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Hematology

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147 views104 pages

Hematology

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Joseph Thieu
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Lats BLOOD COMPONENTS & A ante BLOOD COMPONENTS BLOOD COMPONENT SEPARATION + Blood components separate by density in centrifuge * Heaviest layer: erythrocytes +» Middle layer: buffy coat » Lightest layer: plasma ERYTHROCYTES + Comprise 45% (hematocrit) of total blood volume + Carry O, to tissues: bring CO, to lungs * Biconcave discs (depressed center) + Fit through vessels, 1 surface area (for gas exchange} * No organelles "1 space for hemoglobins ®., a BUFFY COAT + Comprises < 1% of total blood volume * Contains platelets, leukocytes + Platelets clump together + seal damaged blood vessels * Leukocytes ward off pathogens, destroy cancer cells, neutralize toxins PLASMA + Comprises 55% of total blood volume + No cells: 90% water + proteins, electrolytes, gases * Albumin: maintains oncotic pressure, acts as transport protein * Globulins: antibodies, transport proteins + Fibrinogen: involved in clot formation (helps platelets attach) + Electrolytes: include sodium, potassium, calcium, chloride, carbonate “erento “Beomowies “sures aes (0,4 €0) <17% Burry coat (PLATELETS & LEUKOCYTES) 5% ervturocytes Figure 434 Blood components and their relative proportions. 364 OSMOSIS.ORG Chapter 43 Hematology: Blood Components & Function PLATELET PLUG FORMATION (PRIMARY HEMOSTASIS) osms.it/platelet-plug-formation-primary-hemostasis + Hemostasis: blood-loss prevention + First two hemostasis steps: platelets clump, form plug around injury site in five steps, PLATELET PLUG FORMATION ‘STEPS 1. Endothelial injury + Nerves, smooth muscle cells detect injury + Trigger reflexive contraction of vessel {vascular spasm) — { blood flow, loss + Secretion of nitric oxide, prostaglandins stop; secretion of endothelin begins ~> further contraction 2. Exposure + Damage to endothelial cells exposes collagen + Damaged cells release Von Willebrand factor (binds to collagen) PROTEIN LAYER CeLastic Fibers CONNECTIVE TISSUE 1 coLLAGeN Figure 43.2 Layers of an arterial wall 3. Adhesion + GP1B surface proteins on platelets bind to \Von Willebrand factor 4, Activation + Platelet changes shape (forms arms to grab other platelets), releases more von Willebrand factor, serotonin, calcium, ADP, thromboxane A2 (positive feedback loop) + ADP, thromboxane AZ result in GPIIBMIA expression 5. Aggregation * GPIIBVIIA binds to fibrinogen, links platelets = platelet plug ARTERY ENDOTHELIUM, LENDOTHELIAL CELLS. aS ‘SMOOTH MUSCLE CELLS {U CONTRAGTION & RELAXATION OSMOSIS.ORG 365 STEPS of PRIMARY HEMOSTASIS 1) ENDOTHELIAL INJURY ENDOTHELIN \asULar SPaoM ——— ‘SMOOTH MUSCLE CELLS CONTRACTION 2) EXPOSURE 3) ADHESION VON WILLEBRAND'S, PLATELET. GED R DAMA ENDOTHELIAL CELLS: ois pS ays COLLAGEN 4) ACTIVATION 8 a erie nia DIPHOSPHATE a (ape) “~ ~ x = id ks PLATELETS FUNCTIONAL, x xX FORMS EPOXIDE REDUCTASE. Figure 43.5 Vitamin K cycle, A single molecule of Vitamin K can be reused many times. ANTICOAGULATION, CLOT RETRACTION & FIBRINOLYSIS osms.it/clot-retraction-and-fibrinolysi ANTICOAGULATION + Occurs during primary, secondary hemostasis; regulates clot formation + Prevents clots from growing too large —> block blood flow, form emboli + Regulation starts with thrombin (factor I) = Multiple pro-coagulative functions «© Proteins C, $ bind thrombomodulin ‘thrombin —» cleaves, inactivates factors Vivi * Antithrombin Ill binds thrombinffactor X — inactivates both (plus factors Vil IX. Xi, Xl with lower affinity) ANTITHROMBIN I (ANTITHROMBIN) + Other factors prevent platelets adhering PROTEIN ¢: during primary hemostasis ® Nitric oxide, prostacyclin — | THROMBIN, ‘thromboxane AZ ‘THROMBOMODULIN: Figure 43.6 Proteins involved in anticoagulation. Thrombornodulin is found on the surface of intact epithelia cells lining blood vesse's. OSMOSIS.ORG 369 370 OSMOSIS.ORG CLOT RETRACTION + Occurs one hour after primary, secondary hemostasis » Contracts clot + Platelets in clot express integrin allB3 —» binds to fibrin expressing actin, myosin —» lamellipodia contract, fibrin mesh tightens closing wood FIBRINOLYSIS + Occurs two days after primary, secondary hemostasis; degrades clot + Plasminogen — plasmin (via tissue plasminogen activator) + Plasmin proteases fibrin —» clot dissolves BLOOD GROUPS & TRANSFUSIONS BLOOD TRANSFUSIONS * Blood transfusion: person receives blood! elements of blood (usually through intravenous infusion} » Homologous transfusion: anonymous donor * Autologous transfusion: self-donor (e.g. in planned surgery) + Blood is mixed with calcium oxalate to prevent coagulation, refrigerated/frozen for storage BLOOD TYPING + Transfusion blood types not compatible —» autoimmune reaction (hemolytic transfusion reaction) + Two classification systems (based on presence/absence of proteins) + ABO system * Rh system. ‘ABO system + Determined by type of glycoproteins found ‘on red blood cells (RBCs) Type A; type B: type A&B; type O (neither) + Immune system produces antibodies against absent glycoproteins + Type AB: no antibodies > universal ecipients, + Type O: no antigens — universal denors Rh system + Determined by presence of Rh protein © Rh positive; Rh negati + Rh#- can receive blood from either group + Rh- can only receive Rh- blood CROSS MATCHING + Test to confirm donor's blood is safe for recipient + Recipient serum is mixed with donor blood » Agglutination reaction: cannot receive Chapter 43 Hematology: Blood Components & Function BLOOD TYPING B-TYPE A ANTIGEN. 4 TYPE B ANTIGEN 9 Rh ANTIGEN ‘ABO SYSTEM a = a8 ° a Rh SYSTEM Figure 43,7 Blood types are reported as ABO group and Rh + or -. When both classification systems are combined, there are eight possible blood types: A+, A-, B+, | AB#, AB-, O+, O- OSMOSIS.ORG 371 NOTES. Ls CONGENITAL ANEMIA GENERALLY, WHAT IS IT? (PATHOLOGY & CAUSES ) ( SIGNS&SYMPTOMS ) + Inherited macrocytic-normochromic + See individual disorders anerias » Fanconi anemia + See individual disorders COMPLICATIONS + Congenital anomalies, t blood malignancy risk, solid tumor cancers TREATMENT + See individual disorders 368 OSMOSIS.ORG CONGENITAL ANEMIAS Ohba a ay TNL Pau etn’ ‘Autosomal dominant ‘Autosomal cessive or Xlnked EFFECT OF aC) | RBC Ooi aad OC as Peo AS AA Cs OSTN ay Era UTad cr a BCT) BCLs Cae DIAMOND-BLACKFAN ANEMIA (DBA) Sri tuure ex ier rue PATHOLOGY & CAUSES anemia = No other significant cytopathies evident * Autosomal dominant ribosomopat * Sporadic, unpredictable penetrance —> resling in nterted bone marow flue hgh eget ofgenotyieneteogenety syndrome, macrocytic-normachromic on vane ‘of possible congenital anemia, associated congenital anomalies anomalies * Genetic mutation —» ribosomopathy > impaired hematopoiesis + red blood cell aplasia + macrocytic-normechromic OSMOSIS.ORG 369 COMPLICATIONS: + Genetic predisposition to malignancies like myelogenous leukernia, myelodysplastic syndrome, solid tumors * Congenital anomalies increase complication risk SIGNS & SYMPTOMS + Anemia often present at birth > signs and ‘symptoms of impaired oxygen-carrying capacity [e.