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Thrombogenic
Favoring or inducing the formation to clot
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Coagulopathy
Defect due to abnormal conc. or function of coagulation factors
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Petechia
Small pinpoint hemorrhages in skin/mucous membranes
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Ecchymoses
Larger hemorrhages in skin/mucous membranes
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Thrombocytopenia
Reduced number of Thrombocytes
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Thrombocytopenia
Defect (congential/acquired) in platelet function
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Fibrinolysis
Normal or pathologic dissolution of a fibrin clot
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DIC
Disseminated intravascular coagulation
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vWD
von Willebrand disease
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OSPT
One stage prothrombin time
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APTT
Activated partial thromboplastin time
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ACT
Activated clotting time
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Major Stages of Hemostasis
- 1. Blood vessel constriction (neural)
- 2. Platelet activation (primary (temporary) hemostatic plug & Secondrry (stable) hemostatic plug)
- 3. Coagulation activation (tissue factors, thromboplastin)
- 4. Dissolution of fibrin clot
- 5. Endothelial repair
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Hemostasis
- Arrest of bleeding. There are 5 stages.
- 1. Vascular damage>vasoconstriction>platelet adhesion
- 2. Platelet recruitment>aggregation>fibrin formation>primary hemostatic plug (fragile)
- 3. Reinforcement of stable plug with fibrin>secondary hemostatic plug (thrombus)
- 4. Dissolution of fibrin clot: clot retraction & activation of fibronolysis
- 5. Endothelial repair>degradation of fibrin clot.
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Components of the hemostatic system
- 1. Vascular endothelium
- 2. Platelets
- 3. Plasma proteins
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Vascular endothelium (both anti and pro-coagulant properties)
- Anti-coagulant properties
- 1. Smooth surface, -ve charge (single protein layer)
- 2. Secretion of inhibitors of platelet function and fibrin formation: PGI2, NO, ADPase, Tissue factor pathway inhibitor (TFPI), Thrombomodulin
- 3. Secretion of activators of fibrinolysis: Tissue plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA)
- Pro-coagulant properties
- 1. Synthesis & secretion of tissue factor (III Thromboplastin) to initiate clot formation
- 2. Adhesive proteins (von Wilebrand factor) that attach activated platelets to surface
- 3. Secretion of inhibitors of fibrinolysis: Plasminogen activator inhibitor (PAI), Thrmobin activatable fibrinolytic inhibitor (TAFI)
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Evulate Primary hemostasis (3 ways)
- 1. Platelet tests
- Platelet counts: Normal Dogs & Cats > 200,000/ul; Cattle, horse >100,000/ul
- Thombocytopenia: <20,000/ul > bleeding from small vessels
- Platelet function: measure platelet adhesion, aggregation, platelet release reaction
- 2. von Willebrand factor
- Large glycoprotein in vessel wall, made of protein polymers (multimers)
- Assays: ELISA for von Willebrand factor antigen, multimeric analyses, functional tests, genetic tests
- 3. Buccal mucosal bleeding time (BMBT)in vivo test for primary hemostasis (platelets, wall defects & vWF) in small animals. Normal dogs clot in less then 4 min
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Primary Hemostasis disorders
- Acquired
- Thrombocytopenia (<20,000/ul eg. bone marrow dysfunction, immune-mediated)
- Acquired Thrombopathies (eg. liver failer, uremia, drug induced)
- Congenital
- von Willebrand disease (dogs, cats, pigs: delayed clotting after trauma due to weak platelet aggregates)
- Inherited Thrombopathies
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Clotting Factors
- Factor I Fibrinogen (liver)
- Factor II Prothrombin (liver) (Vitamin K-dependent)
Factor III Thromboplastin (tissue factor) (VE)- Factor IV Calcium
Factor V Proaccelerin, Labile factor, Accelerator globulin (VE)- Factor VII Proconvertin, SPCA, Stable factor (liver)
- Factor VIII Antihemophilic factor (AHF, AHF-A), Antihemophilic globulin (VE)
- Factor IX Plasma thromboplastic component (
PTC), Chr istmas factor, AHF-B (liver)- Factor
X Stuart-Prower factor (VE)- Factor XI Plasma thromboplastin antecedent (PTA), AHF-C (liver)
- Factor XII Hageman factor, Glass factor (liver)
- Factor XIII Fibrin stabilizing factor, Laki-lorand factor (liver)
