1. Protein C

2.  Protein C is a major physiological anticoagulant. anticoagulant  It is a vitamin K-dependent serine protease enzyme, that is activated by thrombin into activated protein C (APC). vitamin Kserine protease enzymethrombinvitamin Kserine protease enzymethrombin  The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. protein ScofactorFactor VaFactor VIIIaprotein ScofactorFactor VaFactor VIIIa  The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti- inflammatory. anti- inflammatoryanti- inflammatory

3. Role in disease

4. The Protein C Anticoagulant Pathway:  Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface.  As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C.  Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa.  This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury.

5. Protein C deficiency  Protein C deficiency is a rare genetic feature that predisposes to venous thrombosis and habitual abortion. venousthrombosis habitual abortionvenousthrombosis habitual abortion  The disease belongs to a group of genetic disorders know as thrombophilias. thrombophilias  Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. Activated protein C resistance Activated protein C resistance  This may be hereditary or acquired.

6. Pathophysiology  The main function of protein C is its anticoagulant property as an inhibitor of coagulation factors V and VIII. protein CVVIIIprotein CVVIII  There are two main types of protein C mutations that lead to protein C deficiency:  Type I: Quantitative  Type II: Qualitative

7. Protein S.  Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. vitamin Kglycoproteinvitamin Kglycoprotein  In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b complement

8. Function  The best characterized function of Protein S is its role in the anti coagulation pathway, it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. coagulationProtein CFactors VaVIIIacoagulationProtein CFactors VaVIIIa  Only the free form has cofactor activity.  The property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring. inflammation

9. Protein S deficiency  Protein S deficiency is a disorder associated with increased risk of venous thrombosis. venous thrombosisvenous thrombosis  Decreased (antigen) levels or impaired function (activity) of protein S, leads to decreased degradation of factor Va and factor VIIIa and an increased tendency to venous thrombosis. protein Sfactor Va factor VIIIaprotein Sfactor Va factor VIIIa

10. Type of Protein S deficiency: 1.Hereditary 2.Acquired Protein S deficiency can also be acquired due to :  Vitamin K deficiency or Treatment with warfarin which generally also impairs the coagulation system itself (factors II, VII, IX and X), and therefore predisposes to bleeding rather than thrombosis. warfarinbleedingwarfarinbleeding  Systemic sex hormone therapy and pregnancy  Liver disease and certain chronic infections (for example HIV).

11. Some characteristics of protein C system components. Further information Half-life (hours) Plasma concentration component Neutralizes Va and VIIIa, enhances fibrinolysis, 6 4 ( µ g/ml) Protein C Potentiates action of thrombin on protein C ? 0 ( µ g/ml) * Thrombomodulin Promotes protein C binding to platelets phospholipids ? 35 ( µ g/ml) Protein S Inhibits protein C? 5 ( µ g/ml) Activated protein C inhibitor Binds protein S in an inactive form. ? 160 ( µ g/ml) C4B- binding protein

12. Factor V Leiden mutation  Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder. factor V hypercoagulabilityfactor V hypercoagulability  In this disorder the Leiden variant of factor V, cannot be inactivated by activated protein C. factor Vfactor V

13. Pathophysiology  In the normal person, factor V functions as a cofactor to allow factor X to activate an enzyme called thrombin. Thrombin in turn cleaves fibrinogen to fibrin, which polymerizes to form the dense meshwork that makes up the majority of a clot. cofactorfactor Xenzymethrombin fibrinogenfibrin clot cofactorfactor Xenzymethrombin fibrinogenfibrin clot  Activated protein C (aPC) is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V. protein C anticoagulantprotein C anticoagulant  Such mutation makes factor V less suseptable to cleavage by APC.

14.  Factor V Leiden is a condition in which the coagulation factor cannot be destroyed by aPC.  When factor V remains active, it facilitates overproduction of thrombin leading to excess fibrin generation and excess clotting.  The excessive clotting that occurs in this disorder is almost always restricted to the veins, where the clotting may cause a deep vein thrombosis (DVT). veinsdeep vein thrombosis veinsdeep vein thrombosis  It is also known as protein C-resistance (APC-R)

15. This will lead to many problems, such as:  Women with the disorder have an increased risk of miscarriage stillbirth, as well as preeclampsia due to clotting in the placenta, umbilical cord, or the fetus. preeclampsia  Patients with vein thrombosis have this condition. Patients with vein thrombosis Patients with vein thrombosis

16. Diagnosis  Suspicion of factor V Leiden being the cause for any thrombotic event should be considered in any white patient below the age of 45, or in any person with a family history of venous thrombosis.  This disease can be diagnosed by watching the aPTT as activated protein C is added. With a normal patient, adding APC increases the aPTT. In patients with factor V Leiden, adding APC to plasma of Factor V leiden will fail to prolong APTT. aPTT  There is also a simple genetic test that can be done for this disorder, and will give a quick diagnosis.

17. Antithrombin (AT) deficiency  Antithrombin (AT) is a small protein molecule that inactivates several enzymes of the coagulation system. coagulation  It is a glycoprotein produced by the liver and consists of 432 amino acids, and contains three disulfide bonds. glycoproteinliverdisulfide bondsglycoproteinliverdisulfide bonds

18. Function  The physiological target of antithrombin are those of the contact activation pathway (formerly known as the intrinsic pathway), namely the activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa) and Factor II (thrombin) (IIa) and also the activated form of Factor VII (VIIa) from the tissue factor pathway (formerly known as the extrinsic pathway) contact activation pathwayFactor X Factor IXFactor XIFactor XIIFactor IIFactor VIItissue factor pathwaycontact activation pathwayFactor X Factor IXFactor XIFactor XIIFactor IIFactor VIItissue factor pathway

19. Pathology:  Inherited.  Causes recurrent venous thrombosis, occasionally causes arterial thrombosis.  AT concentrate are available and are used to prevent thrombosis during surgery or childbirth.  The disease leads to increased prothrombin levels.

20. Hyperhomocysteinemia  Definition: An amino acid produced by the body, derived from the digestion of protein-rich foods.  Homocystein is derived from dietary methionin and is metabolized either by the remethylation or the trans-sulphuration pathways.  As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of the vitamins folic acid, pyridoxine (B6), or B12 (which use as cofactors) can lead to high homocysteine levels. folic acidpyridoxineB12folic acidpyridoxineB12

21.  Supplementation with folic acid or B12 reduces the concentration of homocysteine in the bloodstream.  Normal fasting homocysteine plasma levels are between 5,0 and 15,9 mmol/l.  Hyperhomocysteinemia is a medical condition characterized by an abnormally large level of homocysteine in the blood. homocysteinebloodhomocysteineblood

22. Classical Hyperhomocysteinemia Is a rare autosomal recessive disorder but it can also be acquired  Vascular disease and thrombosis are major features of the disease.  Higher levels are associated with increased risk of both venous and arterial thrombosis.

23. Acquired risk factors: - Decreased folate levels. –Decreased vitamin B12 levels. –Decreased vitamin B6 levels. –Drugs (e.g. cyclosporine). –Renal damage. –Smoking. –The risk is increased with age and it is higher in men and menopausal women.