Board Review in Hematology PDF

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BOARD REVIEW IN HEMATOLOGY HEMOSTASIS

o Hyalomere – surrounds the chromomere, nongranular and clear to light blue • Discoid-shape

Definition: The process by which the body stops bleeding and maintains blood in the fluid state within the vascular compartment. 5 General Components: 1. Vascular system 2. Platelets 3. Coagulation Factors 4. Fibrinolytic Factors 5. Naturally Occuring Inhibitors

NOTES: • Endomitosis – nuclear division without cytoplasmic division. • 1 megakaryocyte = 2,000-4,000 platelets • 8-11 days – platelet life-span • Circulating platelets represents 2/3 and the remaining 1/3 are stored in the spleen. • Thrombopoietin – increases platelet production

2 Phases: A. Primary Hemostasis • Reversible • Response of blood vessels and platelets to tissue injury.

PLATELET STRUCTURE A. Peripheral Zone 1. Glycocalyx

B. Secondary Hemostasis • Irreversible • Involves participation of clotting factors. MEGAKARYOCYTE-PLATELET SYSTEM Platelets: Maturation sequence of megakaryoblast takes about 5 days. Platelets are produced directly from the megakaryocyte cytoplasm. As the megakaryocyte matures, clusters of granules aggregate to form platelets. 1. Megakaryoblast • 20-50 um diameter • blue cytoplasm • N/C ratio is about 10:1 • Multiply nucleoli • Fine chromatin 2. Promegakaryocyte • 20-60 um diameter • less basophilic cytoplasm • chromatin becomes coarse • irregularly shaped nucleus, may show slight lobulation • N/C ratio is 4:1 to 7:1 • Demarcating Membrane System (DMS) appears 3. Mature Megakaryocyte • 40-120 um in diameter • cytoplasm contains coarse clumps of granules aggregating into little bundles, which bud off from the periphery to become platelets • multiple nuclei are present • no nucleoli is visible • N/C ratio is less than 1:1 4. Metamegakaryocyte • Disintegrated cells surrounded by platelets • Platelet producing stage 5. Platelet or Thrombocyte • 1-4 um diameter • light blue to purple, very granular o Chromomere – granular and located centrally

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• Amorphous exterior coat or outer membrane • Contains glycoproteins that acts as a receptor and useful in aggregation and adhesion. 2. Plasma Membrane • Consist of 30 or more glycoproteins • Phospholipid bilayer 3. Submembranous Area B. So-Gel Zone 1. Microtubules • Tubulin – maintains platelet shape • For the discoid shape of the platelet 2. Microfilaments • Contains the contratile protein known as thrombosthenin (15%). • Thrombosthenin: Actin and myosin or ctinomyosin – responsible for clot retraction. C. Organelle Zone 1. Alpha Granules – amplifys reaction to injury; 20-200/platelet. • PF4 – inhibits heparin • Beta-thromboglobulin (BTG) – inhibits heparin 1

• Collagen Type I and III o Synthesized by smooth muscle o Located in deeper regions of blood vessel o Promotes adh esion o Facilitates aggregation and release • Collagen Type IV and V o Synthesized by endothelial cells o Located below the endothelium o Promotes adhesion o Cannot facilitate aggregation • Thrombin – increases ADP release; TXA2 synthesis; and coagulation. • Aspirin inhibits cyclooxygenase and prolong BT.

• Platelet-derived Growth Factor (PDGF) – promotes growth and proliferation of smooth muscles. • Thrombospondin (TSP) – (+) aggregation • Chemotactic Factor • Permeability Factor • Bactericidal Factor • Acid Hydrolases • Fibrinogen (FGN) • FVIII:vWF • FV 2. Dense Granules/Bull’s Eye Granules • Calcium • ADP - (+) aggregation • Serotonin - vasoconstriction • ATP • Catecholamines (EP/NEP) D. Membranous System 1. Dense Tubular System • Site of arachidonic acid metabolism • Site of prostaglandin synthesis and Ca++ sequestration • Derived from smooth ER of megakaryocyte 2. Open Canalicular System • For release of granules

