Disorders of coagulation II: Disorders of coagulation II: AcquiredAcquired

Liver diseaseLiver diseaseLiver disease leads to defects of coagulation, platelets and Liver disease leads to defects of coagulation, platelets and

fibrinolysis:fibrinolysis: Reduced synthesis of vitamin K dependent factors caused Reduced synthesis of vitamin K dependent factors caused

by impaired vitamin K absorption by impaired vitamin K absorption Impaired synthesis of other coagulation proteins (factor I Impaired synthesis of other coagulation proteins (factor I

and V ).and V ). Thrombocypenia {hypersplenism) and abnormal platelet Thrombocypenia {hypersplenism) and abnormal platelet

function (cirrhosis).function (cirrhosis). Fibrinolysis impaired:Fibrinolysis impaired: Reduced levels of proteins C and S. antithromhin and , Reduced levels of proteins C and S. antithromhin and ,

antiplasmin lead to susceptibility to disseminated mtravas antiplasmin lead to susceptibility to disseminated mtravas cular coagulation (DI C).cular coagulation (DI C).

Dysfibrinogenaemia may lead to haemorrhage or Dysfibrinogenaemia may lead to haemorrhage or thrombosis.thrombosis.

Disseminated intravascular coagulationDisseminated intravascular coagulation

Background: Background: Disseminated intravascular Disseminated intravascular coagulation (DIC) is a complex systemic coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the thrombohemorrhagic disorder involving the generation of intravascular fibrin and the generation of intravascular fibrin and the consumption of procoagulants and plateletsconsumption of procoagulants and platelets where where the blood starts to coagulate throughout the whole the blood starts to coagulate throughout the whole bodybody. .

DIC is seen in association with a number of well-DIC is seen in association with a number of well-defined clinical situations, including sepsis, major defined clinical situations, including sepsis, major trauma, and abruptio placenta, and with laboratory trauma, and abruptio placenta, and with laboratory evidence of the following: evidence of the following:

1.1. Procoagulant activation Procoagulant activation 2.2. Fibrinolytic activation Fibrinolytic activation 3.3. Inhibitor consumption Inhibitor consumption 4.4. Biochemical evidence of end-organ damage or Biochemical evidence of end-organ damage or

failurefailure

DIC occurs in acute and chronic forms. DIC occurs in acute and chronic forms. Also called Also called consumptive coagulopathyconsumptive coagulopathy. . This depletes the body of its platelets and This depletes the body of its platelets and

coagulation factors, and there is coagulation factors, and there is paradoxically an increased risk of paradoxically an increased risk of hemorrhage. hemorrhage.

Clinical featuresClinical features Both bleeding and thrombosis may occur.Both bleeding and thrombosis may occur. Tissue damage caused by thrombosis leads to Tissue damage caused by thrombosis leads to

necrosis and further activation of coagulation necrosis and further activation of coagulation and fibrinolysis.and fibrinolysis.

Purpura, ecchymoses, gastrointestinal bleeding. Purpura, ecchymoses, gastrointestinal bleeding. Bleeding from intravenous sites and following Bleeding from intravenous sites and following

venepuncture may occur as a result of low levels venepuncture may occur as a result of low levels of coagulation factors and platelets resulting of coagulation factors and platelets resulting from increased consumption.from increased consumption.ii

Renal function may be impaired due to Renal function may be impaired due to microvascular thrombosis.microvascular thrombosis.

EtiologyEtiology Infections: Infections:

SepsisSepsis, particularly with , particularly with gram-negative bacteriagram-negative bacteria Viral Viral Malaria Malaria Rickettsial Rickettsial

Obstetric complications (most common cause), with chemicals Obstetric complications (most common cause), with chemicals from the from the uterusuterus being released into the blood. being released into the blood.

Tissue trauma such as burns, accidents, surgery, heat stroke or Tissue trauma such as burns, accidents, surgery, heat stroke or shockshock. .

Liver diseaseLiver disease Incompatible blood Incompatible blood transfusion reactionstransfusion reactions or massive or massive

blood transfusionblood transfusion (when more than the total circulatory volume is (when more than the total circulatory volume is transfused) transfused)

Graft-versus-host diseaseGraft-versus-host disease Cancers, Cancers, Viral hemorrhagic fevers. Viral hemorrhagic fevers. Envenomation by some Envenomation by some speciesspecies of of venomous snakesvenomous snakes. .

