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DD & BL Unit III / Final Exam > Hemostasis > Flashcards

Flashcards in Hemostasis Deck (89)
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1

Tissue factor

TF is a membrane protein on fibroblasts and other cells in the vessel wall; it is exposed to the blood with endothelial injury

TF binds activated, circulating VIIa in order to begin the extrinsic coagulation cascade

2

Tenase

Cofactor VIII supports IXa and X; X becomes activated to Xa

3

Prothrombinase

Cofactor V supports Xa and II; II becomes activated to IIa

4

Vitamin K-dependent proteins

II, VII, IX, X

Protein C, Protein S

5

Role of Vitamin K in coagulation

Factors II, VII, IX, and X undergo vitamin K-dependent gamma carboxylation of glutamic acid in the liver; this reaction oxidizes vitamin K, which must be reduced by Vitamin K oxidoreductase in order to continue synthesizing functional clotting factors

6

Warfarin - Mechanism

Factors II, VII, IX, and X undergo carboxylation of N-terminal glutamates by enzymes that are Vitamin K-dependent; without this carboxylation they are unable to bind Ca2+ and are non-functional

Vitamin K undergoes redox during this reaction and the recycling of Vitamin K to its reduced, active form by Vitamin K Reductase is inhibited by Warfarin, resulting in depletion of Vitamin K and active coagulation factors

7

Tissue Factor Pathway Inhibitor (TFPI)

Binds and inhibits Tenase and free, activated Xa

8

Antithrombin (AT3)

Binds and inhibits thrombin, as well as factors Xa and XIa

This binding interaction is enhanced by heparin

9

Protein C System

Thrombomodulin (TM) activates PC to APC; APC binds PS as a co-factor to cleave and inactivate Va and VIIIa

10

Tissue Plasminogen Activator (TPA)

Converts plasminogen to plasmin; plasmin cleaves fibrin to fibrin split products (FSPs) and Dimers

11

Plasminogen activator inhibitor-1 (PAI-1)

Binds and inhibits tissue plasminogen activator (TPA), preventing the formation of plasmin and inhibiting fibrinolysis

12

TF-VIIa

Converts X to Xa and IX to IXa

Results in the production of a small amount of thrombin

13

Propagation Phase

Production of Xa (by Tenase) and Thrombin (by Prothrombinase)

14

Role of Thrombin in Amplification

Thrombin activates co-factors VIII and V

Thrombin also activates XI

15

Mechanism of fibrin cross-linking

Factor XIIIa is activated by thrombin to covalently cross-link fibrin, leading to formation of a "hard clot"

16

Contents of Platelet Dense Granules

ATP
ADP
Ca2+
Histamine
Serotonin

17

Contents of Platelet Alpha Granules

Procoagulant proteins - fibrinogen, factor V, vWF
Platelet activation factors
Platelet-derived growth factor

18

Contents of Platelet Lysosomal Granules

Acid hydrolases

19

GPIa/IIa

Binds Collagen in the exposed sub-endothelium at the site of vascular injury

20

GPIIa-IIIb

Binds vWF in the sub-endothelium at the site of vascular injury

Also binds fibrinogen to cross-link platelets

21

GPIb

Binds vWF in the exposed sub-endothelium at the site of vascular injury

22

Platelet Adhesion

Platelets adhere to the injured surface and build at temporary clot by virtue of binding interactions:

GPIba binds vWF
GPIIb/IIIa binds Fibrinogen
GPIa/IIa binds collagen

23

Platelet Activation

Interaction of the extracellular, soluble agonists thrombin, thromboxane A2, and ADP with their respective GCPRs in the platelet membrane signal calcium influx that results in secretion of alpha and dense granule contents; calcium also activates the conversion of arachidonic acid to TXA2 via COX1

End result of agonist binding is a conformational change in the platelet to expose GPIIa/IIIb binding sites for fibrinogen

24

Platelet aggregation

Platelet adhesion & binding of soluble agonists converts GPIIa-IIIb to a high-affinity state where it can bind fibrinogen and vWF; GPIIa-IIIb bound to fibrinogen acts as a bridge to lace platelets together into a mesh; locally, thrombin acts to convert fibrinogen to fibrin, stabilizing the platelet mesh

25

Mechanisms by which endothelial cells inhibit coagulation (3)

1. Secreting a heparin-like molecule to suppress coagulation cascade activity

2. Expressing thrombomodulin which, when bound to thrombin, activates Proteins C and S

3. Secretion of NO and prostacyclin, inhibitors of platelet activation

26

Immune thrombocytopenic purpura ITP)

Caused by the production of auto-antibodies directed against platelet antigens, leading to their removal by macrophages of the RE system

May be acute or chronic

Acute onset is often preceded by viral infection and presents as petechiae and nosebleeds

Chronic is often associated with other auto-immune disorders (SLE, RA, HIV)

27

Treatment for ITP (4)

Corticosteroids - suppress inappropriate immune response to platelets

IVIG - Blocks Fc receptors on splenic macrophages

Splenectomy - prevents sequestration and destruction of opsonized platelets

Rituximab - anti CD20, depletes B cells

28

Alloimmune thrombocytopenia

Production of antibodies against platelet antigens not present on the patient's own platelets

Occurs in the setting of a patient receiving platelet transfusions, or in a neonate through passive transfer of maternal IgG alloantibodies across the placenta to attack fetal platelets

29

Thrombotic thrombocytopenic purpura (TTP)

Due to mutation in or antibodies against the ADAMTS13 protein that normally functions to digest vWF; as a result, large vWF multimers are released from endothelial cells in the setting of damage; these large vWF multimers mediate platelet adhesion and aggregation forming diffuse platelet plugs in small arterioles

Presents as renal insufficiency, mental status changes, thrombocytopenia

30

Von Willebrand Disease - Types

The most common congenital bleeding disorder; 3 types:

Type I - Partial quantitative deficiency of vWF
Type II - Partial qualitative deficiency of vWF
Type III - Total absence of vWF