PRIMARY HEMOSTASIS I. Vascular System A. Arteries B. Veins C. Capillaries II. Platelets: Formation of Primary Hemostatic Plug A. Adhesion • Process where platelet stick to foreign surface receptors: o GpIb – receptor for vWF o vWF – bridge between platelet and collagen. o Gp1a – directly binds collagen in less extent. B. Activation • Morphologic and functional changes in platelets. C. Secretion • Release of granules that promotes aggregation. D. Aggregation • Interaction and adhesion of platelets to one another to form initial platelet plug. • Occurs in the presence of calcium and fibrinogen • GpIIb/IIIa – receptor for fibrinogen

PLATELET CYCLOOXYGENASE PATHWAY Arachidonic acid ↓ cyclooxygenase Prostaglandin Endoperoxide ↓ thromboxane synthetase Thromboxane A2 PLATELET LIPOOXYGENASE PATHWAY A. Blood Vessel Linoleic Acid ↓ lipooxygenase Monohydroperoxide ↓ peroxidase 13 HODE (13-hydroxyoctadecadrenoic acid)

SECONDARY HEMOSTASIS – Involves coagulation factors

13-HODE • Inhibits adhesion • Released by intact blood vessel into endothelial lining • chemorepellant

• Blood factors are classified as: 1. Substrate, substance on which enzyme acts 2. Zymogen, enzyme precursor 3. Cofactor, component that aids in the activation of zymogen to active enzyme 4. Calcium • In conversion of zymogens to enzymes, either they are serine proteases (II, VII, IX, X, XI, XII), which uses serine as the active site and cleave peptide bonds, or they create covalent bonds as transaminases. • Blood factors are produced mostly in the liver and circulate in an inactive precurson form.

B. Platelet Arachidonic Acid ↓ kipooxygenase Monohydroperoxide ↓ peroxide 12-HETE (hydroxyeicosatetraenoic acid) 12-HETE – promotes adhesion NOTES: • Mitochondria – source of ATP for platelet function (10-60/platelet) • TXA2 – promotes aggregation and vasoconstriction

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2

Serine Proteases:

II, VII, IX, X, XI, XII, Prekallikrein, HMWK

Cofactor:

V and VIII

Numeral I II III IV V

Fibrinogen Prothrombin Tissue Factor Calcium Proaccelerin

VII VIII:C

Proconvertin Antihemophilic Factor

IX

X

XI

XII XIII

XII XIII

COAGULATION FACTORS Name Synonym

Prekal HMWK

Prethrombin Tissue Thromboplastin

Plasma Thromboplastin Component (PTC) Stuart-Prower Factor

Plasma Thormboplastin Antecedent (PTA) Hageman Fibrin Stabilizing Factor

Prekallikrein HMWK

Serine Pretease Transglutaminase Serine Pretease Serine Pretease

Factor I

Inherited Coagulopathies Inheritance Coagulopathy Pattern

V

Autosomal recessive

Factor V Def. (OWRENS’s Dse.)

VII

Autosomal recessive

Factor VII Def.

VIII

X-linked recessive Autosomal dominant X-linked recessive

Hemophilia A

X

Autosomal recessive

Factor X Def.

XI

Autosomal recessive

Hemophilia C

Autosomal recessive Autosomal recessive

Factor XII Def.

*

Factor XIII Def.

Autosomal recessive Autosomal recessive

Fletcher Trait

Liver Dse. Vit. K Deficiency Anticoagulant Therapy *

Fritzgerald Trait

*

XII XIII

Prekall HMWK

I II V VII VIII:C IX X XI

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Fibrin clot Serine Pretease Cofactor Serine Pretease Cofactor Serine Pretease Serine Pretease Serine Pretease

Common Common Common Extrinsic Intrinsic Intrinsic Common Intrinsic

No Yes No Yes No Yes Yes No

Yes No Yes No Yes No No Yes

Prothrombin deficiency

vWD Hemophilia B

Liver Dse. Vit. K Deficiency Anticoagulant Therapy Severe liver Disease DIC Fibrinolysis Liver Dse. Vit. K Deficiency Anticoagulant Therapy Severe liver Disease DIC Fibrinolysis Liver Dse. Vit. K Deficiency Anticoagulant Therapy Liver Dse. Vit. K Deficiency Anticoagulant Therapy *

(common in Eastern European Jewish descent/Ashkenazi Jews)

CONDITIONING MOST OFTEN ASSOC. WITH PHYSIOLOGIC VARIATIONS IN COAGULATION AND FIBRINOLYTIC FACTORS Condition

Active Form

Dysfibrinogenemia

Severe liver Disease DIC Fibrinolysis

* Unclear whether any acquired disorders cause FXI and XII deficiencies or Prekallikrein and HMWK deficiency.

