Platelet Biohem And Fibrin Production And Inhibition Flashcards
Primary hemostasis
. Formation of a platelet plug
. Initiated in response to a vascular injury
Platelets
. Cell fragments derived from megakaryocytes
. Maintain vascular integrity through primary hemostasis
. Provide surface to promote coagulation cascades (secondary hemostasis)
. Produces mediators to promote healing (PDGF)
Platelet derived growth factor (PDGF)
Activates Tyr kinase to promote cell proliferation and wound healing
Why do intact endothelial cells not interact with platelets?
. Cells and platelets both have net negative surface charges and may repel each other
. Cells synthesize factors that inhibit hemostasis and platelet aggregation (prostacyclin, thrombomodulin, heparin sulfate, plasminogen activators, NO, ADPase )
Formation of primary platelet plug
. Subendothelial ECM glycoproteins are exposed (collagen, vWF)
. Platelets adhere to glycoproteins or Gp receptors
. Adherence induces signal transduction across platelet membrane leading to activation and release of coagulation mediators (ADP and TXA2)
. Activate platelets recruit other platelets and aggregate
Gp receptors
. Gp that binds to collagen in subendothelium
. Gp that binds vWF in suendothelium
. Gp II-IIIa: binds fibrinogen in blood
Gp IIb-IIIa is a member of the ____ family
Integrin
Platelet aggregation
. Activated platelets undergo conformational change in Gp IIb-IIIa allowing them to bind to fibrinogen w/ high affinity
. Binding to fibrinogen and thrombin stimulates additional platelet aggregation through platelet-platelet interaction
. Bound fibrinogen is enzymatically cleaved to fibrin through coagulation cascades (secondary hemostasis)
. Fibrin becomes entwined in and stabilizes primary hemostasis plug creating secondary plug
Thrombin
. Very potent inducer of platelet aggregation
. Product of hemostasis
. Induces further platelet aggregation and the release of agents like TXA2 and ADP
Bernard-Soulier disease
. Platelet disorder
. Defect in Gp Ib-IX
Glanzmann thrombasthenia
. Platelet disorder
. Defect in Gp IIb-IIIa
Von willebrand disease
. Deficiency/defect in VWF
. Most common bleeding disorder
. Autosomal dominant gene on chromosome 12
. Usually no treatment unless person is going into surgery
. Usually noticed first during dental procedures
Aspirin
. Irreversible inhibitor of COx in platelets
. Prevents inhibited platelet from producing TXA2
. Does not thin the blood
. Not an anticoagulant
Thromboxane A2 (TXA2)
. Very potent inducer of platelet aggregation
. Required for formation of platelet aggregates and platelet plug
Platelet receptor inhibitors
. Agents bind to glycoprotein (Gp) recents on platelets and prevent binding to normal ligand
.
T/F platelet plug is not stable
T, will not stay in place w/o reinforcement
Intrinsic coagulation pathway
. All required components in plasma
. Plasma + phospholipid of platelet -> fibrin for stable clot
Extrinsic coagulation pathway
. Requires external factor (tissue factor) for fibrin formation
. Must add something to plasma for clot to form
Extrinsic pathway of coagulation ____ the process while intrinsic pathway _____ the process
. Extrinsic initiates
. Intrinsic continues
T/F proteases in coagulation are found in plasma as zymogens
T, when active add a to the end of factor name (factor X to factor Xa when active)
What is needed for proper zymogens synthesis of serine proteases
. Vit. K
Steps in initiation of extrinsic pathway
1: vascular injury
2: tissue factor (TF) combines w/ zymogens to form factor VII
3: factor VII-TF complex formed
4: inactive complex turned into VIIa-TF active complex, Ca needed, any active proteases can act on inactive complex to perform conversion
5: Factor X converted to Xa by active complex
6: Xa converts prothrombin (factor II) to thrombin (IIa), needs Ca, phospholipids from platelet membrane, and factor Va as cofactor
7: thrombin converts fibrinogen to fibrin, Factor XIII to XIIIa (needs Ca),
8: factor XIIIa (transglutaminase) cross links fibrin
Steps in continuations/amplification of clotting process
1: thrombin converts factor XI to XIa
2: XIa converts factor IX to IXa (also produced by VIIa-TF complex)
3: XIa converts X into Xa in rxn that requires VIIIa as cofactor (thrombin activates VIII to VIIIa)
4: Xa w/ cofactor Va converts prothrombin to thrombin (common pathway w/ extrinsic), existing thrombin converts V to Va for cofactor
Deficiency of factor VIII results in ____
Hemophilia A
Deficiency in factor IX causes ____
Hemophilia B
Tissue factor pathway inhibitor (TFP I)
. Protease inhibitor that inhibits activity of VIIa and Xa
. Pool of TFP I assoc. w/ endothelial cell surface
. Helps to contribute to non-thrombogenic properties of endothelial cell
. Binds to Xa, then TFP I-Xa complex can bind to VIIa/TF complex to make a complex that can’t activate coagulation