DiagnosisDiagnosisAlthough numerous Although numerous blood testsblood tests are often are often

performed on patients prone to DIC, the performed on patients prone to DIC, the important measures are: important measures are: full blood countfull blood count (especially the (especially the plateletplatelet count), count), fibrin degradation productsfibrin degradation products or or D-dimerD-dimer tests (markers of tests (markers of fibrinolysisfibrinolysis), ), bleeding timebleeding time and and fibrinogenfibrinogen levels. levels.

1.1. Decreased plateletsDecreased platelets2.2. Elevated FDPs or D-dimers (which are Elevated FDPs or D-dimers (which are

produced when fibrin undergoes produced when fibrin undergoes degradation when blood clots are degradation when blood clots are dissolved by dissolved by fibrinolysisfibrinolysis).).

3.3. + 4 Prolonged bleeding time and + 4 Prolonged bleeding time and decreased fibrinogen are markers of decreased fibrinogen are markers of DIC. DIC.

PathophysiologyPathophysiology The processes of coagulation and fibrinolysis lose control, and the The processes of coagulation and fibrinolysis lose control, and the

result is widespread clotting with resultant bleeding. result is widespread clotting with resultant bleeding. One of the critical mediator of DIC is the release of tissue factor One of the critical mediator of DIC is the release of tissue factor

(TF). (TF). TF is present on the surface of many cell types and is not normally TF is present on the surface of many cell types and is not normally

in contact with the general circulation, but is exposed to the in contact with the general circulation, but is exposed to the circulation after vascular damage. circulation after vascular damage.

This plays a major role in the development of DIC in septic This plays a major role in the development of DIC in septic conditions. conditions.

TF is also abundant in tissues of the lungs, brain, and placenta. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with This helps to explain why DIC readily develops in patients with

extensive trauma.extensive trauma. Upon activation, TF binds with coagulation factors that then trigger Upon activation, TF binds with coagulation factors that then trigger

both the intrinsic and the extrinsic pathways of coagulation.both the intrinsic and the extrinsic pathways of coagulation. Excess circulating thrombin results from the excess activation of the Excess circulating thrombin results from the excess activation of the

coagulation cascade. coagulation cascade.

The excess thrombin cleaves fibrinogen, The excess thrombin cleaves fibrinogen, which ultimately (at the end ) leaves which ultimately (at the end ) leaves behind multiple fibrin clots in the behind multiple fibrin clots in the circulation. These excess clots trap circulation. These excess clots trap platelets to become larger clots, which platelets to become larger clots, which leads to microvascular and macrovascular leads to microvascular and macrovascular thrombosis. thrombosis.

This settling of clots in the This settling of clots in the microcirculation, in the large vessels, and microcirculation, in the large vessels, and in the organs is what leads to the in the organs is what leads to the ischemia, impaired organ perfusion, and ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.end-organ damage that occurs with DIC.

Coagulation inhibitors are also consumed Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels in this process. Decreased inhibitor levels will permit more clotting so that a feedback will permit more clotting so that a feedback system develops in which increased system develops in which increased clotting leads to more clotting. clotting leads to more clotting.

At the same time, thrombocytopenia At the same time, thrombocytopenia occurs because of the entrapment of occurs because of the entrapment of platelets. Clotting factors are consumed in platelets. Clotting factors are consumed in the development of multiple clots, which the development of multiple clots, which contributes to the bleeding seen with DIC.contributes to the bleeding seen with DIC.

DIC is associated with a poor prognosis DIC is associated with a poor prognosis and a high mortality rate.and a high mortality rate.

TreatmentTreatment The underlying cause must be treated initially. The underlying cause must be treated initially. Anticoagulants are only given when indicated as Anticoagulants are only given when indicated as

patients with DIC are prone to bleeding. patients with DIC are prone to bleeding. Platelets may be Platelets may be transfusedtransfused if counts are very if counts are very

low, and low, and fresh frozen plasmafresh frozen plasma may be may be administrated.administrated.

The prognosis for those with DIC, depending on The prognosis for those with DIC, depending on its cause, is often grim (bad), leading the initials its cause, is often grim (bad), leading the initials to be known colloquially as "death is coming".to be known colloquially as "death is coming".

