Platelet Biohem And Fibrin Production And Inhibition

Question 1

Primary hemostasis

Answer 1

. Formation of a platelet plug

. Initiated in response to a vascular injury

Question 2

Platelets

Answer 2

. 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)

Question 3

Platelet derived growth factor (PDGF)

Answer 3

Activates Tyr kinase to promote cell proliferation and wound healing

Question 4

Why do intact endothelial cells not interact with platelets?

Answer 4

. 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 )

Question 5

Formation of primary platelet plug

Answer 5

. 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

Question 6

Gp receptors

Answer 6

. Gp that binds to collagen in subendothelium
. Gp that binds vWF in suendothelium
. Gp II-IIIa: binds fibrinogen in blood

Question 7

Gp IIb-IIIa is a member of the ____ family

Answer 7

Integrin

Question 8

Platelet aggregation

Answer 8

. 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

Question 9

Thrombin

Answer 9

. Very potent inducer of platelet aggregation
. Product of hemostasis
. Induces further platelet aggregation and the release of agents like TXA2 and ADP

Question 10

Bernard-Soulier disease

Answer 10

. Platelet disorder

. Defect in Gp Ib-IX

Question 11

Glanzmann thrombasthenia

Answer 11

. Platelet disorder

. Defect in Gp IIb-IIIa

Question 12

Von willebrand disease

Answer 12

. 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

Question 13

Aspirin

Answer 13

. Irreversible inhibitor of COx in platelets
. Prevents inhibited platelet from producing TXA2
. Does not thin the blood
. Not an anticoagulant

Question 14

Thromboxane A2 (TXA2)

Answer 14

. Very potent inducer of platelet aggregation

. Required for formation of platelet aggregates and platelet plug

Question 15

Platelet receptor inhibitors

Answer 15

. Agents bind to glycoprotein (Gp) recents on platelets and prevent binding to normal ligand
.

Question 16

T/F platelet plug is not stable

Answer 16

T, will not stay in place w/o reinforcement

Question 17

Intrinsic coagulation pathway

Answer 17

. All required components in plasma

. Plasma + phospholipid of platelet -> fibrin for stable clot

Question 18

Extrinsic coagulation pathway

Answer 18

. Requires external factor (tissue factor) for fibrin formation
. Must add something to plasma for clot to form

Question 19

Extrinsic pathway of coagulation ____ the process while intrinsic pathway _____ the process

Answer 19

. Extrinsic initiates

. Intrinsic continues

Question 20

T/F proteases in coagulation are found in plasma as zymogens

Answer 20

T, when active add a to the end of factor name (factor X to factor Xa when active)

Question 21

What is needed for proper zymogens synthesis of serine proteases

Answer 21

. Vit. K

Question 22

Steps in initiation of extrinsic pathway

Answer 22

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

Question 23

Steps in continuations/amplification of clotting process

Answer 23

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

Question 24

Deficiency of factor VIII results in ____

Answer 24

Hemophilia A

Question 25

Deficiency in factor IX causes ____

Answer 25

Hemophilia B

Question 26

Tissue factor pathway inhibitor (TFP I)

Answer 26

. 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

Question 27

Antithrombin

Answer 27

. 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)

Question 28

Heparin

Answer 28

. 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

Question 29

Protein C/S pathway

Answer 29

. 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

Question 30

Deficiency in what things is a risk factor for thrombosis

Answer 30

. 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

Question 31

Factor V Leiden

Answer 31

. 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

Question 32

Prothrombin mutation (Factor II mutation)

Answer 32

. 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

Question 33

Non O blood group risk for clot

Answer 33

. 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

Question 34

Elevated homocysteine affect on thrombosis risk

Answer 34

. 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

Question 35

Fibrinolysis

Answer 35

. 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

Question 36

Tissue-PA (t-PA)

Answer 36

. 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

Question 37

Inhibitors that control extent and timing of fibrinolysis

Answer 37

. Alpha2-antiplasmin that inhibits plasmin | . PAI-1 and 2 that inhibit t-PA and u-PA

Question 38

Coronary artery thrombosis

Answer 38

. Central mechanism in pathogenesis of MI

Question 39

Venous thrombosis

Answer 39

. Frequent complication of common medical disorders including MI, CHF, COPD, and stroke

Question 40

Thromboembolism

Answer 40

. 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

Question 41

Platelet receptor inhibitors

Answer 41

. Plavix (clopidogrel) . GpIIb-IIIa inhibitors (REO PRO, AGGRASTAT) . Bind to platelet receptors inhibiting platelet adhesion and aggregation

Question 42

Heparin complications

Answer 42

. Bleeding

Question 43

How is heparin neutralized?

Answer 43

Protamine

Question 44

Heparin-induced thrombocytopenia

Answer 44

. Immune reaction that induces clotting

Question 45

Warfarin

Answer 45

. 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

Question 46

Warfarin complication

Answer 46

Bleeding | . Giving vit. K reverses effects of warfarin if bleeding is risk

Question 47

Direct thrombin inhibitors

Answer 47

. Argatroban, angiomax, and pradaxa | . Reversible bind to thrombin active site

Question 48

Factor Xa inhibitors

Answer 48

. Xarelto | . Eliquis

Question 49

Clot-dissolving drugs

Answer 49

``` . 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 ```

Question 50

Hemophilia

Answer 50

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

Question 51

Cofactors of coagulation that aren’t enzymes

Answer 51

. FV | . FVIII