@. pallor, tachycardia, apnea, lethargy) * Low birth weight, evidence of growth restriction usually present Congenital anomalies * Craniofacial: low-set ears, micrognathia, high-archedieleft palate, broad nasal bridge * Neck: short, may be webbed * Ophthalmological: congenital glaucoma, cataracts, strabismus » Thumbs: duplex/bifia; flat thenar * Urogenital: absentéhorseshoe kidney » Cardiac: ventticular/atvial septal defect, coarctation of the aorta + DBA usually diagnosed within first month of life DIAGNOSTIC IMAGING Renal imaging/echocardiography + Find internal congenital anomalies LAB RESULTS + Complete blood cell count (CBC} with red blood cell indices » | red blood cell count, hemoglobin, hematocrit += Reticulocytopenia "mean corpuscular volume (MCV) = Normal mean corpuscular hemoglobin (MCH), white blood cell, platelet counts + Bone marrow aspirate normal, except few! 370 OSMOSIS.ORG no erythroid precursors + Serum erythropoietin, fetal hemoglobin (HoF) increased secondary to stress hematopoiesis + Elevated erythrocyte adenosine deaminase leaDal OTHER DIAGNOSTICS * Classical physical congenital anomalies associated with DBA = Genetic testing, family history TREATMENT + 25% chance of spontaneous remission MEDICATIONS Corticosteroids + Hemoglobin f observed after steroid ‘therapy initiation + Weigh dose, duration of steroid treatment against adverse effects e.g. growth cisturbances, adrenal suppression, immunosuppression, pathological fractures) SURGERY Curative + Allogeneic hematopoietic stem cell transplant OTHER INTERVENTIONS + Monitor for development of malignancies + Specialist care (e.g. cardiology, nephrology, urology) + Family support, genetic counseling Transfusions + Packed red blood cells, = Maintain Hab > Bala. » Must be leukocyte poor to decrease transmission of cytomegalovirus = Monitor for iron overload, hemosiderosis Chapter 44 Congenital Anemia FANCONI! ANEMIA (FA) (PATHOLOGY & CAUSES) (SIGNS & SYMPTOMS _) + Autosomal recessive/X-linked disorder of chromosome fragility causing inherited bone marrow failure syndrome, macrocytic- normochromic anemia, pancytopenia Physical abnormalities + Short stature, malformations associated with the VACTERL-H (vertebral, anal, cardiac, tracheoesophageal, renal, limb and hydrocephalus) association + Microcephaly, congenital heart disease, imperforate snus, conductive deafness, hypogeritalia, cafe-au-lait spots CAUSES + Mutation of several genes responsible for DNA repair * Impaired cellular repair of DNA cross~ inks —+ impaired regulation of cell cycle, genomic instability -» hematopoietic stem cell loss —» macrocytic~ normachromic anemia —+ bone marrow aplasia —+ pancytopenia + Predisposition for development of blood! solid tumor malignancies + Bone marrow biopsy usually normocellular at birth + Macrocytic-norochromic anemia and ‘other cytopenias develop gradually usually diagnosed within first eight years of life COMPLICATIONS: + Neutropenia: life-threatening infections + Thrombocytopenia: bleeding tendencies + Malignancies: e.g. myelogenous leukemia, myelodysplastic syndrome, solid tumors + Endocrine derangements: hypothalamic pituitary axis disruption during fetal development + Congenital anomalies + Cytopenias develop —+ clinical manifestations — increased bruising/ bleeding, frequent infections + Symptomatic anemia related to impaired oxygen-carrying capacity develops late in disease + History, physical examination LAB RESULTS + CBC assessment, bone marrow ‘examination FA testing indicators + Evidence of single-/multiineage cytopenias with no other identified cause + | absolute neutrophil count, platelet count, absolute reticulocyte count, hemoglobin + Hypocellular bone marrow (without ‘evidence of malignancyfather known cause) + Congenital anomalies + Family history: people of Ashkenazi Jewish descent have t cartier frequency FA-specific testing * Chromosome DEB assay + Laboratory test for chromosomal breakage performed on leukocytes (indicates chromosome instability syndrome; not FA-specific) * Cytometric flow analysis, +» Examines cellular growth, division; cytometry following DNA crosslinking shows cells unable to repair DNA damage, cellular arrest in cell cycle G2 phase + Chromosomal breakage test positive —» FA gene sequencing recommended OSMOSISORG 371 372 OSMOSIS.ORG TREATMENT MEDICATIONS Growth factors * Granulocyte colony-stimulating factor (G- csFy * Granulocyte-macrophage-stimulating factor (GM-CSF) + Thrombopoietin mimetics (e.g. romiplostim} ‘Androgen therapy + (e.g. oxymetholone) sometimes t blood cell count SURGERY Bone marrow failure + Allogeneic hematopoietic stem cell ‘vansplant OTHER INTERVENTIONS + Screen, monitor for malignancies + Specialist care (e.g. cardiology, nephrology, endocrinology} + Family support, genetic counselling Transfusions * Leukoreduced, irradiated packed red biood cells © Symptomatic anemia * Hemodynamic instability + Platelet transfusions Platelet count < 10,000/microL. +» Evidence of severe bruising, bleeding NOTES Lats PSS ee aia Ct DP) Se) delat Sy —— GENERALLY, WHAT ARE THEY? ——— CpatwoLoay causes) ( + Acquired disorders caused by defective hematopoiesis CAUSES + Mostly idiopathic + Gene mutations © JAK2 gene in most myeloproliferative disorders COMPLICATIONS + Can progress to serious conditions = Acute myelogenous leukernia (AML) DIAGNOSIS ) LAB RESULTS + Complete blood count (CBC) * Call line levels + Peripheral blood smear + Morphology + Bone marrow aspiration/biopsy + Morphology, cellularity (normal, hypo, hyper), 9 of blasts + Cytogenetic studies * Chromosomal abnormalities + Molecular tests * Gene mutations SIGNS & SYMPTOMS TREATMENT + Can be asymptomatic + When symptomatic, depends on cell ine affected OTHER INTERVENTIONS * Blood transfusion + Hematopoietic stem cell transplant OSMOSIS.ORG 373 374 OSMOSIS.ORG ESSENTIAL THROMBOCYTOSIS ( PATHOLOGY & CAUSES) C DIAGNOSIS ) * Chronic myeloproliferative neoplasm due to overproduction of megakaryocytes in bone + AKA essential thrombocythemia * T platelets, abnormally shaped; | platelet survival + Thromboses; bleeding episodes may occur; other cell lines may be affected + JAK2 mutation (50%), MPL (5-10%)/ calreticulin + "Spent phase" of myelofibrosis/AML (rarely) SIGNS & SYMPTOMS + Primary symptomatic manifestations due to thrombosis — potential ischemia in various organs, extremities (e.g. stroke, erythromelalgia} + Headache, dizziness, fatigue, vision loss, ‘abdominal pain, nausea * Less frequently, paradoxical bleeding * Epistaxis, bleeding gums, ecchymoses * Splenomegaly sae 1 “patio Figure 454 A peripheral blood smear from an individual with essential thrombocytosis. ‘There are a higher than normal number of platelets visible. ‘LAB RESULTS + Platelets > 450 x 1034pL for = two months; anisocytosis +f bleeding time Bone marrow aspiration/biopsy * Normal cellularity Genetic testing + JAK2 mutation OTHER DIAGNOSTCS + History of thrombosis, bleeding, vasomotor symptoms, first trimester fetal loss TREATMENT MEDICATIONS * Low risk for thrombosis = Antiplatelet drugs (aspirin, anagrelide) * High tisk for thrombosis ° Hydroxyurea, interferon-alpha ‘SURGERY + In severe conditions «© Plateletoheresis (removal of platelets from blood) Chapter 45 Dysplastic & Proliferative Disorders LANGERHANS CELL HISTIOCYTOSIS (LCH) osms.it/langerhans Bl iG Cpatnovogy causes) ( SIGNS & SYMPTOMS ) + Rare, proliferative disorder affecting Langerhans cells (type of dendritic cells), myeloid progenitor cells in bone marrow + AKA histiocytosis X + Osteolytic bone lesions infitrated with histiocytes; histiocytes, lymphocytes, macrophages, eosinophils infiltrate organs: skin, lymph nodes, bones, lungs. liver. spleen, central nervous system (CNS) Prolifera 19 cells * Functionally immature + Immunohistochernistry © CDLa, $100 positive + Abundant, foamy cytoplasm + Folded, grooved nuclei * Birbeck granules, “tennis racket"rod shaped cytoplasmic organelles RISK FACTORS + Usually affects children; also present in adults + Mutations detected; most common (55~ 60%) activates BRAF gene COMPLICATIONS, CNS + Pituitary gland —> diabetes insipidus, pons, basal ganglia; cerebellum > cognitive deficits, neuromotor dysfunction + Liver, spleen’ © Worse prognosis; sclerosing cholangitis may require liver transplant + Lytic bone lesions may be asymptomatic! cause localized pain + Skin lesions, * Brown to purplish papules pustular, purpuric, petechial, vesicular, papulo- nodular; eczerna-like rash + Mucous membranes + Gingivitis, mucosal masslulcers, loose teeth + Lymphadenopathy + Liver, spleen * Hepatic lesions, hepatosplenomegaly * Lungs » Recurrent spontaneous pneumothorax, dyspnoea, chest pain + ONS * Diabetes insipidus, neurological deficits + Systematic symptoms + Fever lethargy, weightloss DIAGNOSIS DIAGNOSTIC IMAGING MRI + CNS involvernent ‘LAB RESULTS: + Accumulation of inflammatory cells, Langerhans cells (large, mononuclear cells with prominent nuclear groove}, few cytoplasmic vacuoles, pale eosinophilic cytoplasm OSMOSIS.ORG 375 376 OSMOSIS.ORG TREATMENT + Spontaneous regression can occur MEDICATIONS + Systemic corticosteroids + Chemotherapeutic agents » Alkylating agents, antimetabolites, vinca alkaloids SURGERY + Surgial excision OTHER INTERVENTIONS + Radiation therapy Figure 45.3 An MRI scan of the head in the sagittal plane demonstrating a subcutaneous soft-tissue mass, destroying the frontal bone. ‘The diagnosis was confirmed as Langerhans histiocytosis on biopsy. agp vga, ie eK, 48 See i : Reha Y Figure 45.2 The histological appearance of Langerhans cell histiocytasis. There are numerous clonal dendritic cells (ight pink) with assaciated eosinophils (red) Chapter 45 Dysplastic & Proliferative Disorders LEUKEMOID REACTION PATHOLOGY & CAUSES cessive, reactive leukocytosis (WBCs: 40,000-100,000/mL), resembling leukemia, with increase in neutrophil precursors, “left shit” (e.g. myeloblasts, promyelocytes, myelocytes) in peripheral blood + Cytoplasmic toxic granulation, Dohle bodies, blue-gray inclusions in peripheral cytoplasm of neutrophils + Lymphocytic reaction can occur COMPLICATIONS + Severelchronic infections * Clostridium difficile infection (CDN), Mycobacterium tuberculosis, Bordetella pertussis, Epstein-Barr virus (EBV) + Sepsis + Non-infectious inflammation © Burns, postoperative state, acute asthma attack, acute episodes of gout + Severe hemolysis + Acute hemorthage += Peritoneal cavity + Tissue necrosis, = Hepatic necrosis, ischeric colitis + Metastatic cancer + Paraneoplastic syndrome » Lung carcinoma, renal cell carcinoma + Drugs + Sulfonamides, dapsone, glucocorticosteroids, granulocyte-colony stimulating factor {G-CSF} * Asplenia + Metabolic + Diabetic ketoacidosis, preeclampsia, uremia SIGNS & SYMPTOMS + Fatigue, weakness, high fever DIAGNOSIS LAB RESULTS “TT WBCs + Rule out blood malignancies +» Mature neutrophil precursors, unlike Immature cells in acute leukernia (blasts < 20%); toxic granulation, Dohle bodies unlike chronic myelogenous leukernia (cMy) +» Serum leukocyte alkaline phosphatase (LAP} score normal/elevated, unlike CML * Confirm CML by Philadelphia chromosome with BCRIABL fusion gene + FISHIPCR * Bone marrow aspiration/biopsy TREATMENT + Treatment of underlying condition OSMOSIS.ORG 377 MYELODYSPLASTIC SYNDROMES (MDS) osms.it/myelodysplastic-syndrome \THOLOGY & CAUSES + Group of malignant hematopoietic stern cell disorders + Abnormal, ineffective hematopoiesis —+ peripheral cytopenia Dysplastic cells + Pseudo Pelger-Huat cells » Bilobed neutrophils + Ring sideroblasts » Erythroblasts with granules of iron. ‘accumulated in mitochondria + Megaloblastoid maturation + Nuclear budding abnormalities + Pawn ball megakaryocytes * Discrete nuclear lobesitnultinucleation CAUSES, + Can be idiopathicisecondary to exposure » Toxins, genotoxic drugs, immunosuppressive agen ‘chemotherapy, radiation therapy (t- MDS, therapy related MDS) * Genetic defects due to + Epigenetic factors, RNA splicing factors, transcription factors, » 5g (q+) deletion most common + Affects elderly individuals; mean age of ‘onset is 70 years COMPLICATIONS: + MOS = pre-leukemias, high risk of conversion to AML + 9 of blasts (1-20%) +» How close individual is to AML (> 20%) + Progresses slowly ~» mast succumb to bleeding, infections before AML 378 OSMOSIS.ORG + Functional defects in red (RBCs), white blood cells (WECs}, platelets > anemia, infections, bleeding SIGNS & SYMPTOMS + Asymptomatic in early stages + Fatigue (anemia), infections (neutropenia), bleeding (thrombocytopenia) ‘LAB RESULTS: * Low RBCs, WBCs, platelets, normalimildly elevated mean corpusculat volume (MCV). increased red cell distribution width (RDW) + Low reticulocyte count, dysplastic RBCs, WACs, normal platelets, 1-20% blasts. + Dysplastic cells, increased blasts * Chromosomal abnormalities, gene mutations TREATMENT MEDICATIONS + Tumor necrosis factor (TNF) inhibitors (eglenalidomide, thalidomide), ONA methylation inhibitors OTHER INTERVENTIONS Allogeneic hematopoietic stem cell trans- plant * Only curative option, for young individuals. + If transplant not an option —» blood product ‘transfusions, infection control (supportive) —®@ Figure 45.4 A neutrophil from a in the peripheral blood smear of an individual with myelodysplastic syndrome. The neutrophil is hypogranulated and has a hypolobated nucleus, known as a pseudo Pelger-Huét nucleus. Chapter 45 Dysplastic & Proliferative Disorders POLYCYTHEMIA VERA (PCV) osms.it/polycythemi \THOLOGY & CAUSES * Chronic myeloproliferative neoplastic disease + Hematopoietic stem cell disorder > erythroid, granulocytic, megakaryocytic lineages proliferate * Increased © RBCs, independent of erythropoietin (EPO); platelets; basophils: eosinophils; cell turnover + hyperuricemia * Polycytheria — increased blood viscosity: increased total blood volume —+ abnormal blood flow + Abnormal blood flow, defective platelet function + vein thrombosis, infarcts, bleeding + PCV may evolve to “spent phase” © Myelofibrosis, extramedullary hematopoiesis in iver, spleen ‘vera RISK FACTORS + Occurs in all ages; median age at diagnosis 60 years = Genetic + JAK2V617F mutation (95% of cases) COMPLICATIONS: + Hypertension, Budd-Chiati syndrome, deep vein thrombosis, arterial thrombosis, myocardial infarction (MI), gout (high cell turnover, hyperuricemia), PCV — AML (care) + Ifuntreated + Thrombotic, hemorrhagic complications = death within months OSMOSIS.ORG 379 SIGNS & SYMPTOMS + Symptoms due to + in RECs — blood viscosity » Headache. fatigue, dizziness, dyspnea, plethora, cyanosis, + Symptoms due to + in basophils + histanine release * Pruritus (intense itching, especially after hot shower) gastric ulcers + Thrombosis * Deep vein thrombosis, Ml, Budd-Chiari syndrome (portal vein thrombosis), erythromelalgia (hyperemic and inflamed extremities due to microvascular occlusion of vesse's) * Bleeding Bleeding gums, epistaxis, ecchymoses, Gibleed + Hepatosplenomegaly, splenomegaly + Hypertension LAB RESULTS + Exclude secondary polycythemia (hypoxia, renal cell, hepatocellular carcinoma): | EPO serum + cBC =1 RBCs, hematocrit, hemoglobin; t platelets/WECs +t Lactate dehydrogenase + { serum EPO + Bone marrow aspiration/biopsy confirms diagnosis + Genetic testing SJAK2 mutation 380 OSMOSIS.ORG Figure 45.5 The clinical appearance of erythromelalgia; a sign of numerous diseases, including polycythemia vera. TREATMENT MEDICATIONS + Hydroxyurea = | REC production + Interferon-alpha = 1 REC destruction + Aspirin = [risk of thrombosis OTHER INTERVENTIONS + Phlebotomy «© | hematocrit, hemoglobin Q- yw Figure 45.6 The clinical appearance of erythromelalgia; a sign of numerous diseases, including polycythemia vera, Chapter 45 Dysplastic & Proliferative Disorders PRIMARY MYELOFIBROSIS (PM) osms.it/ myelofibrosis PATHOLOGY & CAUSES * Chronic myeloproliferative disease of hematopoietic ster cells resulting in bone marrow fibrosis + AKA essential thrombocythemia + Overproduction of megakaryocytes in bone marrow + Increased platelets, abnormally shaped: decreased platelet survival + Thromboses; bleeding episodes may occur: ‘other cell lines may be affected + JAK2 mutation (50%), MPL (5-10%6\/ calreticulin + "Spent phase” of myelofibrosis/AML (rarely) SIGNS & SYMPTOMS + May be asymptomatic + When symptomatic, thrombosis, potential ischemia in various organs * Headache, dizziness, fatigue, numbness in extremities, erythromelalgia, vision loss, abdominal pain, nausea + Less frequently, bleeding * Epistaxis, bleeding gums, bruises + Splenomegaly DIAGNOSIS LAB RESULTS + | RBCs, platelets + Leukoerythroblastosis, dacryocytes Bone marrow biopsy + Hypocellularity, fibrosis, OTHER INTERVENTIONS Bone marrow aspiration * Dry tap, no sample (accumulation of collagen fibers) Figure 45.7 The histological appearance of the bone marrow in an individual with myelofibrosis. The fibrosis is seen as fine silver strands upon staining with reticulin TREATMENT MEDICATIONS + Low risk for thrombosis + Antiplatelet drugs (aspirin, anagrelide) + High risk for thrombosis + Hydroxyurea, interferon-alpha SURGERY + In severe conditions + Plateletpheresis (removal of platelets from blood) OSMOSISORG 381 382 OSMOSIS.ORG De) TB Sale a Ra Dist Dla Ss Ma] PLATELETS tt nomocytc. ormoctromic RBCS COMA CMT Post-povorthemic ae Bre ata) Granulocyte dysplasia: CER Ae : | hypogean Bd unbel o bilabed seudo-Pelger- Het cl Catia Prat tn 7 oranuievtes, cccasional pscudo- Pelger Hust nucle: Lett ’ HYPERCOAGULABLE DISORDERS —— GENERALLY, WHAT ARE THEY? ——— ( PaTHOLOGY 2causes ) ( + Unregulated activation of coagulation cascade —» vascular thrombosis: CAUSES + Inherited/acquired + Secondary to liver disease, autoimmune systemic disorders, renal failure, acute thrombosis, exposure to toxins, anticoagulation therapy COMPLICATIONS + Venous, arterial thrombosis, obstetric SIGNS & SYMPTOMS + Deep vein thrombosis (DVT) —> pulmonary embolism (PE) DIAGNOSIS ) + Family history of thrombophilia, thrombosis under age of 50 years, thrombosis in unusual location (e.g. portal veins), recurrent thromboembolic episodes LAB RESULTS + Assays for specific proteins/factors, antibodies * Genetic testing TREATMENT MEDICATIONS + Anticoagulantsithrombolysis + if symptomatic + Prophylactic anticoagulation when high risk for thrombosis * Eg. perioperatively/in postpartum period If asymptomatic OSMOSISORG 383 384 OSMOSIS.ORG ANTIPHOSPHOLIPID SYNDROME (APS) Poenius iphospholipi PUR ued ( PATHOLOGY & causes ) ( SIGNS & SYMPTOMS ) + Acquired autoimmune multisystern disorder; associated underlying disorders, systemic lupus erythernatosus (SLE) + AKA lupus anticoagulant syndrome * May be idiopathic; may appear after exposure drugs/infectious agents, + Antiphospholipid antibodies (aPL bind to targets —+ induce hypercoagulable state + Pathways » Thromboembolic episodesipregnancy morbidity + Increase in atherosclerosis, fetal loss, neurological damage; aPL-associated increase in vascular tone + Catastrophic APS (rare) * Widespread thrombosis > multiorgan failure COMPLICATIONS: Pregnancy complications + Spontaneous abortions; fetal death + Premature birth due to preeclampsiafplacental insufficiency Cutaneous complications + Lived reticularis (most common} * Obstruction of microvasculature — net- like purplish discolouration of skin + Cutaneous ulcers Ocular complications + Retinal venous/arterial circulation occlusion; anterior ischemic optic neuropathy + Recurrent venous thromboses © DVT + PE — pulmonary hypertension © Superficial thrombophlebitis = Hepaticiportal vein thrombosis + Budd- Chiari syndrome, hepatic infarction, portal hypertension, cirrhosis © Adrenal vein thrombosis -» hemorrhagic infarction + Recurrent arterial thromboses (less commen} » Stroke/transient ischernic attack + Myocardial infarction © Bowel infarction = Multiple capillary, arterial thromboses renal microangiopathy — renovascular hypertension ‘LAB RESULTS hospholinid » Lupus anticoagulant, AKA lupus antibody © Anticardiolipin antibody © Anti-beta, glycoprotein | + 2 one clinical feature ® Vascular thrombosis/pregnancy morbidity + Moderate thrombocytopenia + Prolonged PT, aPTT = Not corrected by plasma transfusions Ise positive in venereal disease lab test, rapid plasma reagin test for syphilis, = Cardiolipin phospholipid as major reagent + one anti TREATMENT MEDICATIONS + Aspirin/anticoagulants (e.g. warfarin) =To stabilize coagulation pathways ° Lifelong systemic therapy with antiplatelet medications Chapter 46 Hypercoagulable Disorders ANTITHROMBIN 111 DEFICIENCY Couey AAU) ie) (PATHOLOGY & CAUSES ) ( DIAGNOSIS ) + Endogenous serine protease inhibitor in coagulation cascade; inactivates thrombin {factor Il), factor Xa, CAUSES * Inherited = Autosomal dominant gene mutation; variable penetrance + Acauired © Defective synthesis; liver disease, therapy with vitamin K antagonists (ea warfarin) © Loss in urine; renal failure/nephrotic syndrome » Depletion in acute thrombosis! disseminated intravascular disease (DIC) COMPLICATIONS, + Venous thromboembolism + Heparin resistance SIGNS & SYMPTOMS + Deep vein thrombosis —> pulmonary embolism LAB RESULTS Genetic testing Functional assay + Reduced plasma antithrombin Il activity + PTiePTTthrombin time *No change + aPTT —» diminished increase following heparin TREATMENT MEDICATIONS * Treat deep vein thrombosis / pulmonary ‘embolism + Anticoagulants with vitamin K antagonists/direct oral anticoagulants (D0Acs) + If = two thromboembolic events occur —> lifelong anticoagulant therapy (e9, vitamin K antagonists/ DOACs} + Prophylactic antithrombin replacement + High-risk thrombophilc situations (e., surgeryipregnancy) OSMOSISORG 385 OSMOSIS.ORG FACTOR V LEIDEN (FVL) C patwoLoay causes) ( + Inherited thrombophilia + Mutant form of coagulation factor V, lacks ‘A1g806 cleavage site CAUSES + FVL — resistance to degradation by activated protein C {aPC} + unregulated activation of coagulation cascade — hypercoagulable state —+ venous thromboembolism (VTE) RISK FACTORS + FVL homozygosity + Coinheritance with other thrombophilia disorders + Pregnancy (physiologic hypercoagulabilty) += Oral hormonal contraceptives SIGNS & SYMPTOMS + VTE + DVTithrombosis in superficial veins of lower extremities/cerebral, portal, hepatic + Possible fetal loss DIAGNOSIS ) ‘LAB RESULTS * Genetic testing © EVL mutation (direct analysis of genomic DNA) © Functional aPC resistance assay {individual's plasma mixed with factor \V-deficient plasma) OTHER DIAGNOSTICS + Family history of thrombophilia + VTE at young agefin unusual location TREATMENT MEDICATIONS + Anticoagulants/thrombolysis © Treat for DVT/PE =f 2 two thromboembolic events lifelong anticoagulant therapy + Prophylactic anticoagulation = High risk thrombophilic situations (e.g. surgery, pregnancy) Chapter 46 Hypercoagulable Disorders PROTEIN C DEFICIENCY (PATHOLOGY & CAUSES ) ( DIAGNOSIS ) + Protein C deficiency + familial LAB RESULTS thrombophilia _romber Functional assay + Vitarnin K-dependent inhibitor of factors v.vill © Protein C deficiency — unregulated activation of coagulation cascade + increased thrombotic risk TYPES + Tye! © Reduced protein C levels + Type ll © Norrnal protein C levels, reduced function CAUSES + Autosornal dominant inherited disorder * Acute thrombosis, disseminated intravascular coagulation, liver disease, vitamin K antagonist anticoagulants COMPLICATIONS + Due to treatment, * Warfarin-induced thrombotic skin necrosis SIGNS & SYMPTOMS * Venous thromboembolism (VTE) + In homozygotes, neonatal purpura fulminans + Reduced protein C OTHER DIAGNOSTICS + Monitor if recurrent VTE, family history of VTE, thrombosis in unusual locationvat young age TREATMENT MEDICATIONS + Anticoagulantsithrombolysis Treat deep vein thrombosis/VTE + Prophylactic protein C concentrate *» Asymptomatic individuals (e.9. perioperativelyiin postpartum period) Warfarin-induced skin necrosis + Stop warfarin; start vitamin K, heparin, protein C concentrate/fresh frozen plasma administration MNEMONIC. ~ Proteins C&S Cand $ inhibit coagulation: ‘they are Clot Stoppers OSMOSIS.ORG 387 388 OSMOSIS.ORG PROTEIN S DEFICIENCY CpatwoLoay causes) ( + Deficiency of protein $ — familial thrombophilia + Protein S + Cofactor of protein C += Protein S deficiency — decreased protein C activity — enhanced activity of coagulation cascade — increased thrombotic risk TYPES + Type | (classic) » Reduced total protein S, free protein S, protein S function + Type Il rare) » Normal total, free protein S, reduced function = Type lll » Reduced free protein S, protein S function; normal total protein S CAUSES + Autosomal dominant inhetited condition * Most individuals heterozygous for PROSI gene mutation + Pregnancy, oral hormonal contraceptive, disseminated intravascular coagulation {DIC}, acute thrombosis, HIV infection, nephrotic syndrome, liver disease SIGNS & SYMPTOMS _) + VTE + In homozygotes, neonatal purpura fulminans + Monitor if recurrent venous thromboembolism (VTE), family history of VTE, thrombosis at young agefin unusual location LAB RESULTS: + Protein S assay TREATMENT MEDICATIONS + Anticoagulantsithrombolysis = Treat deep vein thrombosis, + If asymptomatic, avoid drugs that, predispose to thrombosis (e.g. oral contraceptives} + Prophylactic anticoagulation (e.. preoperatively/in postpartum period) GENERALLY, WHAT ARE THEY? NOTES Lt) / HYPOCOAGULABLE DISORDERS (PATHOLOGY & CAUSES ) + Acquired, inherited disorders; defects in coagulation cascade SIGNS & SYMPTOMS * Bleeding + Thrombosis, only disseminated intravascular disease (DIC) C DIAGNOSIS ) LAB RESULTS + Platelet count + Levels of clotting factors + Prothrombin time (PT) + Partial thromboplastin time (aPTT) + Fiorin degradation products + Genetic testing TREATMENT OTHER INTERVENTIONS + Supportive therapy DISSEMINATED INTRAVASCULAR COAGULATION (DIC) COU eCourant PATHOLOGY & CAUSES + Acquited, paradoxical process of ‘thrombosis, bleeding + Release of procoagulants, tissue factors, bacterial components, enzyrestajor endothelial inury > excessive activation of coagulation cascade — thrombosis of smallimedium blood vessels > activation of fibrinolysis to resolve clots, = fibrin degradation products released into circulation — interfere with platelet aggregation. cit formation + Depletion of platelets, fiorin, coagulation factors -+ consumption coagulopathy CAUSES + Complication of underlying conditions + Obstetric complications (e.g. preeclampsia, obstetric hernorthage, retained dead fetus) * Critica illness (individuals in intensive care unit) + Malignancy + Mucin-secreting adenocarcinoma eg.. lungs, pancreas, stomach, prostate, ovaries) * Acute promyelocytic leukernia (APL) + Infection/sepsis, especially gram-negative bacteria + Massive tissue injury due to trauma, OSMOSIS.ORG 389 390 OSMOSIS.ORG surgery, burn, fracture + Intravascular hemolysis due to blood type incompatibility = Shock + Snakebites COMPLICATIONS + Widespread thrombosis, ischemia, necrosis of brain, heart, kidneys, liver, lungs, adrenals, spleen — organ dysfunction + Microangiopathic hemolytic anemia (MAHA) + Paradoxical tendency to life-threatening bleeding, due to consumption of procoagulatory factors MNEMONIC: DIC TEAR ~ Common causes of DIC Delivery TEAR’ obstetric complications Infections: gram negative\/ Immunological Cancer: prostate, pancreas, lung, stomach Obstretrical complications ‘Toxemia of pregnancy Emboli (amniotic) Abtuptio placentae Retain fetus products SIGNS & SYMPTOMS + Acute: bleeding episodes (e.g. ecchymoses, petechiae, purpura, blood oozing from gingivalforal mucosa, sites of trauma, catheters, intravenous lines) + Chronic: thromboembolism, tissue hypoxia, infarctions LAB RESULTS + | Platelets + | Fibrinogen ~ | Clotting factors + 1 Prothrombin time (PT) + 1 Partial thromboplastin time (aPTT) + 1. D-dimers (fibrin degradation product) * Schistocytes, damaged red blood cells {RBCs} due to MAHA + Physiologic compensation — ab results normal » For chronic (solid tumors, large aortic aneurysms) TREATMENT MEDICATIONS + Oxygen, IV fluids OTHER INTERVENTIONS + Replace clotting factors with fresh frozen plasma (FFP), cryoprecipitate, fibrinogen + Platelet transfusions, if platelet count < 30,000 + RBC transfusions for severe bleeding Chapter 47 Hypocoagulable Disorders HEMOPHILIA A Cpatnovogy causes) ( DIAGNOSIS ) + Most common inherited clotting factor deficiency; classic hemophilia + Xlinked recessive disorder + Mutated gene FB on X chramosame CAUSES + Quantitative/qualitative deficiency of factor Vill + insufficient activation of the intrinsic pathway — defect in commen coagulation pathway — increased tendency for bleeding + Peritoneal dialysis, RISK FACTORS + More common in individuals who