Blood Coagulation and Fibrinolysis Flashcards
The arrest of bleeding or prevention of hemorrhage
Hemostasis
Steps in hemostasis:
- Vascular spasm / vasoconstriction
- Platelet plug formation / primary hemostasis
- Blood coagulation / secondary hemostasis
- Dissolution of the fibrin clot / tertiary hemostasis
Smooth muscle contraction resulting from trauma to the vessel wall is….
Vascular Spasm
Stages of platelet plug formation:
- Platelet adhesion to the damaged surface and activation
- Platelet recruitment
- Platelet aggregation
Platelet adhesion and role of von Willebrand factor (vWf)
- Platelet …….. binds to …….. – Structural changes e.g. development of pseudopods to promote platelet-platelet interactions.
- ………. binds to platelet receptor, …….. resulting in changes in the platelet membrane
- Binding also exposes ………. for binding of fibrinogen
- GpIA, collagen
- Von Willebrand factor, Glycoprotein IB
- GpIIB/IIIA
vWf deficiency is associated with a
- Defect in the formation of the platelet plug (primary hemostasis)
- Defect in coagulation (due to low levels of factor VIII) – defect in secondary hemostasis
vWF complexes with ……..; carries it, stabilizes it and prevents its degradation.
Factor VIII
Role of von Willebrand factor (vWF) in platelet adhesion
vWf acts as a bridge between specific glycoproteins (GPIb) on the surface of platelets and collagen fibers – Facilitates platelet adhesion to the vessel wall and platelet aggregation
Immediately following the initial platelet adhesion, the platelets are activated. What are the two actions of platelets that can occur next?
- Synthesis and release of thromboxane A2
2. Release of platelet granule contents (ADP), that activate other platelets, promoting aggregation
Binding of ADP to its receptor results in the following intracellular events
- Increases intracellular Ca2+
- Decreases intracellular cAMP levels (both of which facilitate platelet aggregation)
- Aggregation of platelets cannot take place without ADP stimulation
Increased …… stimulates platelet cells to synthesize TXA2
Intracellular Calcium
What is the function of Thromboxane A2?
TXA2 induces platelet aggregation by activating other platelets. It diffuses out of the cell to enhance vasoconstriction.
Platelet aggregation is mainly mediated by ……….
Fibrinogen. Fibrinogen binds to GPIIB/IIIA on adjacent platelets
Disease: A defect in Glycoprotein IIB/IIIA causes….
Glanzmann Thrombasthenia
Steps formation of platelet plug (Primary hemostasis)
- Exposure of subendothelial collagen (INJURY)
- Platelet adhesion via GPIA and GPIB (via vWF) to subendothelial collagen (PLATELET ADHESION)
- Platelet activation, shape change and degranulation (ADP release) (SHAPE CHANGE)
- ADP binds to neighboring platelets to increase intracellular calcium and decrease intracellular cAMP; Increased TXA2 (GRANULE RELEASE)
- Platelets recruited to the site of injury (RECRUITMENT)
- Platelet aggregation via fibrinogen linking adjacent platelets via GPIIB/IIIA (AGGREGATION/PLUG)
What is the aim of blood coagulation?
convert soluble fibrinogen to insoluble fibrin (threads that stabilize the platelet plug). The conversion of fibrinogen to fibrin requires thrombin
How is thrombin produced?
The formation of Thrombin occurs via 2 pathways:
1) Intrinsic pathway
2) Extrinsic pathway
…….. is required for the hepatic synthesis of Prothrombin (Factor II), VII, IX, X, Proteins C and S
Vitamin K
What is the co-enzyme for y-carboxylase
Vitamin K
What cofactor is required for the Vitamin K dependent clotting factors, II, VII, IX, and X?
Calcium ions
What fibrinolysis?
Dissolution of the fibrin clot (tertiary hemostasis)
Which Factor and pathway is most sensitive to Vitamin K?
Factor VII (Extrinsic Pathway)
Which factors are released that cause vascular spasm?
Endothelin and Serotonin
What activates Phospholipase A2?
Calcium
What is the function of Phospholipase A2?
Cleaves phospholipids to release arachidonic acid
What is aggregated to form a soft clot?
Fibrin monomers are linked together by hydrogen bonds
What is aggregated to form a hard clot?