Other acquired disorders of Other acquired disorders of coagulationcoagulation

1.1. DrugsDrugs Anticoagulants and drugs affecting Anticoagulants and drugs affecting

anticoagulation can disturb coagulation.anticoagulation can disturb coagulation. Chemotherapy Chemotherapy 2. 2. Acquired coagulation inhibitorsAcquired coagulation inhibitors

These antibodies to coagulation factors are These antibodies to coagulation factors are idiopathic, com moner in the elderly, or occur idiopathic, com moner in the elderly, or occur in malignancy (e.g. lym phoma), connective in malignancy (e.g. lym phoma), connective tissue disease (e.g. SLE) and with tissue disease (e.g. SLE) and with paraproteins (e.g. myeloma). paraproteins (e.g. myeloma).

They lead to excessive bleed ing, both They lead to excessive bleed ing, both spontaneously and following injury.spontaneously and following injury.

3. Vitamin K deficiency3. Vitamin K deficiency Vitamin K is required to activate factors II, VII, IX and X Vitamin K is required to activate factors II, VII, IX and X

and protein C and S. and protein C and S. It is fat-soluble and derived from vegetables in food It is fat-soluble and derived from vegetables in food

and intestinal flora. and intestinal flora. Deficiency occurs in patients on poor diets, those Deficiency occurs in patients on poor diets, those

taking broad-spectrum antibiotics which reduce the gut taking broad-spectrum antibiotics which reduce the gut flora, in biliary tract disease and with intestinal flora, in biliary tract disease and with intestinal malabsorption.malabsorption.

4. Haemorrhagic disease of the newborn4. Haemorrhagic disease of the newborn Newborn infants are at an increased risk of bleeding Newborn infants are at an increased risk of bleeding

because of hepatic immaturity and low levels of vitamin because of hepatic immaturity and low levels of vitamin K. K.

It is normal to give an injection of vitamin K (1 mg) to It is normal to give an injection of vitamin K (1 mg) to all newborn infants in the UK. all newborn infants in the UK.

HEPERCOAGULAABILITY STATEHEPERCOAGULAABILITY STATE..

ANTITHROMBIN III DIFICIENCY.ANTITHROMBIN III DIFICIENCY. PROTEIN S DIFICIENCYPROTEIN S DIFICIENCY PROTEIN C DIFICIENCYPROTEIN C DIFICIENCY DYSFIBRINOGENAEMIADYSFIBRINOGENAEMIA ACTIVATED PROTEIN C-RESISTANCEACTIVATED PROTEIN C-RESISTANCE HEPARIN COFACTOR DIFICIENCYHEPARIN COFACTOR DIFICIENCY DISPLASMINOGENAEMIADISPLASMINOGENAEMIA PLASMINOGEN ACTIVATOR DIFICIENCYPLASMINOGEN ACTIVATOR DIFICIENCY PLASMINOGEN ACTIVATOR INHIBITOR EXCESSPLASMINOGEN ACTIVATOR INHIBITOR EXCESS ashjan319ashjan319

Thrombosis and thrombophiliaThrombosis and thrombophilia Thrombosis:Thrombosis: ThrombosisThrombosis is a specific medical term for a is a specific medical term for a

blood clot that remains in the place where it blood clot that remains in the place where it formed. formed.

Thrombosis is the pathological process Thrombosis is the pathological process whereby platelets and fibrin interact with the whereby platelets and fibrin interact with the vessel wall to form a haemosta tic plug (vessel wall to form a haemosta tic plug (clotclot or or thrombusthrombus) ) to cause vascular obstruction, to cause vascular obstruction, instructing the flow of instructing the flow of bloodblood resulting in resulting in ischaemia, which means ischaemia, which means deficiency of blood deficiency of blood in a part, due to functional constriction or in a part, due to functional constriction or actual obstruction of a blood vesselactual obstruction of a blood vessel e.g. e.g. Myocardial infarction and deep vain Myocardial infarction and deep vain thrombosis. thrombosis.

It may he It may he arterialarterial, causing ischemia, or , causing ischemia, or venous venous leading to stasis. leading to stasis.

The thrombus may he subsequently lysed by The thrombus may he subsequently lysed by fibrinolysis. fibrinolysis.

Thrombosis underlies ischaemic heart. Thrombosis underlies ischaemic heart. cerebrovascular and peripheral vascular disease: cerebrovascular and peripheral vascular disease: venous occlusion and pulmonary embolism: and venous occlusion and pulmonary embolism: and it plays an important part in pre-eclampsia.it plays an important part in pre-eclampsia.