. Deficiency may be related to protein S deficiency
Antithrombin
. Protease inhibitor that irreversible inhibits thrombin and Xa and IXa
. Can inhibit VIIa and XIa when they are bound to certain cofactors
. Inhibition faster in presence of heparan sulfate (in subendothelium) and heparin (drug)
Heparin
. Glycosaminoglycan (like heparan sulfate)
. Low molecular weight heparin can activate antithrombin to inhibit factor Xa but not thrombin
. Standard heparin is potent and inactivates thrombin as well and achieves rapid anticoagulation
Protein C/S pathway
. Activated protein C destroys cofactors, Va and VIIIa
. Thrombin binds to thrombomodulin on endothelium
. Protein C binds and is converted by thrombin to activated protein Ca
. Ca and cofactor protein S cleave and destroy Va and VIIIa
Deficiency in what things is a risk factor for thrombosis
. Antithrombin deficiency (inc. risk not well known)
. Protein Ca deficiency (5-10 fold greater risk)
. Protein S deficiency (5-1o fold greater risk)
. Mutant form V Leiden instead of factor V
Factor V Leiden
. 5% North American whites are heterozygous
. 4-8 fold greater risk for DVT in heterozygous, 80-fold higher in homozygous
. Change (Arg -> Gln) in factor V is mutation
. protein Ca can’t cleave it bc cleavage site is removed w/ mutation
. Remains active longer leasing to excess coagulation
Prothrombin mutation (Factor II mutation)
. 2-3% whites have it
. 2-3x greater risk for DVT
. Polymorphism located in noncoding region of prothrombin gene (guanine replaced w/ adenine where polyA tail attached pre-mRNA)
. Causes inc. prothrombin production bc more stable mRNA
. Excess prothrombin contributes to hypercoagulability
Non O blood group risk for clot
. 2 fold inc. risk compared w/ O type
.VWF levels 25% higher in non-O types
. When combined with another inherited coagulopathy can inc. Risk by 7-fold
Elevated homocysteine affect on thrombosis risk
. Assoc. w/ clot
. Inc. in homocysteine from vit. B, folate deficiencies, kidney disease, low level thyroid hormones, psoriasis, and antiepileptic drugs
. Genetic variant of Mehtylenetetrahydrofolate (MTHF) reductase causes impairment of folate processing and inc. homocysteine
Fibrinolysis
. Breakdown of fibrin clot
. Factors involved require fibrin for binding and must be biosynthesized causing time delay in initiation after vascular injury
. Initiation stimulated from stasis as result of presence of clot
. Plasminogen activates to plasmin via tissue-PA and urokinase PA
. Plasmin cleaves fibrin to form D-dimers of fibrin degradation products
Tissue-PA (t-PA)
. Released from activated endothelial cells following its biosynthesis that is stimulated by activation of endothelial cell
. Binds to fibrin clots and activated plasminogen to plasmin by specific bond cleavage
Inhibitors that control extent and timing of fibrinolysis
. Alpha2-antiplasmin that inhibits plasmin
. PAI-1 and 2 that inhibit t-PA and u-PA
Coronary artery thrombosis
. Central mechanism in pathogenesis of MI
Venous thrombosis
. Frequent complication of common medical disorders including MI, CHF, COPD, and stroke
Thromboembolism
. Frequently seen after surgical procedures, esp. in obese patients, those w/ cancer, or prior thromboembolic episodes
. When high risk, incidence of DVT is 20%, pulmonary embolism is 2%, and fatal pulmonary embolism is 1%
. High risk in elderly patients
Platelet receptor inhibitors
. Plavix (clopidogrel)
. GpIIb-IIIa inhibitors (REO PRO, AGGRASTAT)
. Bind to platelet receptors inhibiting platelet adhesion and aggregation
Heparin complications
. Bleeding
How is heparin neutralized?
Protamine
Heparin-induced thrombocytopenia
. Immune reaction that induces clotting
Warfarin
. Inhibits K-dependent gamma-carboxylase in liver that is important in zymogen production of prothrombin, factor VII, IX, and X by competing with K as cofactor
. Impairs coagulation because gamma-carboxylation is needed for zymogens to bind to Ca
. Slower than heparin
. Only acts on factors synthesized after drug administration, pre-existing coagulation factors will remain functional
Warfarin complication
Bleeding
. Giving vit. K reverses effects of warfarin if bleeding is risk
Direct thrombin inhibitors
. Argatroban, angiomax, and pradaxa
. Reversible bind to thrombin active site
Factor Xa inhibitors
. Xarelto
. Eliquis
Clot-dissolving drugs
. Drugs that activate paslminogen . T-PA, u-PA, or streptokinase . Drugs act to break down existing clots . Don’t inhibit formation of new clots . Main complication: bleeding
Hemophilia
A and B are x-linked
. Conversion of X to Xa in intrinsic pathway is impaired
. Hemarthroses: bleeding into joints
. Hematoma: hemorrhages into subQ CT or muscle
Cofactors of coagulation that aren’t enzymes
. FV
. FVIII