Factor XIIIa (activated by thrombin) cross links with fibrin monomers via covalent bonds. Thus, converting the soft clot into a hard clot
Lab tests for the coagulation cascade:
– Clotting time: Tests for integrity of the extrinsic, intrinsic and common pathways
– Prothrombin time (INR or PT): Tests for integrity of the extrinsic pathway
– Activated Partial Thromboplastin time (aPTT): Tests for integrity of the intrinsic pathway
……. is a very sensitive indicator of vitamin K deficiency and for follow-up of patients on warfarin therapy
Prothrombin Time (INR or PT)
Patients with Deep Vein Thrombosis are likely to have increased levels of….
Fibrin degradation products and D-dimer levels
Which chemical mediators are released by healthy endothelium and prevent platelet aggregation?
PGI2 (prostacyclin) and nitric oxide
What is the function of Prostacyclin?
Increases intracellular cAMP levels in platelets and inhibits platelet activation. It is a thromboxane antagonist
Name the 2 anti-coagulant factors and their functions.
• Antithrombin III –
Binds to and inhibits factor Xa, thrombin (IIa) and other activated clotting factors
– Heparin (glycosaminoglycan) acts by activating this factor and preventing coagulation
• Protein C and S (also require vit K for -carboxylation) – Protein C is activated by the binding of thrombomodulin to thrombin
– Protein S is a cofactor for protein C
– Proteins C and S act together to inactivate cofactors Va and VIIIa of the coagulation cascade
How do the following drugs affect the coagulation cascade? Aspirin Heparin Warfarin Streptokinase
- Aspirin– prevents the formation of thromboxane in platelets. Irreversible inhibitor of cyclooxygenase (COX)
- Heparin – activates antithrombin III and inactivates thrombin
- Warfarin (oral anticoagulant) – blocks epoxide reductase in liver and prevents the regeneration of the active form of Vitamin K. Inhibits the synthesis of the mature vitamin-K dependent clotting factors
- Streptokinase – thrombolytic agent; plasminogen activator; converts plasminogen to plasmin enabling the dissolution of clots
Increased Bleeding time is an indicator of….
- Low platelet count
- vWf deficiency
- Platelet receptor defects
Define Bleeding Time and Clotting Time.
Bleeding Time: time taken from the initial injury to the formation of the platelet plug
Clotting Time: Time taken for the formation of the stable fibrin
What are the two tests for Coagulation Disorders?
Prothrombin Time (PT or INR) Activated Partial Thromboplastin Time (aPTT)
Prothrombin Time measures for defects in:
Extrinsic Pathway: Factor 3, 7, 5, 10, Prothrombin (Factor 2), Fibrinogen
Activated Partial thromboplastin time measures defects in:
Intrinsic Pathway: Factor 8, 9, 11, 12,10, 5, Prothrombin, Fibrinogen
What test is used to identify the platelet glycoprotein defects?
Flow cytometry
Inherited disorders of the Intrinsic Coagulation Pathway
Hemophilia A and B
- X-linked recessive
- Clinical Features: Easy Bruising, Massive hemorrhage after trauma or surgery, Spontaneous hemorrhage
- Hemophilia A- Factor 8 (low levels)
- Hemophilia B- Factor 11 (low levels)
Hemathrosis…..
Bleeding into joint cavity
Platelet Count, Bleeding Time, Clotting Time, Prothrombin Time, APTT for Hemophilia A & B
Platelet Count: Normal Bleeding Time- Normal Clotting Time- Increased Prothrombin Time- Normal APTT- Increased
Von Willebrand Disease: Cause and Defect
Defect in platelet plug formation and instability of Factor VIII
Von Willebrand Disease: Clinical Features
– Increased mucosal bleeding
– Epistaxis (Bleeding from the nose)
– Increased post-operative bleeding
Platelet Count, Bleeding Time, Clotting Time, Prothrombin Time, APTT for Von Willebrand Disease
Platelet Count: Normal
Bleeding Time- Increased
Prothrombin Time- Normal
APTT- Increased
Disease: Presents with Low Platelet Count and Increased Bleeding Time
Thrombocytopenia
Disease: GpIB defect
Bernard Soulier Syndrome
Identified by Flow Cytometry
Disease: GpIIB/ IIIa defect
Glanzmann Thrombasthenia
Identified by Flow Cytometry
Increased Clotting time, Prothrombin Time, and APTT indicate which type of disorder?
Coagulation Disorder