It becomes more common with age.It becomes more common with age. ThromboembolismThromboembolism is a general term describing is a general term describing

both thrombosis and its main complication both thrombosis and its main complication which is embolisation.which is embolisation.

The thrombus may he subsequently lysed The thrombus may he subsequently lysed by fibrinolysis. by fibrinolysis.

Thrombosis underlies ischaemic heart. Thrombosis underlies ischaemic heart. cerebrovascular and peripheral vascular cerebrovascular and peripheral vascular disease: venous occlusion and pulmonary disease: venous occlusion and pulmonary embolism: and it plays an important part in embolism: and it plays an important part in pre-eclampsia.pre-eclampsia.

It becomes more common with age.It becomes more common with age. ThromboembolismThromboembolism is a general term is a general term

describing both thrombosis and its main describing both thrombosis and its main complication which is complication which is embolisationembolisation..

CausesCauses In classical terms, thrombosis is caused by In classical terms, thrombosis is caused by

abnormalities in one or more of the following (abnormalities in one or more of the following (VirchowVirchow's triad, who is a 's triad, who is a German physician and German physician and pathologist known for his contributions to cell pathologist known for his contributions to cell theory and the study of diseasetheory and the study of disease):):

The composition of the blood The composition of the blood (hypercoagulability) caused for example, by (hypercoagulability) caused for example, by genetic deficiencies or autoimmune disorders.genetic deficiencies or autoimmune disorders.

Damage of the vessel wall (endothelial cell Damage of the vessel wall (endothelial cell injury) such as by trauma, infection, or turbulent injury) such as by trauma, infection, or turbulent flow at bifurcations. flow at bifurcations.

Slowing down of the blood flow (hemostasis) Slowing down of the blood flow (hemostasis) past the point of injury (which may occur after past the point of injury (which may occur after long periods of sedentary behavior - for long periods of sedentary behavior - for example, sitting on a long airplane flight).example, sitting on a long airplane flight).

1 & 2 are most important for venous 1 & 2 are most important for venous thrombosis.thrombosis.

3 is more important for arterial thrombosis.3 is more important for arterial thrombosis.High altitude has also been known to High altitude has also been known to

induce thrombosis. induce thrombosis. Occasionally, abnormalities in coagulation Occasionally, abnormalities in coagulation

are to blame. are to blame. Intravascular coagulation follows, forming Intravascular coagulation follows, forming

a mass of red blood cells, leukocytes, and a mass of red blood cells, leukocytes, and fibrin.fibrin.

ClassificationClassification::

There are two distinct forms of There are two distinct forms of thrombosis:thrombosis:1- 1- Arterial thrombosisArterial thrombosis2- Venous thrombosis2- Venous thrombosis

Arterial thrombosisArterial thrombosis

A blood clot within an artery is known as an A blood clot within an artery is known as an arterial thrombosis.arterial thrombosis.

This occurs in relation to damaged endothelium, This occurs in relation to damaged endothelium, where exposed collagen and released tissue where exposed collagen and released tissue factor cause platelet aggregation and fibrin factor cause platelet aggregation and fibrin formation. formation.

Arterial thrombosis is responsible for heart Arterial thrombosis is responsible for heart attacks, strokes and peripheral vascular disease attacks, strokes and peripheral vascular disease (thrombosis in leg arteries). (thrombosis in leg arteries).

Heart attacks and strokes are a major cause of Heart attacks and strokes are a major cause of death and serious illness.death and serious illness.

The causes of arterial thrombosisThe causes of arterial thrombosis::

Arterial thrombosis usually affects individuals who Arterial thrombosis usually affects individuals who already have:already have:

1.1. AtherosclerosisAtherosclerosis, or narrowing of the arteries. , or narrowing of the arteries. 2.2. StrokeStroke3.3. Myocardial infarction (usually coronary Myocardial infarction (usually coronary

thrombosis due to rupture of an atherosclerotic thrombosis due to rupture of an atherosclerotic plaque) plaque)

4.4. Thoracic outlet syndrome (may precipitate Thoracic outlet syndrome (may precipitate arterial thrombosis as well asarterial thrombosis as well as venous) venous)

Risk factors for arterial thrombosisRisk factors for arterial thrombosis The main risk factors for arterial thrombosis include:The main risk factors for arterial thrombosis include: SmokingSmoking High blood pressureHigh blood pressure Increased levels of cholesterolIncreased levels of cholesterol DiabetesDiabetes Increasing ageIncreasing age Family historyFamily history Poor dietPoor diet Excess body weightExcess body weight Physical inactivity.Physical inactivity.Of these, the major risk factors are smoking, high blood Of these, the major risk factors are smoking, high blood

pressure (hypertension), and increased cholesterol pressure (hypertension), and increased cholesterol levels.levels.

