Sandbox Reserved 596: Difference between revisions
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== '''Protein Z''' == | == '''Protein Z''' == | ||
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The coagulation cascade involves many coagulation factors that act as serine proteases with active sites centered around their serine residues. These serine protease coagulation factors, like factors VII, IX, X, and protein C are vitamin K-dependent proteins, meaning their γ-carboxyglutamic acid residue (Gla) construction within the liver requires fat-soluble vitamin k. Factor Xa (FXa), an essential enzyme found at the intersection of the two coagulation pathways, is formed on platelet membranes through the interaction of factor IXa, complexed with its cofactor VIIIa, on factor X. FXa complexed with its cofactor Va promotes thrombin production from the cleaved zymogen prothrombin. The cascade continues to flow towards its final processes of prothrombin being cleaved into thrombin and thrombin then cleaving fibrinogen to form a meshwork of fibrin until a blood clot stops the bleeding. To ensure that a clot does not form anywhere other than the injury site, any FXa that dissociates from the membrane must be inhibited. FXa is regulated by two serine protease inhibitors (serpins), antithrombin and protein z-dependent inhibitor (ZPI) that are inactive to FXa until paired with their cofactors heparin and protein z (PZ) respectively. [3] | The coagulation cascade involves many coagulation factors that act as serine proteases with active sites centered around their serine residues. These serine protease coagulation factors, like factors VII, IX, X, and protein C are vitamin K-dependent proteins, meaning their γ-carboxyglutamic acid residue (Gla) construction within the liver requires fat-soluble vitamin k. Factor Xa (FXa), an essential enzyme found at the intersection of the two coagulation pathways, is formed on platelet membranes through the interaction of factor IXa, complexed with its cofactor VIIIa, on factor X. FXa complexed with its cofactor Va promotes thrombin production from the cleaved zymogen prothrombin. The cascade continues to flow towards its final processes of prothrombin being cleaved into thrombin and thrombin then cleaving fibrinogen to form a meshwork of fibrin until a blood clot stops the bleeding. To ensure that a clot does not form anywhere other than the injury site, any FXa that dissociates from the membrane must be inhibited. FXa is regulated by two serine protease inhibitors (serpins), antithrombin and protein z-dependent inhibitor (ZPI) that are inactive to FXa until paired with their cofactors heparin and protein z (PZ) respectively. [3] | ||
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''Figure 2'' | ''Figure 2'' | ||
[[Image:Figure_2.JPG]] | [[Image:Figure_2.JPG]] | ||
== '''ZPI''' == | == '''ZPI''' == | ||
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Although PZ is conserved across many different species [5], the complete pathophysiological importance of PZ is still not completely known because many any clinical studies have resulted in conflicting conclusions. In 2001 Rice et al. wished to study just four important polymorphisms of the PROZ gene possibly linked to venous thrombosis but ultimately found and studied that PZ has 14 unique polymorphisms possible due to specific mutations. | |||
Lichy et al. studied specific the affects of mutations of Fg79a and promoter A-13g on cerebral ischema. | Lichy et al. studied specific the affects of mutations of Fg79a and promoter A-13g on cerebral ischema. | ||
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In 2002 Gris et al. examined PZ levels in pathologic pregnancies and found that low PZ levels caused extreme insufficiency of the placenta following the mother/fetus circulatory connection. Low PZ levels were also linked to antiphospholipid antibodies syndrome (aPL), suggesting PZ-ZPI complex incompetency by Steffano et al. and confirmed by a later study by McColl et al. Kemkes-Matthes et al. found that patients with thromboembolic episodes and factor V Leiden mutations suffered greatly from early thrombosis due to PZ deficiency. Lower levels of plasma PZ have also been linked to chronic inflammatory diseases like Bençet’s disease and ischemic colitis, and acute coronary syndromes (ACS). [1,6] | In 2002 Gris et al. examined PZ levels in pathologic pregnancies and found that low PZ levels caused extreme insufficiency of the placenta following the mother/fetus circulatory connection. Low PZ levels were also linked to antiphospholipid antibodies syndrome (aPL), suggesting PZ-ZPI complex incompetency by Steffano et al. and confirmed by a later study by McColl et al. Kemkes-Matthes et al. found that patients with thromboembolic episodes and factor V Leiden mutations suffered greatly from early thrombosis due to PZ deficiency. Lower levels of plasma PZ have also been linked to chronic inflammatory diseases like Bençet’s disease and ischemic colitis, and acute coronary syndromes (ACS). [1,6] | ||
