmitted in
saliva
o Manifestations:fever, generalized lymphadenopathy, sore throat, and the
appearance in the blood of atypical lymphocytes and several antibodies
o Virus remains in B-lymphocytes for life:once an individual is infected, the
virus will remain present in the B lymphocytes for a lifetime
o Clinical course
●​ Insidious onset
●​ Incubation period of 4-6 wks., followed by prodromal period, which lasts
for several days, characterized by malaise, anorexia, and chills.
●​ This is followed by fever, pharyngitis, and lymphadenopathy (esp. in the
cervical, axillary, and groin areas.)
●​ 3% to 15% of people develop maculopapular rash
Ÿ Neoplastic disorders of hematopoietic and lymphoid tissue: Represent the most important
of the white cell disorders
Ÿ Lymphomas:Cancers of the lymphatic tissue (Hodgkin disease and non-Hodgkin
lymphoma)​​
Ÿ Leukemias:cancers of the blood​
Ÿ Plasma cell disorder (multiple myeloma):order of humoral immune system plasma cell
Ÿ Hodgkin’s lymphoma
o Characteristic cell Reed-Sternberg
o Originates IN the lymph node usually
o Pathophysiology: proliferation of abnormal lymphocytes - immune deficiencies
o Manifestations: painless enlargement of node or nodes usually initially above
diaphragm (axillary, supraclavicular, cervical)
 o Constitutional S/S: Fever, night sweats, pruritis, weight loss
Ÿ Consequences: abnormal lymphocytes immune deficiency
Ÿ Diagnostic methods for HL, esp. Reed Sternberg cells on biopsy
Ÿ Non Hodgkin Lymphoma
o Originates outside the nodes, spreads to nodes
o No Reed Sternberg cells
Ÿ Leukemias
o Pathophysiology (neoplasm of hematopoietic precursor cell of bone marrow)
§ Marrow makes abnormal leukocytes (leukemia cells)
§ Proliferate rapidly, impinge on other normal cells, impacting function,
normal marrow replaced by leukemia cells
o High WBC
o Incidence: most common cancer in children and adolescents
Ÿ Classified by cell lineage and whether it is acute or chronic
o Acute: less differentiated, rapid onset and progression, more aggressive
o Chronic: better differentiated, less aggressive
Ÿ Leukemias from Lymphoid bone marrow cell line
o Acute lymphocytic (lymphoblastic) leukemia (ALL)
o Chronic lymphocytic leukemia (CLL)
o Both involve immature lymphocytes and their progenitors in the bone marrow,
the spleen, lymph nodes, CNS, and other tissue.
Ÿ From Myeloid WBC line
o Acute myelogenous (myeloblastic) leukemia (AML)
o Chronic myelogenous leukemia (CML)
o Both involve the pluripotent myeloid stem cells in bone marrow and interfere
with the maturation of all blood cells.
Ÿ Clinical manifestations of acute leukemias (AML and ALL)
Ÿ ALL and AML have similar presentation
o abrupt onset of symptoms, anemia, fatigue, low-grade fever, night sweats
 o weight loss from rapid proliferation and hypermetabolism of the leukemic cells
o Bruising/bleeding caused by decreased platelet count
o Bone pain and tenderness because of bone marrow expansion.
o Infection due to neutropenia; esp. when neutrophils < 500 cells/μL.
o Generalized lymphadenopathy, splenomegaly, and hepatomegaly caused by
infiltration of leukemic cells: most common in ALL.

Ÿ Complications of acute leukemias

o Leukostasis
o Hyperuricemia- elevated serum uric acid levels)
Ÿ Multiple myeloma
o Abnormal plasma cells proliferate in marrow
o Bence-Jones protein in urine
o Consequences: bone lesions, pathological fractures, hypercalcemia, renal
impairment