Symptoms of arterial thrombosisSymptoms of arterial thrombosisThe build up of atheroma causes the The build up of atheroma causes the

narrowing of the arteries, which can lead narrowing of the arteries, which can lead to heart disease and heart attacks, strokes to heart disease and heart attacks, strokes or peripheral vascular disease.or peripheral vascular disease.

EmbolisationEmbolisation If a bacterial infection is present at the site of If a bacterial infection is present at the site of

thrombosis, the thrombus may break down, thrombosis, the thrombus may break down, spreading particles of infected material spreading particles of infected material throughout the throughout the circulatory systemcirculatory system ( (pyemiapyemia, , septic embolusseptic embolus) and setting up metastatic ) and setting up metastatic abscesses wherever they come to rest. abscesses wherever they come to rest.

Without an infection, the thrombus may become Without an infection, the thrombus may become detached and enter circulation as an detached and enter circulation as an embolusembolus, , finally lodging (staying) in and completely finally lodging (staying) in and completely obstructing a blood vessel (an obstructing a blood vessel (an infarctioninfarction), where ), where the effects of an infarction depend on where it the effects of an infarction depend on where it occurs.occurs.

22 - -Venous thrombosisVenous thrombosis A venous thrombosis is a A venous thrombosis is a blood clotblood clot that forms that forms

within a within a veinvein. . Superficial venous thrombosesSuperficial venous thromboses can cause can cause

discomfort but generally do not cause serious discomfort but generally do not cause serious consequences, unlike the consequences, unlike the deep venous thrombosesdeep venous thromboses (DVTs) that form in the (DVTs) that form in the deep veins of the legs or in the pelvic veins.deep veins of the legs or in the pelvic veins.

Since the veins return Since the veins return bloodblood to the to the heartheart, if a , if a piece of a blood clot formed in a vein breaks off piece of a blood clot formed in a vein breaks off it can be transported to the right side of the it can be transported to the right side of the heart, and from there into the heart, and from there into the lungslungs. .

A piece of thrombus that is transported in A piece of thrombus that is transported in this way is an this way is an embolismembolism: the process of : the process of forming a thrombus that becomes embolic forming a thrombus that becomes embolic is called a is called a thromboembolismthromboembolism. .

Deep venous thrombosisDeep venous thrombosis Renal vein thrombosisRenal vein thrombosis hepatic vein thrombosishepatic vein thrombosis

Risk factorsRisk factorsGeneralGeneral

Older age Older age Female gender Female gender Smoking Smoking Obesity Obesity Pregnancy Pregnancy Minor injuriesMinor injuries

MedicalMedical Surgery Surgery Trauma Trauma Oral contraceptive use Oral contraceptive use Malignancy Malignancy Kidney disorders Kidney disorders Lupus anticoagulant Lupus anticoagulant Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria Inflammatory bowel disease Inflammatory bowel disease Disseminated intravascular coagulationDisseminated intravascular coagulation

FamilialFamilial Antithrombin III deficiency Antithrombin III deficiency Protein C deficiencyProtein C deficiency/Protein S deficiency /Protein S deficiency APC resistance (Factor V Leiden) APC resistance (Factor V Leiden) Dysfibrogenemia Dysfibrogenemia Hypoplasminogenemia Hypoplasminogenemia Familial homocysteinemiaFamilial homocysteinemia

ThrombophiliaThrombophilia It is a term used to describe both: the It is a term used to describe both: the

inheritance and acquired haemostatic inheritance and acquired haemostatic disorders which predispose to thrombosis. disorders which predispose to thrombosis.

It should be suspected and screened for in It should be suspected and screened for in patients who patients who are youngare young. Have a . Have a positive positive family historfamily history. Have y. Have a thrombosis in an a thrombosis in an unusual siteunusual site and in and in females with recurrent females with recurrent fetal lossfetal loss..

