MLAB 1227- Coagulation Keri Brophy-Martinez

1. MLAB 1227- CoagulationKeri Brophy-Martinez Physiologic Control of Hemostasis

2. Overview • Control of the hemostatic mechanism is also 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 and endothelial cells • 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.