Hemostasis Flashcards
Define hemostasis
Processes that prevent blood loss at sites of vascular injury but maintain fluid state of circulating blood
Imbalances –> Hemophilia or Hypercoagulability
Describe how platelets adhere to the extracellular matrix exposed at a site of vascular injury.
What is the role of von Willebrand factor and glycoprotein Ib (GPIb)?
What is the importance of von Willebrand factor in the normal function of factor VIII?
- Endothelial Cells produced vWF, which is secreted onto ECM when damage to vasculature occurs
- GPIB (a receptor on platelets) interacts with vWF, which is bound to the ECM, and creates a bridge between the platelet and exposed collagen
- vWF also binds to coagulation factor VIII (8), which is required for an effective coagulation response, and binding to vWF greatly increases its half life
Describe the morphological changes that occur upon platelet activation.
What sorts of compound are secreted by activated platelets? (2 types of secretory granules)
-As platelets adhere, they undergo a shape change as a response to Ca2+ and subsequent remodeling of the cytoskeleton
(Go from normal disc shape to spiny spherical shape with filopodia)
-Platelets secrete 1) Dense Granules (ADP, ATP, Ca++, Histamine, Serotonin, and Epinephrine), and 2) a-Granules (fibrinogen, fibronectin, vWF, Factor V, and platelet-derived growth factor/other cell signaling molecules)
What do platelets secrete that leads to vasoconstriction?
Free Arachidonic Acid
(Substrate for cyclooxygenase, which converts it to Prostaglandin G2)
AA –> Prostaglandin G2 –> Prostaglandin H2 –Thromboxane Synthase–> Thromboxane A2
***Thromboxane A2, Serotonin, and Epinephrine –> Vasoconstrictors***
Explain the process of platelet aggregation, including the roles of aggregation signals, GpIIb-GpIIa, and fibrinogen.
Aggregation Signals: ADP and Thromboxane A2 (both released by platelets –> positive feedback)
GpIIb-GpIIIa (receptors on platelets) and bind Fibrinogen, which stabilizes interactions between platelets/the aggregate
von Willebrand Disease
- Pathophysiology
- Diagnosis
- Treatment
***Most Common inherited bleeding disorder - especially type 1 (80% of cases); also type 2 and 3)
-There is a decrease in vWF protein levels/function, as well as factor VIII (8) levels
Diagnosis –> excessive bruising/nosebleeds in childhood; often first noted during tooth extraction or other minor surgeries
Treatment –> Desmopressin (stimulates relase of vWF and Factor VIII from Endothelial Cells)
Bernard-Soulier Syndrome
- Pathophysiology
- Treatment
-Giant Platelets and some degree of Thrombocytopenia
Pathophysiology –> Platelets fail to aggregate in response to stimuli due to a defect in interactions between Gp1b and vWF
Treatment –> Preventative (minimize bleeding risk) and eventually platelet transfusion to treat bleeding
Glanzmann Thrombasthenia
- Pathophysiology
- Treatment
Pathophysiology –> Defects in GpIIb and/or GpIIIa leading to prolonged bleeding time due to severe reduction in platelet aggregation in response to stimuli (ADP, collagen, epinephrine)
Treatment –> Preventative (good dental hygiene to prevent gingival hemorrhage), as well as treatment of bleeding with platelet transfusion
What is the importance of vitamin K in the coagulation cascade?
Vitamin K is required by carboxylase to form the amino acid residue y-carboxyglutamate in Factors II (Prothrombin), VII, IX, and X (2, 7, 9, 10)
***Vitamin K 1972***
(Note: this is extremely important, as y-carboxyglutamate binds Ca++ ions strongly, which interact with negatively charged membrane lipids and restrict clot formation to the site of injury)
How does warfarin function in the prevention of blood clotting?
Inhibits Vitamin K epoxide reductase (which normally regenerates active, reduced form of Vitamin K)
Outline activation of thrombin via the extrinsic pathway.
Include the roles of the various components of the extrinsic Xase complex.
In the presence of Ca++…
Tissue Factor (Thromboplastin) –> 7 (serine protease, cleaves factor 10) –> 10a (serine protease, catalyzes slow cleavage of prothrombin (2)) Prothrombin becomes –> Thrombin –> 5 –> combines with 10a forming prothrombinase complex, which quickly cleaves prothrombin and generates large quantities of ***Active thrombin*** (key event in coagulation)
What are the roles of thrombin in (i) generating the insoluble fibrin clot and (ii) sustaining and accelerating the extrinsic and intrinsic coagulation pathways?
Roles of Thrombin:
- Cleaves Fibrinogen, which is soluble, resulting in the formation of the insoluble soft fibrin clot
- Activates Factors 5 and 7 (V and VII), thereby sustaining/accelerating the extrinsic pathway
- Activates Factor 8 (VIII), a major protein cofactor that is needed for the intrinsic pathway
Outline the activation of thrombin via the intrinsic pathway as it is thought to occur in the body.
General order: 12, 11, 9, 8, 10, 5, 2, 1
(XII) 12 –> 12a (negative surface exposure)
(XI) 11 and prekallikrein (found in blood complexed with a protein called high-molecular-weight kininogen (HMWK)) are converted to 11a and kallikrein via 12a (XIIa)
11a activates 9 (IX)
9a (IXa) slowly activates 10 (X) which generates low levels of active Thrombin
Thrombin activates 8 (VIII) to 8a
***8a, 9a, and Ca++ come together and rapidly activate 10 (X)***
10a then leads to conversion of prothrombin to thrombin and generation of soft fibrin clot
Outline the pathophysiology of hemophilia A and B.
Both are X-linked, recessive bleeding disorders
Hemophilia A:
- Most Common
- Deficiency in factor 8 (VIII) production
Hemophilia B (Rare - 1 in 30,000 births):
-Deficiency in factor 9 (IX) production
Both treated with recombinant factor 8 and 9, respectively
How does thrombin, via thrombomodulin, protein C, and protein S function in anticoagulation?
Thrombin: binds thrombomodulin and activates Protein C (serine protease), which then binds to Protein S
Protein C/S Complex –> degrades factor 5a and 8a (Va and VIIIa), which blocks clotting
