1. PHYSIOLOGIC CONTROL OF HEMOSTASIS MLAB 1227- Coagulation Keri Brophy-Martinez

2. Overview Control of the hemostatic mechanism is directed by:  Blood flow  Liver clearance  Positive Feedback amplification  Negative Feedback inhibition  Biochemical inhibitors

3. Control Mechanisms Blood flow  Initially, vasoconstriction to site assists fibrin formation  As blood flow returns to normal, coagulation is limited since there is a dilution of the concentration of activated factors  Activated factors are taken away from fibrin clot bound to inhibitory proteins. Liver Clearance  Liver removes activated coagulation factors complexed with their inhibitors from the circulation  Liver removes the plasmin-antiplasmin complexes and FDPs

4. Control Mechanisms Positive Feedback Amplification  Several systems used  Thrombin Activates platelets Promotes release of factor Va, to help in forming coag protein complexes Activates VIII Activates Xa which feeds back to activate more VII Blue boxes are targets Heavy arrows are positive feedbacks

5. Control Mechanisms Negative Feedback Inhibition  Some activated factors can destroy other factors in the cascade  Thrombin At higher concentrations, can inactivate factors V and VIII, with the help of Protein C  Fibrin Likes thrombin, so once it is adsorbed onto fibrin meshwork, thrombin is slowly released. Results in lack of thrombin to cleave fibrinogen  Fibrin degradation products Interfere with fibrinogen conversion

6. Biochemical Inhibitors Naturally occurring inhibitors  Antithrombin, heparin cofactor II, Protein C and Protein S, Tissue factor pathway inhibitor, Protein Z, alpha— Macroglobulin, Alpha-1 antitrypsin, C1-inhibitor, Thrombin activatable fibrinolysis inhibitor, alpha-2-antiplasmin Soluble plasma proteins Function  To regulate enzymatic reactions of serine proteases  Prevent inappropriate activation of the cascade, limiting the extent of fibrin clot formation and clotting.

7. Natural Inhibitors Antithrombin (AT)  Previously called antithrombin III (AT-III)  Produced in the liver by hepatocytes  Neutralizes all serine proteases, such as thrombin, XIIa, XIa, IXa, Xa, kallikrein, plasmin so it is considered broad spectrum  The action of AT is accelerated by the presence of Heparin (either naturally released from basophils or given therapeutically as an anticoagulant)

8. Natural Inhibitors Heparin Cofactor II  Inhibits thrombin, but has little activity against other proteases  Activity is accerlerated by heparin

9. Natural Inhibitors The Protein C pathway Protein S  Produced by liver  Vitamin K dependent  Acts as a cofactor to Protein C to enhance its ability to degrade factors Va and VIIIa Protein C  Produced by liver  Vitamin K dependent  Inactivates factors Va and VIIIa  Protein C is activated by Thrombin (IIa)  Action is enhanced by Protein S

10. Natural Inhibitors Tissue factor pathway inhibitor (TFPI)  Inhibits the F-VIIa-TF complex  Suppression of extrinsic pathway

11. References McKenzie, Shirlyn B., and J. Lynne. Williams. "Chapter 30." Clinical Laboratory Hematology. Boston: Pearson, 2010. Print.