Blood Coagulation

Question 1

Steps in hemostasis

Answer 1

1. Vascular spasm / vasoconstriction
2. Platelet plug formation / primary hemostasis
3. Blood coagulation / secondary hemostasis
4. Dissolution of the fibrin clot / tertiary hemostasis

Question 2

Vascular spasm

Answer 2

Trauma to vessel wall results in smooth muscle contraction

Cannot cause long term bleeding cessation.

Question 3

Primary Hemostasis

Answer 3

Platelet plug formation

Stages:
Platelet adhesion to damaged tissue
Activation of platelet aggregation

-Defects in platelet plug formation result in increased bleeding time.

Question 4

Steps in platelet adhesion

Answer 4

1. Platelet glycoprotein Ia (GPIa) binds to subendothelial collagen
2. Von Willedrand factor (vWF) binds to platelet glycoprotein Ib (GPIb) resulting in changes to the platelet membrane
3. Membrane changes expose GPII/IIIa for binding of fibrinogen.

Question 5

Von Willebrand Factor

Answer 5

vWf acts as a bridge between specific glycoproteins(GPIb) on the surface of platelets and collagen fibres –Facilitates platelet adhesion to the vessel wall and platelet aggregation

Carries and stabilized Factor VIII in the intrinsic pathway.

Deficiency is associated with a defect in the formation of the platelet plug (primary hemostasis) and a defect in coagulation (due to low levels of factor VIII)

Question 6

Platelet Aggregation

Answer 6

1. Adhesion platelets release granule contents (ADP, Ca++) that activate other platelets.

ADP binding facilitates cellular release of Ca++ and decreases cAMP.

2. Ca++ activates phospholipase A2 which cleaves PIP2 to arachidonic acid. COX then forms prostaglandins (G2, H2) then finallly Thromboxane A2 which induces platelet aggregation and vasoconstriction.
   - Platelets aggregation is maintained mainly by fibrinogen which binds to GPIIb/IIA receptors.

Question 7

Secondary Hemostasis

Answer 7

Blood Coagulation

Converts blood from liquid form to a solid, gel-like state.

Converts fibrinogen to insoluble fibrin (requires thrombin)

Question 8

Production of thrombin

Answer 8

Coagulation cascade via 2 pathways

1. intrinsic
2. extrinsic

Question 9

Extrinsic Pathway

Answer 9

Tissue Injury —> release of tissue factor (Factor III)
Tissue factor activates VIII to VIIIa

VIIIa and tissue factor (in the presence of Ca++ and platelet phospholipids) activates X to Xa.

Question 10

Intrinsic Pathway

Answer 10

Rough endothelial surface –> Exposure to collagen
Activation of XII to XIIa.

XIIa activates XI to XIa.

XIa activates IX to IXa.

Thrombin activates VIII to VIIIa.

IXa and VIIIa, (in the presence of platelet phospholopids and Ca++) activates X to Xa.

Question 11

Common Pathway

Answer 11

Thrombin (IIa.) acts on V —> Va.

Xa and Va. (in the presence of Ca++ and platelet phospholipids) form Prothrombinase Complex

Prothrombinase complex splits prothrombin to thrombin

Thrombin forms fibrin from fibrinogen

Thrombin activates XIII to XIIIa.

XIIIa establishes covalent cross-links in fibrin

Question 12

Actions of Thrombin in coagulation

Answer 12

1. Activates Factor VIII in the intrinsic pathway (needed for Factor X activation)
2. Activates Factor V in the common pathway
   (along with activated factor X cleaves (activates) factor II (prothrombin to thrombin))
3. Activates Factor XIII in the common pathway
   (required for fibrin cross-linkages)

Question 13

Fibrinogen

Answer 13

Plasma protein synthesized by the liver

Thrombin cleaves the fibrinopeptides of fibrinogen to form the fibrin monomer

fibrin monomers aggregate and are linked to each other via hydrogen bonds, forming the fibrin polymer (soft clot)

Question 14

Vitamin K

Answer 14

Cofactor for gamma-carboxylase that forms mature clotting factors II, VII, IX, X as well as protein C and protein S

Gamma-carboxylase is inhibited by warfarin

Question 15

Tertiary Hemostasis

Answer 15

Fibrinolysis

Dissolution of the fibrin clot

Inactive Plasminogen gets incorporated into the developing clot.

A tissue plasminogen activator, urokinase, or strptokinase activates plasminogen to plasmin which degrades fibrin.

• Plasminogen activator inhibitor 1&2 inhibits activation to plasmin.
• Antiplasmin inhibits plasmin activity.

Question 16

Control of hemostasis

Answer 16

Normal endothelial cells are anti-thrombic

PGI2 and NO are released by healthy endothelial cells to prevent platelet aggregation

Coagulation automatically initiates fibrinolysis

Question 17

Antithrombin III

Answer 17

Anti-coagulation factor

Binds and inhibits Factor Xa.

Activated by Heparin

Question 18

Proteins C and S

Answer 18

Anti-coagulation factors

Act together to inhibit Factors Va. and VIIIa.

Protein C binds throbomodulin to thrombin. Protein S is a cofactor for this reaction

Question 19

Warfarin

Answer 19

Blocks epoxide reductase in liver preventing the regeneration of the active form of Vitamin K.

Inhibits the synthesis of the mature vitK dependent clotting factors II, VII, IX, X

Question 20

Streptokinase

Answer 20

Drug

thrombolytic agent; plasminogen activator; converts plasminogen to plasmin enabling the dissolution of clots

Question 21

Bleeding Time

Answer 21

Tests the time from initial injury to platelet plug formation.

Prolonged bleeding time is an indicator of

• Low platelet count
• vWF deficiency
• Platelet receptor defects (GPIIb/IIIa)

Question 22

Clotting Time

Answer 22

Time to formation of stable fibrin

Prolonged clotting time is an indicator of defects in the coagulation pathway

Specific defects of the extrinsic/ intrinsic pathways are indicated by prothrombin time & Activated partial thromboplastin time (APTT) respectively

Question 23

Prothrombin time

Answer 23

or International normalized ratio (INR)

Test extrinsic and common pathway factors:
III - Tissue factor
VII

II - Prothrombin
I - Fibrinogen
V
X

Question 24

Activated Partial Thromboplastin Time

Answer 24

APTT

Tests intrinsic and Common Pathway Factors:
XII
XI
IX
VIII

V
X

Question 25

Hemophilia

Answer 25

Inherited coagulation disorder of the intrinsic pathway. Increased clotting time and APTT X-linked recessive Type A- Factor VIII Type B - Factor IX Characterized by: Tendency toward bruising Spontaneous hemorrhage especially in joints

Question 26

Von Willebrand Disease

Answer 26

Defect in platelet plug formation Instability of Factor VIII (carried and stabilized vWf) Most common inherited bleeding disorder ``` Clinical features: Presents with the clinical features similar to hemophiliaA -Increased mucosal bleeding -Epistaxis -Increased post-operative bleeding ```

Question 27

Bernard-Soulier syndrome

Answer 27

Glycoprotein Ib deficiency results in deficient platelet plug formation and increased bleeding time.

Question 28

Thrombasthenia of Glanzman and Naegeli

Answer 28

GpIIb/IIIa deficiency results in deficient platelet plug formation and increased bleeding time

Question 29

Thrombocytopenia

Answer 29

Low platelet count results in deficient platelet plug formation and increased bleeding time