Protein CProtein C

Protein C is a major physiological Protein C is a major physiological anticoagulantanticoagulant. .

It is a It is a vitamin Kvitamin K-dependent -dependent serine proteaseserine protease enzymeenzyme, that is activated by , that is activated by thrombinthrombin into into activated protein C (APC). activated protein C (APC).

The activated form (with The activated form (with protein Sprotein S and and phospholipid as a phospholipid as a cofactorcofactor) degrades ) degrades Factor VaFactor Va and and Factor VIIIaFactor VIIIa..

The protein C pathway’s key enzyme, The protein C pathway’s key enzyme, activated protein C, provides activated protein C, provides physiologic physiologic antithrombotic activityantithrombotic activity and exhibits both and exhibits both anti-inflammatoryanti-inflammatory. .

Role in diseaseRole in disease

The Protein C Anticoagulant The Protein C Anticoagulant Pathway:Pathway:

Thrombin escaping from a site of vascular injury Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the binds to its receptor thrombomodulin (TM) on the intact cell surface. intact cell surface.

As a result, thrombin loses its procoagulant As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of properties and instead becomes a potent activator of protein C. protein C.

Activated protein C (APC) functions as a circulating Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and inactivates the phospholipid-bound factors Va and VIIIa. VIIIa.

This effectively down-regulates the coagulation This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular cascade and limits clot formation to sites of vascular injury. injury.

Protein C deficiencyProtein C deficiency

Protein C deficiency is a rare genetic feature Protein C deficiency is a rare genetic feature that predisposes to that predisposes to venousvenous thrombosisthrombosis and and habitual abortionhabitual abortion. .

The disease belongs to a group of genetic The disease belongs to a group of genetic disorders know as disorders know as thrombophiliasthrombophilias..

Activated protein C resistance is the inability Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. of protein C to cleave factors V and/or VIII.

This may be hereditary or acquired.This may be hereditary or acquired.

PathophysiologyPathophysiology

The main function of The main function of protein Cprotein C is its is its anticoagulant property as an inhibitor of anticoagulant property as an inhibitor of coagulation factors coagulation factors VV and and VIIIVIII. .

There are two main types of protein C There are two main types of protein C mutations mutations that lead to protein C deficiency:that lead to protein C deficiency:

Type IType I: : QuantitativeQuantitative Type IIType II: : QualitativeQualitative

Protein SProtein S..

Protein SProtein S is a is a vitamin Kvitamin K-dependent -dependent plasma plasma glycoproteinglycoprotein synthesized in the synthesized in the liver. liver.

In the circulation, Protein S exists in In the circulation, Protein S exists in two forms: a two forms: a freefree form and a form and a complexcomplex form bound to form bound to complementcomplement protein C4b protein C4b

FunctionFunction

The best characterized function of Protein S is The best characterized function of Protein S is its role in the anti its role in the anti coagulationcoagulation pathway, it pathway, it functions as a cofactor to functions as a cofactor to Protein CProtein C in the in the inactivation of inactivation of Factors VaFactors Va and and VIIIaVIIIa. .

Only the free form has cofactor activity.Only the free form has cofactor activity. The property of Protein S enhances the The property of Protein S enhances the

phagocytosis of the apoptotic cell, allowing it to phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of be removed 'cleanly' without any symptoms of tissue damage such as tissue damage such as inflammationinflammation occurring. occurring.

Protein S deficiencyProtein S deficiency

Protein S deficiencyProtein S deficiency is a disorder is a disorder associated with increased risk of associated with increased risk of venous thrombosisvenous thrombosis. .

Decreased (antigen) levels or impaired Decreased (antigen) levels or impaired function (activity) of function (activity) of protein Sprotein S, leads to , leads to decreased degradation of decreased degradation of factor Vafactor Va and and factor VIIIafactor VIIIa and an increased tendency to and an increased tendency to venous thrombosis. venous thrombosis.

Type of Protein S deficiencyType of Protein S deficiency::

1.1. HereditaryHereditary

2.2. Acquired Acquired

Protein S deficiency can also be acquired due to :Protein S deficiency can also be acquired due to : Vitamin K deficiency or Treatment with Vitamin K deficiency or Treatment with warfarinwarfarin

which generally also impairs the coagulation which generally also impairs the coagulation system itself (factors II, VII, IX and X), and system itself (factors II, VII, IX and X), and therefore predisposes to therefore predisposes to bleedingbleeding rather than rather than thrombosis.thrombosis.

Systemic sex hormoneSystemic sex hormone therapy and therapy and pregnancypregnancy Liver disease and certain chronic infections (for Liver disease and certain chronic infections (for

example HIV). example HIV).

Some characteristics of protein C Some characteristics of protein C system componentssystem components..

componentPlasma concentration

Half-life (hours)

Further information

Protein C4 (µg/ml)6Neutralizes Va and VIIIa, enhances fibrinolysis,

Thrombomodulin0 (µg/ml) *?Potentiates action of thrombin on protein C

Protein S35 (µg/ml)?Promotes protein C binding to platelets phospholipids

Activated protein C inhibitor

5 (µg/ml)?Inhibits protein C

C4B- binding protein160 (µg/ml)?Binds protein S in an inactive form.

Factor V Leiden mutationFactor V Leiden mutation

Factor V LeidenFactor V Leiden (sometimes (sometimes Factor Factor VLeidenVLeiden) is the name given to a variant of ) is the name given to a variant of human human factor Vfactor V that causes a that causes a hypercoagulabilityhypercoagulability disorder. disorder.

In this disorder the Leiden variant of In this disorder the Leiden variant of factor Vfactor V, cannot be inactivated by activated protein , cannot be inactivated by activated protein C. C.

