coagulation cascade and thrombogenesis

Question 1

describe the basic coagulation cascade.

Answer 1

2 separate pathways lead to the same common pathway. goal of both is to make factor X.
Intrinsic pathway: collagen basement membrane and activated platelets activate XII –> XI –> IX –> VIII –> X. measured by PTT. PTT is good for monitoring heparin.
Extrinsic pathway: tissue thromboplastin –> VII –> X. measured by PT. good for monitoring warfarin.
Common pathway: X –> II (prothrombin to thrombin)–> fibrinogen becomes fibrin. Aggregation occurs in presence of calcium.

Question 2

How do complement and kinin pathways relate to the coagulation cascade?

Answer 2

kinin-kallikrein pathways play a role in pain, inflammation, coagulation, and blood pressure.
basically, high molecular weight kininogen and low molecular weight kininogen are precursors. HMWK can activate XII (intrinsic pathway, aka Hageman factor). It can also be converted to bradykinin when kallikrein is present, which causes increased vasodilation, permeability, and pain.
XII, in turn, can convert prekalikrein to kallikrein. kallikrein converts HMWK to bradykinin, and also promotes plasminogen to plasmin conversion. plasmin activates compliment and promotes fibrinolysis.
note that ACE inactivates bradykinin (may be why patients on ACE-I sometimes get angioedema). `

Question 3

What role does vitamin K play in coagulation? important enzymes in vitamin K metabolism? clinical tie-in?

Answer 3

oxidized vitamin k –> reduced vit K by epoxide reductase. Warfarin inhibits vitamin K epoxide reductase.
reduced vitamin K is a cofactor for maturation of factors 2, 7, 9, 10, C, and S.
neonates lack enteric bacteria, which produce vitamin K.

Question 4

What factor is carried by vWF?

Answer 4

8 (VIII)

Question 5

How do endothelial cells prevent thrombosis?

Answer 5

1. block exposure to subendothelial collagen and underlying tissue factor
2. produce PGI2 (prostacyclin) and NO- cause vasodilation and inhibition of platelet aggregation.
3. secrete heparin like molecules that augument antithrombin III (antithrombin inhibits factors 2, 7, 9, 10,11, 12, but esp. 10a and thrombin (II)
4. secrete tissue plasminogen activator (tPA), wich convers plasminogen to plasmin. plasim cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation
5. secrete thrombomodulin- redicrects thrombin to activate protein C, which inactivates factors V and VIII.

Question 6

What are 2 main reactions involved in anticoagulation?

Answer 6

protein c –> activated protein c via thrombin-thrombomodulin complex in the endothelial cells.
activated protein C –> cleaves and inactivates Va and VIIIa. does this with the help of protein S.
plasminogen becomes plasmin with the help of tPA. plasmin cleaves the fibrin mesh, destroys coagulation factors (and blocks platelet aggregation).

Question 7

What does antithrombin do? drug-tie in?

Answer 7

inhibites active forms of 2, 7, 9, 10, 11, and 12. but principle targets are thrombin (2) and Xa.
heparin enhances the activity of antithrombin.

Question 8

What are factor V leiden mutations?

Answer 8

mutations that produce a factor V resistant to inhibition by activated protein C.

Question 9

primary hemostasis

Answer 9

1. injury causes vasoconstriction mediated by endothelin and by reflex nerves.
2. vWF from the wable-palade bodies and the alpha granules of platelets bind exposed subendothelial collagen. vWF binds platelets via GpIb.
3. platelets begin to degranulate: they release ADP from the dense granules, which causes translocation of GIIb/IIIa receptors. they also release calcium.
   they also release TXA2, which promotes platelet aggregation.
4. platelet aggregation: platelets use fibrinogen to bind to eath others’ GPIIb/IIIa receptors. forms a primary platelet plug.

Question 10

what drugs act on thrombogenesis?

Answer 10

aspirin: inhibits COX and TXA2 synthesis
clopidogrel and ticlopidine inhibit ADP-induced expression of GpIIb/IIIa
abciximab inhibits GpIIb/IIIa directly
ristocetin activates vWF to bind GpIb. useful for diagnosis- normal platelet aggretation response is NOT seen in von willebrand disease.

Question 11

ESR: definition, causes for increase and decrease

Answer 11

acute phase reactants in plasma (like fibrinogen) can cause RBC aggregation, thereby increasing RBC sedimentation rate. increased ESR is seen in infection, autoimmune diseases, malignancy, ulcerative colitis, pregnancy
decreased ESR is seen in polycythemia, sickle cell anemia, CHF, microcytosis, hypofibrinogenemia.