CHARACTERISTICS OF COAGULATION FACTORS Factor

Acquired Coagulopathy

Afibrinogenemia

IX

INHIBITORS OF COAGULATION - major site of inhibition: endothelium and platelet 1. Protein C – degrades FVa and FVIIIa 2. Protein S – degrades FVa and FVIIIa 3. ATIII – major inhibitor of thrombin, also inhibits FIXa, Xa, Xia, XIIa, Kallikrein, and Plasmin. 4. Heparin Cofactor II – inhibit thrombin 5. α2-macroglobulin – forms a complex with thrombin, kallikrein and plasmin, thus inhibiting their activities. 6. Extrinsic Pathway Inhibitor (EPI) and Lipoprotein Assoc. Coagulation Inhibitor (LACI) – inhibits the VIIa-tissue factor and Kallikrein, it also inhibits FXIa and plasmin. 7. C1 Inhibitor – inactivator of FXIIa and Kallikrein, it also inhibits FXIa and plasmin. 8. α1-antitrypsin – inhibitor or thrombin, Xa and Xia.

Present in BaSO4 Adsorbed Plasma

Yes Yes Yes Yes

Autosomal recessive Autosomal dominant Autosomal recessive

II

Glass Factor Contact Factor Laki-Lorand Factor Fibrinase Plasma transglutamase Fibrinoligase Fletcher Factor Fritzgerald Factor Contact activat’n Cofac. Williams Factor Flaujeac Factor

Vitamin K Dependent

No No No No

DISORDERS OF COAGULATION CAUSING CLOTTING FACTOR DEFICIENCIES

Accelerator globulin (aCg) Stable factor, SPCA Antihemophilic globulin Antihemophilic Factor A Platelet Cofactor A Christmas Factor AHF-B Platelet Cofactor B Stuart Factor Prower Factor Autoprothrombin III AHF-C

Pathway Paticipation

Intrinsic Common Intrinsic Intrinsic

Stress, Tissue Necrosis, Inflammation Pregnancy Oral Contraceptives Hypermetabolism Vigorous Exercise Chronic Thrombocytopenia

Hypothyroidism Child birth Surgical operations, Trauma Myocardia Infarction Acute illness

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Factor Increases

Factor Decreases

I I, VIII, IX, X I, VIII, VII, IX, X I, VII, plasminogen VIII, XI, XII VIII

XIII, XI, ATIII

IX, XI, plasminogen I, VIII

II. Quantitative Platelet Disorders

PLATELET DISORDERS PRIMARY HEMOSTASIS DISORDERS

A. Thrombocytopenia • Decreased platelet count due to: a. Generalized BM suppression/Aplastic Anemia – decrease in all cell types – acquired thru ionizing radiation and chemotherapeutic agents – Fanconi’s Anemia (congenital) – renal glucosuria, mental retardation – Caused by chloramphenicol, benzene b. Decrease platelet survival due to increase platelet destruction – DIC – mass consuption of platelet – ITP – formation of AutoAbs for plt. c. Increase platelet sequestration by the lesion – Splenomegaly 2/3 (70-80%) platelet – circulation 1/3 (20-30%) platelet - spleen d. Selective Suppression of Megakaryocytes – Associated with chlorothiazide e. TAR Syndrome – Seen in neonates – Absent or decreased and abnormal megakaryocyte in BM – Congenital deformities of arm f. Myelophthisic Process – Space-occupying lesions in BM like fibrosis, leukemia etc. g. Ineffective thrombopoiesis assoc. with ethanol abuse, sever IDA, and PNH h. May Hegglin Anomaly – Wiskott-Aldrich Syndrome - Triad • Immune platelet destruction a. Isoimmune/Post-Transfusion Purpura – Lack platelet-specific antigen located in platelet membrane glycoprotein III. b. Neonatal Isoimmune Thrombocytopenia - caused by transplacental passage of maternal IgG against fetal platelet Ags. c. Patients Refractory to Platelet Tranfusion - Characterized by failure to increase the platelet count after transfusion d. Immune Thrombocytopenic Purpura e. Dug0induced Thrombocytopenia - Associated with quinine, quinidine, sulfonamides, rifampicin, chloraquin.

