Hemostasis Vitamine complex

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Four elements of hemostasis: vasoconstriction, platelet aggregation, coagulation cascade
        activation, and fibrin deposition.
Factor II = prothrombin (activated to IIa or thrombin)
Factor III = tissue factor
Serine proteases include XII, XI, X, IX, VII, and II. These all circulate as zymogens.
Serine protease cofactors include VIII, V, III (tissue factor), and high-mol-wt-kininogen (HMWK).
        These increase reaction kinetics by concentrating the serine proteases and their substrates.

       Vitamin K is required to put the γ-carboxy glutamate side chain on X, XI, VII, II, protein C,
       and protein S. This side chain is required for binding to the platelet plug.

Other clotting elements include fibrinogen and XIII.
       Factor XIII covalently bonds fibrin strands together, strengthening the clot. It also
       incorporates a plasmin inhibitor into the clot to resist fibrinolysis.

The extrinsic pathway only uses Factor VII and tissue factor (the extrinsic protein). Extrinsic
       pathway is the most important coagulative pathway.
Tissue factor is never normally in contact with the bloodstream. Vascular damage exposes tissue
       factor, which contacts small amounts of VIIa in the blood. Together these activate Factor X.
       This initiates the common pathway.

             (Raymond removed image showing tissue factor and VIIa activation of X.)

The intrinsic pathway uses no extrinsic blood components. Only Factors VIII, IX, and IX are
        important for coagulation.
Factor XII is activated by exposure to subendothelium. XIIa activates prekallikrein to kallikrein,
        using HMWK as a cofactor. Kallikrein activates more XII, starting a positive feedback loop.
        Factor XIIa also activates Factor XI, again using HMWK as a cofactor.
Factor XIa activates IX on the phospholipid-rich surface of activated platelets.
At this point, Factor VIII has already been activated by small amounts of IIa from extrinsic pathway.
VIIIa and IXa together are the “tenase complex” and activate Factor X on the surface of the
        platelet plug. Factors IX and X are both Vitamin K dependent since they must bind the
        platelet plug.
This initiates the common pathway.

Factor VIII is a critical cofactor for IXa during activation of Factor X. Deficiency of Factor VIII
        is called Hemophilia A. Deficiency of Factor IX (less common) is called Hemophilia B.
The common pathway starts with activation of Factor X either by VIIa+tissue factor or by the
        VIIIa+IXa “tenase complex.” Both these reactions must occur on the plaletet surface.
At this point, Factor V has already been activated by small amounts of IIa from extrinsic pathway.
Factor Xa couples with its cofactor Va to form the “prothrombinase complex.” This activates
        Factor II (prothrombin) to IIa (thrombin). Again, this rxn occurs on the platelet surface.
Thrombin (IIa) then cleaves fibrinogen to fibrin monomers, which loosely polymerize. IIa also
        activates Factors XIII, VIII, V, and protein C.
Factor XIIIa “spot welds” fibrin strands together and incorporates α2-antiplasmin into the clot to
       protect against fibrinolysis by plasmin.

Coagulation Screening tests (APTT and PT)
The PT (prothrombin time) measures the extrinsic pathway (VII) and common pathway (X, V,
       II, and fibrinogen).
The APTT (activated partial thromboplastin time) measures the intrinsic pathway (XII, HMWK,
       prekallikrein, XI, VIII) and the common pathway.
Neither test measures XIII.
Increased PT or APTT suggests deficiency in a coag factor, or an auto-antibody against a factor.
A mixing study (mix patient + normal plasma) is used to distinguish between deficiency and
       --In a coag factor deficiency, the prolonged time will be corrected.
       --In autoimunity against a coag factor, the prolonged time will not be corrected.

                     (Raymond removed image depicting the mixing study.)
Hemophilia A is a factor VIII defiency. X-linked recessive inheritance.
Characterized by deep tissue bleeding, especially in joints (hemarthrosis).
Treatment is injection of VIII.

Hemophilia B is a factor IX deficiency. X-linked recessive inheritance.

The most common congenital bleeding disorder. Autosomal dominant inheritance.
vWF helps platelets adhere to subendothelial collagen, and protects factor VIII from being
       degraded by Protein C.
Characterized by bleeding from mucosal surfaces, menorrhagia, and petechia.
The amount of vWF is measured using ELISA.
The function of vWF is measured using ristocetin, an anitbiotic that aggregates platelets only in
       the presence of good vWF.
APTT is often normal in vWF.
Treated with DDAVP, which causes endothelial cells to release their vWF stores.

Vitamin K deficiency
The most common acquired bleeding disorder.
Without Vitamin K, liver produces inactive X, IX, VII, and II (prothrombin).
Factor VII has the shortest half-life, so an increased PT is a good sign of Vitamin K deficiency.

Liver disease causes similar problems, but will have increased PT and APTT. Liver disease will
       cause all factors except VIII to drop (because VIII is produced outside the hepatocyte).

(Raymond removed images of the vitamin K-dependent coagulation factors: II, VII, IX, X, C, S.
Also removed images of the intrinsic, extrinsic and common pathway to fibrinogen activation, an
       image of vWF, and an image of the activation events that take place on platelets.)

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Description: Hemostasis Vitamine complex