PathophysiologyPathophysiology

In the normal person, factor V functions as a In the normal person, factor V functions as a cofactorcofactor to allow to allow factor Xfactor X to activate an to activate an enzymeenzyme called called thrombinthrombin. Thrombin in turn cleaves . Thrombin in turn cleaves fibrinogenfibrinogen to to fibrinfibrin, which polymerizes to form , which polymerizes to form the dense meshwork that makes up the majority the dense meshwork that makes up the majority of a of a clotclot. .

Activated Activated protein Cprotein C (aPC) is a natural (aPC) is a natural anticoagulantanticoagulant that acts to limit the extent of that acts to limit the extent of clotting by cleaving and degrading factor V.clotting by cleaving and degrading factor V.

Such mutation makes factor V less suseptable to Such mutation makes factor V less suseptable to cleavage by APC.cleavage by APC.

Factor V Leiden is a condition in which the Factor V Leiden is a condition in which the coagulation factor cannot be destroyed by aPC. coagulation factor cannot be destroyed by aPC.

When factor V remains active, it facilitates When factor V remains active, it facilitates overproduction of thrombin leading to excess overproduction of thrombin leading to excess fibrin generation and excess clotting.fibrin generation and excess clotting.

The excessive clotting that occurs in this The excessive clotting that occurs in this disorder is almost always restricted to the disorder is almost always restricted to the veinsveins, where the clotting may cause a , where the clotting may cause a deep vein thrombosisdeep vein thrombosis (DVT). (DVT).

It is also known as protein C-resistance (APC-It is also known as protein C-resistance (APC-R) R)

This will lead to many problems, such as:This will lead to many problems, such as: Women with the disorder have an increased Women with the disorder have an increased

risk of miscarriage stillbirth, as well as risk of miscarriage stillbirth, as well as preeclampsiapreeclampsia due to clotting in the placenta, due to clotting in the placenta, umbilical cord, or the fetus.umbilical cord, or the fetus.

Patients with vein thrombosis have this Patients with vein thrombosis have this condition.condition.

DiagnosisDiagnosis Suspicion of factor V Leiden being the cause for Suspicion of factor V Leiden being the cause for

any thrombotic event should be considered in any any thrombotic event should be considered in any white patientwhite patient below the below the age of 45age of 45, or in any person , or in any person with a with a family historyfamily history of venous thrombosis. of venous thrombosis.

This disease can be diagnosed by watching the This disease can be diagnosed by watching the aPTTaPTT as activated protein C is added. With a as activated protein C is added. With a normal patient, adding APC normal patient, adding APC increasesincreases the aPTT. the aPTT. In patients with factor V Leiden, adding APC to In patients with factor V Leiden, adding APC to plasma of Factor V leiden plasma of Factor V leiden will fail to prolong APTTwill fail to prolong APTT. .

There is also a simple genetic test that can be There is also a simple genetic test that can be done for this disorder, and will give a quick done for this disorder, and will give a quick diagnosis.diagnosis.

Antithrombin (AT) deficiencyAntithrombin (AT) deficiency

AntithrombinAntithrombin (AT) is a small protein (AT) is a small protein molecule that inactivates several enzymes molecule that inactivates several enzymes of the of the coagulationcoagulation system. system.

It is a It is a glycoproteinglycoprotein produced by the produced by the liverliver and and consists of 432 amino acids, and contains consists of 432 amino acids, and contains three three disulfide bondsdisulfide bonds..

FunctionFunction

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

Pathology:Pathology:

Inherited.Inherited. Causes recurrent Causes recurrent venous thrombosisvenous thrombosis, ,

occasionally causes occasionally causes arterial thrombosisarterial thrombosis.. AT concentrate are available and are used AT concentrate are available and are used

to prevent thrombosis during surgery or to prevent thrombosis during surgery or childbirth.childbirth.

The disease leads to increased prothrombin The disease leads to increased prothrombin levels.levels.

HyperhomocysteinemiaHyperhomocysteinemia

Definition: Definition: An amino acid produced by the body, An amino acid produced by the body, derived from the digestion of protein-rich foods.derived from the digestion of protein-rich foods.

Homocystein is derived from dietary methionin and Homocystein is derived from dietary methionin and is metabolized either by the remethylation or the is metabolized either by the remethylation or the trans-sulphuration pathways.trans-sulphuration pathways.

As a consequence of the biochemical reactions in As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of which homocysteine is involved, deficiencies of the vitamins folic acid, pyridoxine (B6), or B12 the vitamins folic acid, pyridoxine (B6), or B12 (which use as cofactors) can lead to high (which use as cofactors) can lead to high homocysteine levels. homocysteine levels.

Supplementation with folic acid or B12 Supplementation with folic acid or B12 reduces the concentration of homocysteine reduces the concentration of homocysteine in the bloodstream.in the bloodstream.

Normal fasting homocysteine plasma levels Normal fasting homocysteine plasma levels are between 5,0 and 15,9 mmol/l.are between 5,0 and 15,9 mmol/l.

HyperhomocysteinemiaHyperhomocysteinemia is a medical is a medical condition characterized by an abnormally condition characterized by an abnormally large level of homocysteine in the blood.large level of homocysteine in the blood.

Classical HyperhomocysteinemiaClassical Hyperhomocysteinemia

Is a rare autosomal recessive disorder Is a rare autosomal recessive disorder but it can also be acquiredbut it can also be acquired

Vascular diseaseVascular disease and thrombosis are and thrombosis are major features of the disease.major features of the disease.

Higher levels are associated with Higher levels are associated with increased risk of both increased risk of both venous and venous and arterial thrombosis.arterial thrombosis.

Acquired risk factorsAcquired risk factors::

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

men and menopausal women.men and menopausal women.