are biologically male; individuals who are biologically female more likely to be carriers SIGNS & SYMPTOMS + Varies according to mutation, factor Vill activity + Asymptomatic/spontaneous bleeding + < 10% factor Vil + Easy bruising » Prolonged bleeding, after injuryisurgery = Hematomas (e.g. muscle hematomas, hemophilic pseudoturnors} » Gastrointestinal (Gi) bleeding = Hematuria © Severe epistaxis += Painful hemarthrosis + progressive joint irregularity, disability (knee most common) » Intracerebral hemorrhage LAB RESULTS + Normal platelet count + Normal prothrombin time (extrinsic pathway not affected) * Prolonged partial thromboplastin time {intrinsic pathway affected) + Factor Vill clotting assay + Genetic testing TREATMENT MEDICATIONS Desmopressin (DDAVP) + For mild quantitative hemophilia A +" stimulates von Willebrand factor (WWF) release + promotes stabilization of residual factor Vill OTHER INTERVENTIONS + Recombinant factor Vill infusions + If severe deficiency, immune system may perceive supplemental factors as foreign + production of antibodies (inhibitors) elimination of injected factorsfanaphylaxis + Avoid sports, trauma, medications that promote bleeding + Local measures * Treat hemarthrosis, hematomas (e 9. resting of affected part, application of ice) OSMOSIS.ORG 391 Figure 474 An abdorninal MRI scan in the coronal plane demonstrating a hematoma of the right psoas muscle in an individual with hemophilia Figure 47.2 An MRI scan of the knee demonstrating hemarthrosis. Individuals with hemophilia are at increased risk of hemarthrosis. HEMOPHILIA B osms.it/hemop (PATHOLOGY & CAUSES) C DIAGNOSIS ) + Mutated gene F9 on X chromosome + AKA Christmas disease * Qualitative/quantitative deficiency of coagulation factor IX — insufficient activation of intrinsic coagulation pathway — impaired hemostasis, + Less common SIGNS & SYMPTOMS * Spontaneous bleeding, delayed bleeding after trauma, hemarthrosis, hematomas, epistaxis, intracranial, GVgenitourinary tract, bleeding 392 OSMOSIS.ORG LAB RESULTS + Normal platelet count, prothrombin time (intrinsic pathway affected) + Factor IX clotting assaylgenetic mutation testing TREATMENT MEDICATIONS DDAVP + Not helpful in hemophilia B; stimulates WF — stabilizes only factor Vill, not IX OTHER INTERVENTIONS + Infusions of recombinant factor IX Chapter 47 Hypocoagulable Disorders VON WILLEBRAND DISEASE (PATHOLOGY & CAUSES ) + Most common inherited bleeding disorder of primary hemostasis + Defective platelet function with normal platelet count, * Quantitative/qualitative deficiency of vWF + impaired platelet aggregation, adhesion, dysfunction of factor Vill -+ deficiency in coagulation cascade — bleeding tendency + Hemostatic pressure (e.g. surgeryitrauma) TYPES Type! + Most common + Autosomal dominant, partial quantitative deficiency Type ll + Autosomal dominant, qualitative deficiency Type Ill * Autosomal recessive, severe quantitative deficiency + Typically asymptomatic * Surgery/traura provoke clinical manifestation + Spontaneous mucosal, cutaneous bleeding (e.g. epistaxis, easy bruising, excessive bleeding from wounds, bleeding gums) + Menorrhagia * Gl bleeding + Internalaint bleeding (Type Il) C DIAGNOSIS ) LAB RESULTS + Abnormal PFA-100 test + | factor Villa + LVWE + PTT prolonged * | platelet aggregation, presence of ristocetin + Collagen-binding function reduced + Platelet count norma’ TREATMENT MEDICATIONS + DDAVP. * Type |, Type + Factor VIIWWE concentrates + After major injury; during operation; ‘Type lil II not responding to DDAVP + High-purity vWF concentrates OTHER INTERVENTIONS + Local measures, tranexamic acid for mild bleeding OSMOSIS.ORG 393 Le} PV) ats) PATHOLOGY & CAUSES + Malignant neoplastic monoclonal proliferation of hematopoietic blood cells + Abnormal blood cells/precursors accumulate in bone marrow —+ physical ‘suppression — prevent maturation TYPES, Acute + Acute lymphoid leukernia = Acute myeloid leukemia Chronic * Chronic lymphoid leukemia * Chronic myeloid leukemia RISK FACTORS + Numerical, structural chrornosoral aberrations * Ionizing radiation, chemotherapy + Benzene exposure COMPLICATIONS + Infections, bleeding —+ death SIGNS & SYMPTOMS Cellular maturation absent + Anemia —* fatigue, shortness of breath, pallor + Thrombocytopenia — bruising, petechiae, epistaxis + Neutropenia —+ bacterial infections —» fever, pneumonia, sepsis 394 OSMOSIS.ORG GENERALLY, WHAT ARE THEY? Neoplastic infiltration * Bone marrow = Bone pain + Thymus © Palpable mass, airway compression * Liver and spleen = Hepatosplenomegaly * Lymph nodes + Lymphadenopathy * Meningeal infiltration © Headaches, vorniting, nerve palsies, nuchal rigidity LAB RESULTS * Blood count + Blood smear * Bone marrow smear + Immunophenotyping TREATMENT MEDICATIONS + Chemotherapy SURGERY + Bone marrow transplantation OTHER INTERVENTIONS + Radiation therapy Chapter 48 Leukernias ACUTE LYMPHOID LEUKEMIA (ALL) PATHOLOGY & CAUSES + Neoplastic monoclonal proliferation of lymphoid stem cells (lymphoblasts) in bone marrow + Immature lymphoblasts accumulate in bone marrow —» physical suppression —» prevent maturation TYPES B cell acute lymphoblastic leukemia (B-ALL) + Most common (85%) + Origin © Pre-B cells of bone marrow + Associated with translocations t(12,21), 4{9,22) T cell acute lymphoblastic leukemia (T-ALL) * Origin © Pre-T cells in thymus * Associated with NOTCH1 mutation RISK FACTORS + Young age (most common leukemia in children) = B-ALL: peak incidence at three years old ° T-ALL: peak incidence at 15-20 years old + Down syndrome (after age five} * Radiation exposure SIGNS & SYMPTOMS + Abrupt onset Cellular maturation absent + Anemia — fatigue, shortness of breath, pallor + Thrombocytopenia > bruising, petechiae, epistaxis + Neutropenia — bacterial infections — fever, pneumonia, sepsis Neoplastic infiltration + Bone marrow = Bone pain + Thymus + Palpable mass, airway compression + Liver and spleen = Hepatosplenomegaly = Lymph nodes = Lymphadenopathy + Meningeal infiltration + Headaches, voriting, nerve palsies, ‘nuchal rigidity ‘LAB RESULTS: Blood count, smear of peripheral blood + T lymphoblasts + t white blood cells Bone marrow smear + Hypercelluiar bone marrow, lymphoblast domination (> 20%) TALL « "Starry sky” pattern produced by phagooytosing macrophages + Mitotic figures Immunophenotyping + Terminal deoxynucleotidyl transferase (TAT) + Positive nuclear staining, distinguish from acute myeloid leukernia (AML) BALL + Express tumor markers CD10, CD19, cD20 TALL + Express tumor markers CD1, CD2, CD5, cD7, CDH OSMOSISORG 395 TREATMENT MEDICATIONS + Aggressive chemotherapy with prophylactic injections to scrotum, cerebrospinal fluid (CSF) +.95% complete remission, 75% cure rate » More successful in children > two years old + If spread to brain * Intrathecal chemotherapyitadiation therapy + Tyrosine-kinase inhibitors _\_/ MNEMONIC: ABCDE ~ Characteristics of Acute leukemias Acute: Blasts predominate Children Drastic course Elderly Few WBC's (+ Fevers} Figure 481 A bone marrow film from an individual with acute lymphoid leukemia. ACUTE MYELOID LEUKEMIA (AML) PATHOLOGY & CAUSES + Neoplastic monoclonal proliferation of myelogenous