I. Bleeding Disorders (Vascular Defects) A. Hereditary Connective Tissue Defects 1. Ehler-Danlos Syndrome • (+) hyperextensible joints and hyperplastic skin • defect in peptidase enzyme that converts procollagen to collagen. • Increase vascular fragility Note: Marfan Syndrome – increase vascular fragility.

2. Pseudoxanthoma Elasticum • Connective tissue elastic fibers in small arteries are calcified and structurally abnormal. B. Acquired Connective Tissue Defects 1. Scurvy (Vitamin C Deficiency) • Deficiency in ascorbic acid which is important in the formation of the intact vascular basement membrane. • (+) gingival bleeding and hemorrhage into subcutaneous tissues and muscles. • Vit. C is responsible for hydroxylation of lysine and proline during collagen formation. 2. Senile Purpura • Degeneration of collagen, elastin, and subcutaneous fat. C. Hereditary Alteration of Vessel Wall 1. Hereditary Hemorrhagic Telangiectasia • ESLER-WEBER-RENDU • Dilated small blood vessels with poor wall support and decrease ability to contract • Most common vascular wall defect • Walls are thinner • Telangiectasias are permanent 2. Congenital Hemangiomat a • KASABACH-MERRITT Syndrome • Assoc. with tumors composed of vessels that commonly swell and bleed at the surface. D. Endothelial Damage 1. Autoimmune Vascular Purpura a. Drug-induced Purpura • Aspirin, coumarin, penicillin, sulfonamides, sedatives b. Allergic Purpura c. Henoch-Schoenlein Purpura • Associated with abdominal pain secondary to GI bleeding • Henoch – “abdominal” pain secondary to GI bleeding • Schoenlein – “joint” pain

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B. Thrombocytosis (Splenectomy) a. Primary (Autonomous) • Increased in platelet; uncontrolled proliferation of platelet • Myeloproliferative (CML, PV, MMM, ET) b. Secondary (Reactive) 4

• Moderate increase platelet; asymptomatic • Ex. Splenectomy; after blood loss

– Lack alpha and dense granules Syndrome

III. Qualitative Platelet Disorders A. Hereditary 1. Adhesion Defects a. Bernard-Soulier Syndrome • Lack of GpIb (receptor for vWF) • (+) “giant platelets” (>20 um) b. vWD • most frequently inherited coagulopathy • lacks vWF

Gray-Platelet Wiskott-Aldrich Hermansky-Pudlack Chediak-Higashi

Normal Normal Abnormal

Abnormal Abnormal Normal

+ -

B. Acquired a. Aspirin (Acetyl Salicylic Acid) – inhibits cyclooxygenase thru irreversible acetylation of the enzyme’s active site.

Note: The interaction of vWF with the platelet is primarily through the GpIb receptor, and both the vWF and GpIb must be present for normal platelet adhesion. In vwD, it is the plasma component that is defective, whereas Bernard-Soulier, it is the platelet.

SECONDARY HEMOSTASIS DISORDERS I. Inherited Disorders of Coagulation A. Intrinsic 1. Factor XII (Hageman) / HMWK (Fritzgerald) / Prekallikrein (Fletcher) Deficiencies • DON'T suffer from bleeding disorder 2. Factor XI (Hemophilic C/Rosenthal’s Syndrome) Deficiency 3. Factor VIII:C Deficiency (Classic Hemophilia or Hemophilia A) • MOST severe • Sex or crosslinked • Therapy: a. Cryoprecipitate (Prothrombin Complex Concentrates) o Contains FII, VII, IX, X o Bypasses the need for FVIII:C o Reserve for life threatening situations b. DDAVP o An analogue of ADH that maybe substituted for blood components o Increase plasma FVIII:C by causing its release from endogenous stores. o intravenous 4. Factor IX Deficiency (Hemophilia B or Christmas Disease) • Therapy: FFP or FIX Concentrate 5. vWF Deficiency • deficiency of FVIII:C and vWF • MOST inherited coagulopathy • Therapy: Cryoprecipitate (the only component that contains FVIII:C)