- vWH
von Willebrand factor (VE)- Pre-Ka Prekallikrein (PK), Fletcher factor (liver)
- HMW-K High molecular w
eight kininogen (HMWK, HF), Fitzergald factor (liver)- t-PA Tissue-type plasminogen activator (liver)
- u-PA
Urokinase-type plasminogen activator PL Platelet phospholipid
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Intrinsic Pathway
- Factor XII Collagen, Trauma, other activators XIIa
- Factor XI
Factor IX XIA & Calcium IXs- Which combines with VIIIa, ca2 and PL, to make the tenase complex, activating X in the common pathway
- Most Factors except XII get positve feedback from thrombin
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Extrinsic Pathway
- Tissue factor (III) traumaVII (Xa can give positive feedback here)III & VIIa can either directly activate X to Xa in the common pathway or go to Factor IXa to form the Tenase complex
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Common Pathway
- Factor X activated by Tenase complex or III & VIIA XaFactor Xa with prothrombin (II), Ca2, PL, Va form Prothrombinase complex
- Thrombin activated by prothrombinase complex
- Activates Fibrinogen (I) to Fibrin
- Thrombin also activates
XIII to XIIIa - Fibrin and XIIIa, with calcium, form Fibrin polymers
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Factor's dependent on Vit. K for hemostasis
Biosynthesis of Factor II, VII, IX, and X are dependent on Vit. K
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Factors affected by heparin
Factors IX, X, XI, XII and Thrombin
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Secondary Hemostasis summary (8)
- 1. There are 2 major pathways: intrinsic pathway or contact pathway and extrinsic pathway or tissue factor pathway
- 2. Both converge at a common point
- 3. ~13 (?) soluble factors are involved in clotting
- 4. Biosynthesis of II, VII, IX and X are dependent on vitamin K
- 5. Heparin affects factors IX, X, XI, XII and Thrombin
- 6. Most of these factors are proteases - normally inactive and sequentially activated
- 7. In birds, reptiles and marine animals, Factor XII (intrinsic pathway) is deficient - resulting in prolonged clotting time
- 8. Acquired defects (platelet defects, liver diseases, DIC) more common than hereditary defects (hemophilia) in animals
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Evaluation of secondary hemostasis
- 1. One stage Prothrombin time (OSPT or PT)
- 2. Activated Partial Thromboplastin time (APTT)
- 3. Activated Clotting time (ACT)
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One stage Prothrombin time (OSPT or PT)
- For evaluating extrinsic & common pathways (defects in factor VII, V, K, Prothrombin, Fibrinogen, eg. rodenticie poisioning)
- Plasma + tissue factor + ca -> clotting time (dogs < 10 sec)
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Activated Partial Thromboplastin time (APTT)
- For evaluating intrinsic & common pathways (defects in Factors XII, XI, X, IX, VIII, Prothrombin, Fibrinogen)
- Plasma + Activator of XII + PL + Ca -> clotting time (dogs < 45 sec)
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Activated Clotting time (ACT)
- Activator (diatomaceous earth) + whole blood -> clotting time (normal: dogs 60-90 sec. cats 160 sec): Less sensitive than APTT
- For evaluating intrinsic and common pathways (decreased platelet count)
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Secondary Hemostasis Disorders
- Vit K antagonism/deficiency
- rodenticide poisoning (dicoumarol)
- cholestatic liver disease
- Sever malabsorption
- Liver failure
- Disseminated intravascular coagulation (DIC)
- pathological activation of both coagulation mechanism & fibrinolytic system in blood vessels -> decreased thrombocytes + FDPs (eg, cause cancer, infectious diseases)
- Coagulation factor deficiency (Dogs, cats. Congenital)FVIII deficiency - Hemophilia A
- FIX deficiency - Hemophilia B
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Dissolution of Fibrin clot
- 1. Clot retraction - shrinking of fibrin clot
- a. mediated by platelet contractile proteins -actin, myosin, thrombosthenin
- b. Functions - stablize clot, promote tissue repair, activate fibrinolysis
- 2. Fibinolysis - degradation of fibrin clot by plasmin
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Fibrinolytic system (tertiary hemostasis)
Plasminogen has to be activated to plasmin. It has both inhibitors and activators.
- Inhibitors: Plasminogen activator inhibitors (PAI 1,2,3)
- Activators: Extrinsic: Urokinase, tPA
- Intrinsic: Kallikrein, XIIa, XIa
- Exogenous: Streptokinase
The Plasmin, with alpha2-antiplamin and alpha2-macroglobulin, change fibrin to fibrin degradation products
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