ster cells (myeloblasts) in bone marrow + Immature myeloblasts accumulate in bone marrow —» physical suppression —+ prevents maturation TYPES, Acute promyelocytic leukemia + Associated with translocation t(15,17) = disruption of retinoic acid receptor > promyelocytes accumulate Acute monocytic leukemia 396 OSMOSIS.ORG Acute megakaryocytic leukemia RISK FACTORS + Adults age; peak at 60 + Radiation, chemotherapy + Myeloproliferative disorders + Down syndrome (before age five) COMPLICATIONS + Disseminated intravascular coagulation (o1c) SIGNS & SYMPTOMS * Abrupt onset Chapter 48 Leukemias Cellular maturation absent SURGERY + Anemia + fatigue, shortness of breath, + Bone marrow transplantation pallor + Thrombocytopenia —» bruising, petechiae, epistaxis + Neutropenia — bacterial infections + fever pneumonia, sepsis Neoplastic infiltration + Symptoms less common in AML than ALL + Bone marrow Bone pain + Thymus Palpable mass, airway compression * Liver and spleen Hepatosplenoregaly + Lymph nodes ymphadenopathy + Meningeal infiltration Headaches, vomiting, nerve palsies, Figure 48.2 The histological appearance of a nuchal rigidity myeloid sarcoma, also known as a chloroma, The tumor is an extramedullary manifestation Neoplastic infiltration of acute myeloid leukemia, + Symptoms more common in AML than AL * Skin eukeria cutis 2° Swelling (classic) DIAGNOSIS LAB RESULTS: Blood count, blood smear + T leukocytes, anemia Bone marrow smear +t myeloblasts > 20% + Myeloblasts containing Auer rods [aggregates of myeloperoxidase) Figure 48.3 A CT scan of the head in the TREATMENT axl plane demonsratng a mye sarcoma MEDICATIONS extradural and destroying the overlying bone. + Chemotherapy + All-trans retinoic acid treatment For promyelocytic leukemia OSMOSIS.ORG 397 398 OSMOSIS.ORG Acute (2) Blasts predominate Children Drastic course Elderly Few WBC's (+ Fevers} CHRONIC LYMPHOID LEUKEMIA (CLL) osms.it/chronic-lymphoid (PATHOLOGY & Causes ) ( + Neoplastic monoclonal proliferation of mature, functionally abnormal 8 lymphocytes in bone marrow, blood + Mature B lymphocytes accumulate in bone marrow —» physical suppression —» prevent maturation CAUSES + Chromosomal abnormalities + Mutation of proteins involved in tyrosine kinase pathway (e.g. Bruton's tyrosine kinase) RISK FACTORS, * Adult age; most common leukemia in adults + Family history + Agent Orange exposure COMPLICATIONS + Abnormal Ig secretion * Hypogammaglobulinemia, autoimmunity (eg. autoimmune hemolytic anemia) + Richter syndrome + Progresses into aggressive lymphorna (eg diffuse large B cell lymphoma) SIGNS & SYMPTOMS + Late onset VW Cellular maturation absent + Anemia — fatigue, shortness of breath, pallor + Thrombocytopenia —+ bruising, petechiae, epistaxis + Neutropenia —> bacterial infections —» fever, pneumonia, sepsis Neoplastic infiltr + Symptoms less common in AML than ALL + Bone marrow = Bone pain + Thymus + Palpable mass, airway compression + Liver and spleen = Hepatosplenomegaly + Lymph nodes + Lymphadenopathy + Meningeal infiltration + Headaches, vomiting, nerve palsies, nuchal ‘LAB RESULTS: Blood count, blood smear + Lymphocytosis > 5,000 per mm! + Smudge cells: discuption of fragile cell membranes of abnormal lymphocytes Immunophenotyping + CDS, CD20, CD23 OTHER DIAGNOSTICS Surgery + Lymph node biopsy 1 small, round lymphocytes infitration Proliferation centers {pathognonic) TREATMENT MEDICATIONS + Chemotherapy + Immunotherapy ‘SURGERY * Bone marrow transplant OTHER INTERVENTIONS * Radiation therapy Figure 48.6 A CT scan in the coronal plane demonstrating splenomegaly as a ‘consequence of chronic lymphoid leukemia. Chapter 48 Leukemias Figure 48.4 The gross pathological appearance of the spleen in a case of chronic lymphoid leukemia, The lymph nodes at the hilum of the spleen are also involved Figure 48.5 The histological appearance of chronic lymphocytic leukernia. There is @ proliferation contre (also known as @ pseudofollicie) composed of malignant lymphocytes with bigger, larger nuclei. This proliferation centre is surrounded by small, darker staining lymphocytes OSMOSISORG 399 400 OSMOSIS.ORG CHRONIC MYELOID LEUKEMIA (CML) osms.it/chronic—myeloid PATHOLOGY & CAUSES + Neoplastic monoclonal proliferation of mature granulocytes/precursors + Mature granulocytes accumulate in bone matrow —» physical suppression —+ prevent maturation + Associated with Philadelphia chromosome (9, 22) BCR-ABL1 fusion — chimeric protein with strong tyrosine kinase activity (> 90% of individuals) RISK FACTORS + Adult age (> 40 years}, radiation exposure, benzene exposure SIGNS & SYMPTOMS * Classified by clinical signs, lab results Chronic phase (85% at time of diagnosis) + Leukocytosis (predominantly neutrophils) + Asymptomaticinon-specific symptoms + Fatigue, weight loss, loss of energy, fever Accelerated phase + > 20% basophils in blood/bone marrow + 10-19% myeloblasts in blood/bone marrow + Anemia * Splenomegaly, hepatomegaly, lymphadenopathy + Recurrent infections. + Bleeding, petechiae, ecchymoses + Treatment less effective Blast crisis + Terminal phase; rapid progression, low survival rate + > 20% myelobiastsslymphoblasts in blood! bone marrow + Increasing anemia, thrombocytopenia, basophilia * Bone pain, fever + Significant splenomegaly LAB RESULTS: Blood count, blood smear + f granulocytes (basophils, eosinophils, neutrophils) Bone marrow biopsy + Hypercellularity (cells of myeloid cell line/ precursors) + Karyotypic analysis + Fluorescent in situ hybridization (FISH), PCR: BCR-ABL1 gene mapping + Mild fibrosis ae. iy Figure 487 A bone marrow smear demonstrating a small, hypolobated megakaryocyte, typical of chronic myelogenous leukernia, Chapter 48 Leukernias TREATMENT MEDICATIONS + Tyrosine kinase inhibitors ‘SURGERY + Bone marrow transplantation CAN eats a ote) a oh vn Crea aa —— cri Greet vcramononee | SS8C | aSeoms ease Cad vonioa, | Ot —_— = as cc Greaings ‘bone marrow) owone seine ‘cetktngs | jecning | tzaorte ymphooyem 10% blasts. Parra orca Poel (ome Blast 1 bast, CELLULAR Carty OSMOSIS.ORG 401 NOTES. Laos} Pal T sy GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES + Lymphocytic tumors + Nodal lymphomas: develop in lymph nodes + Extranodal iymphomas: develop infspread to other organsitissues + Neoplastic B cells do not produce antibodies + Attract non-neoplastic inflammatory cells (eg.T cells} via chemokines + Activate fibroblasts to make collagen, eosinophils TYPES, Hodgkin's lymphomas + Spread contiguously (to nearby lymph nodes: rarely extranodal) » Prognosis better for Hodgkin's: contiguous spread allows direct, targeted treatment + Reed Sternberg cells Non-Hodgkin's lymphomas + Spread non-contiguously + No Reed-Sternberg cells CAUSES * Genetic mutation in lymphocytes + no apoptosis + cell divides — becomes neoplastic cell + Possible link between viruses (e.g. HIV, EBV}, lymphomas COMPLICATIONS: + Metastasis to spinal cord — spinal cord compression —+ sensoryimotor deficits 402 OSMOSIS.ORG + Metastasis to bone marrow — crowds ‘out normal marrow progenitor cells —> decreases healthy erythrocytes/leukocytes! platelets SIGNS & SYMPTOMS + B (systemic) symptoms: fever, night sweats, weight