2. Aggregation Defects a. Glanzmann’s Thrombasthenia (GT) • Lack of GpIIb/IIIa (receptor of fibrinogen) • Failure of platelet to aggregate even with stimulus (EAC) • (-) clot formation b. Afibrinogenemia • Similar to GT but fibrinogen is lacking • Treated with cryoprecipitate 3. Secretion Defects a. Storage Pool Defects • Gray Platelet Syndrome – Lacks alpha-granules • Wiskott-Aldrich Syndrome – Characterized by triad of thrombocytopenia, recurrent infection, and eczema. • Hermansky-Pudlak – Characterized by triad of tyrosine-positive oculocutaneous albinism, accumulation of ceroid-like pigment in macrophage, and bleeding tendency. – Lack dense granules • Chediak Higashi Anomaly – Characterized by albinism, recurrent infection and giant lysosomes in all granule contg. cells.

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+ + -

b. Granule Release Defects (Aspirin-like) • Prostaglandin Enzyme Deficiency – Defect in cyclooxygenase; abnormal TXA2 activity – Irreversible

Platelet Aggregation Test EAC Ristocetin Bernard Soulier vWD Glanzzman’s T.

Granules Alpha Dense

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B. Extrinsic 1. Factor VII Deficiency

3. Protein S Deficiency • Destroys Factor V and VIII • Influenced by warfarin therapy 4. Homocytinuria

C. Common 1. Factor X Deficiency (Stuart-Prower) • Therapy: FFP or PT Complex Concentrate 2. Factor V Deficiency (Owren’s Dse) 3. Factor II Deficiency 4. Factor I Deficiency 5. Factor XIII Deficiency

B. Secondary 1. Lupus Anticoagulant • Associated with high risk of throbosis due to prostacyclin inhibition. Factor Deficiency

II. Acquired Disorders of Coagulation and Fibrinolysis A. Hepatic Disease • Liver is the primary site of procoagulant, fibrinolytic and inhibitory synthesis. B. Vitamin K Deficiency • Due to: decrease dietary intake absence of normal flora in GIT obstructive jaundice anatagonist drug (courmarin) • Prolong APTT and PT C. Circulating Anticoagulant • Majority are antibodies which is stimulated by blood transfusion. D. Therapeutic Anticoagulation • Coumarin (oral) – discovered in Wisconsin • Warfarin – most frequently used; interferes with the carboxylation of the Vit Kdependent plasma factors in the liver by interrupting the enzymatic phase which results into non-functional proteins circulating plasma – reffered to as Protein Induced by Vitamin K Anatagonist (PIVKA) • Heparin (IV anticoagulant) E. MaIIssive Transfusion Effects • Increase citrate (binds to calcium which result to bleeding) • Decrease labile factors and platelet in stored blood. F. DIC • Increase: TCT, PT, APTT, FSP • Decrease: Platelet count, FGN, ATIII • (+) D-Dimer Test • Treatment: FFP, Platelet Concentrate, Cryoprecipitate

BT

CT

PT

APTT

Stypven

TT

Ducket’s

↑ N N N N N ↑ N N N N N ↑

N ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ N ↑

N ↑ ↑ ↑ ↑ N N N ↑ N N N ↑

N ↑ ↑ ↑ N ↑ ↑ ↑ ↑ ↑ ↑ N ↑

N ↑ ↑ ↑ N N N N ↑ N N N ↑

N ↑ N N N N N N N N N N ↑

N N N N N N N N N N N Abnormal Abnormal

o

1 Hemostasis Fibrinogen Prothrombin Parahemophilia Factor VII Hemophilia A vWD Hemophilia B Factor X Hemophilia C Factor XII Factor XIII DIC

NOTE: Factor VIII Deficiency – negative for bleeding tendency PT APTT

= Extrinsic / Common = Intrinsic / Common

SUBSTITUTION STUDIES PT

APTT

TT

I II V VII VIII IX X XI or XII

Abn Abn Abn Abn N N Abn N

Abn Abn Abn N Abn Abn Abn Abn

Abn N N N N N N N

C C C C C C C C

Factor

Fresh Plasma

Aged Plasma

Adsorbed Plasma

I II

         

         

         

VIII IX X XI XII XIII

A. Primary 1. Antithrombin III Deficiency • Recurrent venous thromboembolism • Treated with heparin 2. Protein C Deficiency • Recurrent superficial or deep vein thrombophlebitis and frequent pulmonary emboli • Influenced by warfarin therapy • Types I – decrease Ag level and activity II – normal Ag level,...