Hemostasis Flashcards
Stages of hemostasis
- vascular spasm/vasoconstriction 2. platelet plug formation/1° hemostasis
- blood coagulation/2° homeostasis 5. disolution of fibrin clot/3° homeostasis
Vascular spasm
- trauma to vessel wall results in smooth muscle contraction caused by:
- local myogenic spasm
- endothelin and serotonin released from vessel wall
- nervous reflexes
-transient effect
Platelet adhesion (general)
- first step in plug formation
- normally prevented by negative charges on platelets and endothelial cells
- mediated by platelet receipts glycoprotein Ib/Ia
- receptors bind to components of exposed subendothelial matrix (basement membrane) eg: collagen, vWF
- platelets change shape and release granule contents (ADP, Ca2+) that activate other platelets
- binding of ADP to recepor facilitates release of Ca2+ adn decreases cAMP
- increased intracellular Ca2+ activates PLA2 nd leads to TXA2 release
Platelet adesion steps
- Plately GpIa binds collagen-development of pseudopods promote platelet-platelet interactions
- vWF bind GpIb
- binding exposed GPIIb/IIa for binding of fibrinogen
von Willebran factor
- bridge between GpIb and collagen fibbers
- complexes with factor VIII
- defect associated with platelet plug formation defect (1° homeostasis) and coagulation devect (low factor VIII, 2)
Platlet Aggregation
- mediated by fibrinogen
- binds to GpIIb/IIIa on adjacent platlets
- GpIIb/IIIa defect: thrombastenia of Glanzman and Naegeli
Lab tests for platelet plug formation
- bleeding time up–>defect leads to this
- vWF down
- platelet # down
- GpIb down
- GpIIb/IIIa down
Extrinsic Clotting Pathway
1e. Tissue injury—>release tissue factor (factor III)
2e. Tissue factor III: Factor ViII—>VIIa
3e. Factors III & VIIa & Ca2+ (IV): X—>Xa
Intrinsic Pathway
1i. Rough endothelial surface and exposure of collagen: XII–>XIIa
2i. XIIa: XI—>XIa; (also activates kallikrein for what its worth)
3i. XIa: IX—>IXa
4i. Thrombin (IIa): VIII—>VIIIa
5i. IXa, VIIIa, platelet phospholipids and Ca2+: X–>Xa
Common Pathway
1c. Thrombin (IIa): V–>Va
2c. Xa and Va and Ca2 form prothrombinase complex
3c. Prothrombinase complex: II–>IIa (prothrombin to thrombin)
4c. Thrombin (Ca2+): Fibrinogen (I)—>Fibrin (Ia) (soft clot as monomers aggregate linked by H-bonds)
5c. Thrombin (Ca2+): XIII—->XIIIa
6c. XIIIa: Crosslinks fibrin monomners (hard clot)
XIIIa
- crosslinks fibrin to form hard clot
- highly specific transglutaminase
Actions of thrombin
- Convert fibrinogen to fibrin
- Activate XIII to XIIIa which crosslinks fibrin
- Activation of factor V
- Activation of factor VIII
Extrinic pathway uses;
III, VII (injury)
Intrinsic pathway uses:
XII, XI, IX, VII (pathological processeses like atherosclerosis)
Components of prothrombinase comples
Xa, Va, Phospholipid, Ca2+
Components reqiring phospholipids
prothombinase complex, intrinsic tenase complex
Test for extrinsic coagulation pathway defect:
- Increased prothrombin time (INR) (PT) (also in common pathway))
- sensitive indicator of vitamin K deficiency (Factor VII very senstive to this)
Test for intrinsic coagulation pathway defect:
Increased APTT (partial thromboblastin time)
γ-Carboxylase
- performs vitamin K depended carboxylation of Prothrombin (Factor II), VII, IX, X, and Proteins C, S, and Z
- form mature clotting factors capable of activation, contain γ-carboxyglutamate
- γ-carboxylation facilitates Ca2+ binding by introducing 2 adjacent negative charges to coordinate calcium ions and allows complex to bind to phospholipids on platelete membrane
- factor VII (which is extrinsic) is most sensitive to Vit K deficiency
- inibited by warfarin
Warfarin
Inhibits epoxide reductase in liver, necessary for the regeneration of the active form of Vitamin K
(inhibits γ-Carboxylase, preventing production of mature Prothrombin (Factor II), VII, IX, X and Proteins C, S, and Z (but those are more anticoagulants))
Fibrinolysis
Inactive plasminogen incorporated into developing clot
- activated by tissue plasminogen activator, urokinase, or streptokinase to plasmin
- can be inibited by plasminogen activator inhibitor 1 & 2
- α2-antiplasmin inhibits Plasmin
- fibrin broken down to fibrin degredation products/D-dimers–>elevated in DVT, measured to estimated rate of fibrinolysis and follow up on thrombosis patients
Contorl of hemostasis
- normal endothelia are anti-throbotic
- put out PGI2 and NO that prevent platelet aggregation
- PGI2-increases cAMP in platelets and hihibits platelet activation–>thromboxane antagonist
- coagulation automatically initiates fibrinolysis
Antithrombin III
- bind and inhibits factor Xa and IIa (thrombin)
- anticoagulent
- activated by Heparin
Heparin
Activates antithrombin III (bind and inhibits factor Xa and IIa (thrombin))
Protein C and S
- require vit K and γ-Carboxylase
- inactivate cofactors Va and VIIIa
- Protein C is activated by binding of thombomodulin to thrombin
- S is a cofactor for C
Streptokinase
Thrombolytic agent, activates plasminogen to plasmin to break down clots
Hemophilia A
- Inherited Factor VIII deficiency
- X linked
- Intrinsic pathway (increasted clotting time and increased APTT)
- similar to hemophilia B
Hemophilia B
- Inherited Factor IX deficiency
- X linked
- Intrinsic pathway (increasted clotting time and increased APTT)
- similar to hemophilia A
Characteristic Hemophila lab findings/symptoms/signs
- easy bruising
- masvie hemorrhage after trauma and surgical procedure
- spontaneous hemorrhages, particularly in the joints–>hemarthrosis
- Bleeding time=normal (platelet plug)
- Platelet count normal
- clotting time increased (defect in intrinsic pathway)
- PT/INR-normal (tests extrinsic and common)
- APTT-increased
- Assay indvidual factors to distiguish b/w the two
Von Willebrand Disease
- Deficiecny of vWF
- most common inherited bleeidng disorder
- defect in platelet plug formation
- instability of factor VII (may lead to increased APTT)
- clinical features similar to hemophila A
- increased mucosal bleeding
- epistaxis
- post op bleeding
- bleeding time prolonged
- platelt count-normal
- APTT-prolonged (factor VII levels low to normal)
- vWF levels low
Platelet defects
- quatitative–>low platelet count and increased bleeding time–>thrombocytopenia
- qualitative–>normal platelet count and increased bleeding time: Bernard soulier syndrome (GbIb defect) or Thrombastenia of Glanzman and Naegeli (defect of GpIIb/IIIa)
Bernard soulier syndrome
normal platelet count and increased bleeding time: GbIb defect
Thrombastenia of Glanzman and Naegeli
normal platelet count and increased bleeding time: (defect of GpIIb/IIIa)