loss, fatigue, loss of appetite, chills DIAGNOSIS DIAGNOSTIC IMAGING CT scan, positron emission tomography (PET) scan + Stage of lymphorna LAB RESULTS: Lymph node biopsy * Confirmation, type TREATMENT * Depends on extent, stage, category; age, health of individual; coexisting diseases MEDICATIONS * Chemotherapy ‘SURGERY + Stem cell transplant OTHER INTERVENTIONS + Radiation therapy Chapter 49 Lymphomas HODGKIN’S VS. NON-HODGKIN’S COREY (aan) COA NODE Roos ‘Classe nodular sero. ve cea, Iymohacye-depleted,ymohocyt-ich) Nodular mphocye predominant (has popcom cells no Rood Sternberg cl) Painless localized mphadenopathy Der eR Ary ENS ‘Smal ymphacycImphoplasmacytc, ‘earanodal marginal zane (MALT). foticulr, mane cal ifse large Bel, ‘Brkt precursor T-lymphoblaet, Peripheral Tcl Painless oalzed lymphadenopathy, Po) *B"eymptoms RISK FACTORS: “B"symptoms andlor symtoms of extranodal spread ‘Associated acquired or congenital mmunodeiceney Endemic Burt phoma toselyassocated with EBV HODGKIN'S LYMPHOMA PATHOLOGY & CAUSES + B-cell tumors; Reed-Sternberg cells: arg= mononuclear, neoplastic cells; two cells fused, two nuclei (resemble owl eyes) TYPES, Classical Hodgkin's lymphoma (CHL) + More common + Reed-Stemberg cells express CD45/CD20; not CD15/CD30 + Histological subtypes: background inflammatory cells, fibrosis Histological CHL subtypes + Nodular sclerosis Hodgkin's lymphoma + Most common: esp. in young adults » Neoplastic, inflammatory cells surrounded by collagen from fibroblasts forming nodules += Lacunar cells (Reed-Sternberg cells with shrunken cytoplasm, nucleus appears as if in middle of lacunafake) * Good prognosis + Mixed cellularity » Second most common; more common in older adults + Prevalent in HIV-positive individuals, » Mixed inflammatory background OSMOSISORG 403 composed of eosinophils, neutrophils, plasma cells, histiocytes surrounding Reed-Stemberg cells + Lymphooyte-rich Reed-Sternberg cells surrounded by lymphocytes * Best prognosis, caught early + Lymphocyte-depleted * Rarest; median age: 30-37 years ® No reactive lymphocytes, abundance of Reed-Stemberg cells + Prevalent in HIV-positive individuals Worst prognosis, advanced stage diagnosis Nodular lymphocyte predominant Hod- gkin's lymphoma + More common in individuals who are biologically male + Abnormal B cells express CD20/CD45; not cD15/CD30 + Lymphocyte-predominant cells: no Reed Sternberg cells + Large groups of lymphocytes form nodules around lobulate-nucleated ‘popcorn’ cells (variant of Reed Sternberg cells) + Slow-growing, highly curable + Small risk of transformation non-Hodgkin's lymphoma aggressive STAGING + Stage 1: limited to one lymph node group! group of adjacent lymph nodes + Stage 2: = two lymph node regions on same side as diaphragm + Stage 3: lymph nodes on both sides (superior, inferior) of diaphragm + Stage 4: lymph nodes superior, inferior to diaphragm; liver/spleerylungs/bone marrow + Subdivisions * Category A:no symptoms * Category B: B symptoms preset » Category E: organsitissues beyond lymph system 404 OSMOSIS.ORG SIGNS & SYMPTOMS + Painless cervical lymphadenopathy © Mediastinal lymphadenopathy: nodular sclerosis subtype * Cytokine release: fever, drenching night sweats, weight loss Rarely present with nodular lymphocyte predominant Hodgkin's lymphoma + B symptoms Nodular sclerosis: about 50% Mixed cellularity: common Lymphocyte-rich: rare Lymphocyte-depleted: common DIAGNOSIS DIAGNOSTIC IMAGING * CT scan, PET scan LAB RESULTS + Lymph node biopsy Figure 494 A CT scan of the chest in the coronal plane demonstrating a large mediastinal mass. The mass is a focus of Hodgkin's lymphoma, TREATMENT MEDICATIONS Rituximab + For nodular lynphocyte predominant. Hodgkin's lymphoma + Monoclonal antibody, binds CD20, induces complernent-mediated lysis —+ apoptosis Figure 49.3 The gross pathology of a soleen that has been infiltrated by Hodgkin's lymphoma. Chapter 49 Lymphomas Figure 49.2 The histological appearance of Hodakin's lymphoma, Reed-Sternberg cells are pathognomonic of this disease. NON-HODGKIN'S LYMPHOMA osms.it/non-hodgkin PATHOLOGY & CAUSES + B/T cell tumors, no Reed-Sternberg cells, TYPES B cell lymphomas + More common + Neoplastic 8 cells: CD20 on surface + Rate of growth: siow/aggressive/highly aggressive B cell lymphoma subtypes * Diffuse large B cell lymphoma © Aggressive = Most common * Follicular lymphoma *Siow arowing + Chromosomal transiocation:t(14.18) “+ BCL2 gene placed atterIg heavy chain promoter —» overexpression of BCL2 ~ inhibition of apoptosis -» cell proliferation *BCL2 promotes cell viabilty, blocks apoptosis + Burkitt lymphoma Highly aggressive arry sky” appearance under microscope + Stars: tingible bodies (macrophages) with phagocytosed dead neoplastic cells + Sky: dark neoplastic lymphocytes = Chromosomal translocation: (8,14) — Myc gene moved adjacent to IaH OSMOSISORG 405 promoter sequence —> upregulation of ‘Myc gene —» Myc gene stimulates cell growth, metabolism —» increased cell division * Variant in individuals of African descent: extranodal involvement of jaw, associated with EBV infection » Variant in individuals of non-African descent: extranodal involvement of abdomen (e.g. at ileocecal junction), less frequently associated with EBV infection + Mantle cell lymphoma » Aggressive * Chromosomal translocation: t (11,14) + BCL1 gene moved to Ig promoter = upregulation of BCL2 gene + stimulation of cell growth + Marginal zone lymphoma * Indolent * Most common type © Associated with mucosa-associated lymphoid tissue (extranodal) in cases of chronic inflammation of stomach lining (e.g. chronic H. pylori infection} » May occur in lymph nodes (nodal marginal zone iymphoma)ispleen {splenic marginal zone lymphorna} * Lymphoplasmnacytic lymphorna ® Indolent + Bone marrow, lymph nodes, spleen © Waldenstrom macroglobulinemia: neoplastic cells produce M proteins {IgM} in high levels —+ IgM released into aad 1s 3g letra ee AQT tel Thy Crea ad BURKITT (VERY AGGRESSIVE) Aolesce young adults Mostyaduts (Most common type) Mosty ads (Fis with aged abate DC oat Aut (Fiske twit age) Cane pray (agaressive) Pans MARGINAL ZONE aa) CE aL pn (ORE) uaa aNd AGGRESSIVE) 406 OSMOSIS.ORG Coane ‘Axis trom germina centr B al Cina forms: endemic sporadic, mmunodeRcency-assciated: Stary sk" appearance ‘Asis from germinal centr or post germinal center Bea Difuseextrancdel involvement, oten present in Gi wact Variant arises trom thymic (med & cals ‘Ales fom 8 cll of the mocosa-associated ‘yoo tissue MALT) ten present in Gl act {Gastric MALT Hymphoma linked with H pyr Forms lmphoepitheal lesions "Aises rom germinal cari B cals (eentroctes and centoblats Painless, relapsinglemiting pater of lymphadenopathy: Microscopic and gross nodulor appearance May transform into more aggressive NEL "arises frm peripheral 8 lymphocytes Manes fram Waldenstiom macroglobuinern ‘Matgnant cals resemble plasma calls with large amounts of Barophie cytoplasm: Nucous contains "spoke wheal the" chromatin "isos from pre-gerinal enter 8 calls of the mantle zone, Results from deregulation of cylin D1: Difuse growth pattern; Cells nave “notched” nucle

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