Blood Coagulation Flashcards
Steps in hemostasis
- Vascular spasm / vasoconstriction
- Platelet plug formation / primary hemostasis
- Blood coagulation / secondary hemostasis
- Dissolution of the fibrin clot / tertiary hemostasis
Vascular spasm
Trauma to vessel wall results in smooth muscle contraction
Cannot cause long term bleeding cessation.
Primary Hemostasis
Platelet plug formation
Stages:
Platelet adhesion to damaged tissue
Activation of platelet aggregation
-Defects in platelet plug formation result in increased bleeding time.
Steps in platelet adhesion
- Platelet glycoprotein Ia (GPIa) binds to subendothelial collagen
- Von Willedrand factor (vWF) binds to platelet glycoprotein Ib (GPIb) resulting in changes to the platelet membrane
- Membrane changes expose GPII/IIIa for binding of fibrinogen.
Von Willebrand Factor
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)
Platelet Aggregation
- Adhesion platelets release granule contents (ADP, Ca++) that activate other platelets.
ADP binding facilitates cellular release of Ca++ and decreases cAMP.
- 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.
Secondary Hemostasis
Blood Coagulation
Converts blood from liquid form to a solid, gel-like state.
Converts fibrinogen to insoluble fibrin (requires thrombin)
Production of thrombin
Coagulation cascade via 2 pathways
- intrinsic
- extrinsic
Extrinsic Pathway
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.
Intrinsic Pathway
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.
Common Pathway
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
Actions of Thrombin in coagulation
- Activates Factor VIII in the intrinsic pathway (needed for Factor X activation)
- Activates Factor V in the common pathway
(along with activated factor X cleaves (activates) factor II (prothrombin to thrombin)) - Activates Factor XIII in the common pathway
(required for fibrin cross-linkages)
Fibrinogen
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)
Vitamin K
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
Tertiary Hemostasis
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.
Control of hemostasis
Normal endothelial cells are anti-thrombic
PGI2 and NO are released by healthy endothelial cells to prevent platelet aggregation
Coagulation automatically initiates fibrinolysis
Antithrombin III
Anti-coagulation factor
Binds and inhibits Factor Xa.
Activated by Heparin
Proteins C and S
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
Warfarin
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
Streptokinase
Drug
thrombolytic agent; plasminogen activator; converts plasminogen to plasmin enabling the dissolution of clots
Bleeding Time
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)
Clotting Time
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
Prothrombin time
or International normalized ratio (INR)
Test extrinsic and common pathway factors:
III - Tissue factor
VII
II - Prothrombin
I - Fibrinogen
V
X
Activated Partial Thromboplastin Time
APTT
Tests intrinsic and Common Pathway Factors: XII XI IX VIII
V
X
Hemophilia
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
Von Willebrand Disease
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
Bernard-Soulier syndrome
Glycoprotein Ib deficiency
results in deficient platelet plug formation and increased bleeding time.
Thrombasthenia of Glanzman and Naegeli
GpIIb/IIIa deficiency
results in deficient platelet plug formation and increased bleeding time
Thrombocytopenia
Low platelet count
results in deficient platelet plug formation and increased bleeding time
