Coagulation and Hemostasis

Much of this is a summary of an excellent summary posted by user OveractiveBrain on SDN (Student Doctor Network)

http://forums.studentdoctor.net/threads/does-ptt-increase-with-warfarin.915457/


In this discussion "a" means activated and "i" means inactive. So for example, factor Xi becomes Xa when it is activated.

Primary Hemostasis:

• This is formation of a platelet plug as opposed to the more stable fibrin plug.
• Two steps, adhesion and aggregation:
• Adhesion
• Vessel injury causes release of vWF from endothelial cells.  vWF utilizes glycoprotein Ib on platelets to help platelets adhere to vessel wall (as opposed to adhering to each other which = aggregation). At this point platelets are activated and release TXA2 and ADP which further activate nearby platelets.
• Aggregation
• Activated platelets express glycoprotein IIb/IIIa.  Fibrinogen (aka factor Ii) binds IIb/IIIa on different platelets to bridge them together and help them stick to each other (ie aggregation)

Secondary Hemostasis:

http://annals.org/data/Journals/AIM/19887/1FF1.jpeg

By Joe D - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1983833

• Secondary Hemostasis is formation of the more stable fibrin plug and involves coagulation factors and the cascade.
• Intrinsic pathway and extrinsic pathway both lead to the same thing: the common pathway which ends with fibrinogen (aka factor Ii)  converting to fibrin (aka factor Ia).
• Common pathway:
• Xi and Vi are activated and converted to Xa and Va which both act to activate Factor II.  IIi is also called prothrombin and IIa =  thrombin.
• Thrombin acts to cleave fibrinogen to fibrin. aka factor IIa converts factor I to Ia.
• Extrinsic pathway:
• Consists of only factor VII which is turned on by Tissue Factor to activate factor X and the Common Pathway.
• Intrinsic pathway: 
• Consists of the remainder of factors: Damaged surface activates XII -> XI -> IX -> which combines with VIII to activate X and the Common Pathway.

Relevant Labs and Drugs:

• Labs:
• PTT or aPTT - more letters so measures longer pathway ie intrinsic pathway. An activator such as silica, kaolin is added to plasma and the time it takes to clot is measured.
• PT - fewer letters measures shorter pathway ie extrinsic pathway. Tissue Factor is added to plasma and the time it takes to clot is measured. 
• INR - is a standardized way of reporting PT lab values.  Replaces PT clinically.
• Antiplatelet agents: 
• Both Aspirin and Clopidogrel act to prevent platelet activation and aggregation.
• Aspirin is a COX2 inhibitor which prevents formation of TXA2. 
• Clopidogrel inhibits P2Y12 (acts via Gi signaling) receptors for ADP.  (also Prasugrel, Ticagrelor, Cangrelor, Ticlopidine)
• Integrilin (Eptifibatide) is a IIb/IIIa inhibitor
• Cilostazol is a PDE inhibitor which increases cAMP which interferes with downstream activation of platelet aggregation by ADP. (also Dipyridamole)
• Anticoagulants:
• Warfarin/Coumadin antagonizes the action of Vitamin K (K for German "Koagulationsvitamin")  and thus affects the vitamin K-dependent factors. "Active" Vitamin K is needed for an important post-translational modification (carboxylation of glutamic acid residues by gamma-glutamyl carboxylase) of factors II, VII, IX, X which allows them to bind phospholipid surfaces inside blood vessels. Warfarin inhibits the enzyme which gives us "activated" Vitamin K (Vit K epoxide reductase) and thus warfarin is slow to act because existing pools of these factors continue to function normally.  Protein C and S which are important anti-coagulants in the body also depend on Vit K and thus are also inhibited by warfarin.  This is why patients started on warfarin are sometimes thought to be transiently hypercoagulable justifying a heparin "bridge".  Looking at factors II, VII, IX, X we see that warfarin should affect the intrinsic, extrinsic, and common pathways and thus both PT and PTT are prolonged by warfarin.  However, clinically, the INR or PT is followed to determine the appropriate dose of warfarin because factor VII of the extrinsic pathway has a short half life and thus more responsively reflects the effects of the given dose of warfarin.   Again using INR or PT to follow warfarin dose is a clinical tool, biochemically/physiologically both PT and PTT are affected by warfarin.
• Heparin acts to increase the activity of antithrombin which inhibits many factors in the intrinsic and common pathways.  Its effect is thus clinically followed by measuring the PTT although it can also prolong the PT.
• LMWH - coming soon
• New generation anticoagulants mainly affect common pathway.  Routine monitoring via coagulation assays is not normally necessary as these drugs have more predictable pharmacokinetics.  In cases of hemorrhage, it may become necessary to assess cogulation studies (PT/PTT etc).
• Dabigatran (Pradaxa) is a direct thrombin (IIa) inhibitor. 
• Rivaroxaban (Xarelto) and Apixaban (Eliquis) are factor Xa inhibitors.