Inherited thrombophiliaInherited thrombophilia:: This has been increasingly recognized recently. This has been increasingly recognized recently. Presentation may be during early child-hood or in Presentation may be during early child-hood or in

adulthood, e.g. at commencement of oral contra ceptives. adulthood, e.g. at commencement of oral contra ceptives. Inheritance of a variant form of factor V (tactor V Leiden) Inheritance of a variant form of factor V (tactor V Leiden)

is the most common (up to 5% of the population). is the most common (up to 5% of the population). Activated factor V Leiden is relatively resistant to Activated factor V Leiden is relatively resistant to inactivation by protein C. inactivation by protein C.

The risk of thrombosis is increased 5- to 10-fold in The risk of thrombosis is increased 5- to 10-fold in heterozygotes. and 50- to I00 fold in homozygotcs. heterozygotes. and 50- to I00 fold in homozygotcs.

Rarer causes include protein protein S or antithrombin Rarer causes include protein protein S or antithrombin deti ciency or functional abnormality, defective deti ciency or functional abnormality, defective fibrinolysis, mutantfibrinolysis, mutant prothromhin and homocystinuria. prothromhin and homocystinuria.

The combination of two abnormalities often underlies The combination of two abnormalities often underlies severe cases. severe cases.

Acquired thrombophiliaAcquired thrombophilia Post operative venous thrombosis.Post operative venous thrombosis. Venous stasis or immobility.Venous stasis or immobility. Malignancy.Malignancy. Blood disorders: e.g. increased viscosity.Blood disorders: e.g. increased viscosity. Oestrogen therapy.Oestrogen therapy. The Lupus Anticoagulant.The Lupus Anticoagulant. Factor IX concentrates Factor IX concentrates

Lupus anticoagulant syndromeLupus anticoagulant syndrome Despite its name, this syndrome usually presents with arte rial Despite its name, this syndrome usually presents with arte rial

or venous thrombosis or recurrent miscarriages. or venous thrombosis or recurrent miscarriages. It may he associated with systemic lupus erythematosus or It may he associated with systemic lupus erythematosus or

other connective tissue disorders, with malignancy or other connective tissue disorders, with malignancy or infections or the idiopathic. infections or the idiopathic.

Patients may show a spectrum of antibod ies which interfere Patients may show a spectrum of antibod ies which interfere with phospholipid-dependent coagula tion tests in vitro and/or with phospholipid-dependent coagula tion tests in vitro and/or react with cardiolipin.react with cardiolipin.

The A PTT is prolonged and not corrected by a 5o:50 mix of The A PTT is prolonged and not corrected by a 5o:50 mix of normal plasma in patient plasma. normal plasma in patient plasma.

Anticoagulant therapy is needed for patients with thrombosis.Anticoagulant therapy is needed for patients with thrombosis. Paradoxically, it is associated with venous or arterial Paradoxically, it is associated with venous or arterial

thrombosis and recurrent pregnancy loss due o placenta thrombosis and recurrent pregnancy loss due o placenta infarction.infarction.

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. .

It should not be confused with It should not be confused with C peptideC peptide or or c-reactive proteinc-reactive protein or or protein kinase Cprotein kinase C..

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

Its actions are related to development of Its actions are related to development of thrombosisthrombosis and and ischemic strokeischemic stroke. .

Role in disease

The Protein C Anticoagulant The Protein C Anticoagulant PathwayPathway::

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

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

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

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

T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein S Protein S

GeneticsGenetics The The PROCPROC gene is located on the second gene is located on the second chromosomechromosome..

Protein C deficiencyProtein C deficiency Protein C deficiency is a rare genetic feature that Protein C deficiency is a rare genetic feature that

predisposes to predisposes to venousvenous thrombosisthrombosis and and habitual abortionhabitual abortion. It was first described in 1981. . It was first described in 1981. The disease belongs to a group of genetic The disease belongs to a group of genetic disorders know as disorders know as thrombophiliasthrombophilias..The prevalence of protein C deficiency has been The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general estimated to about 0.2% to 0.5% of the general population.population.

Protein C deficiency is associated with an Protein C deficiency is associated with an increased incidence of venous increased incidence of venous thromboembolism , whereas no association with thromboembolism , whereas no association with arterial thrombotic disease has been found.arterial thrombotic disease has been found.

Activated protein C resistanceActivated protein C resistance is the inability of is the inability of protein C to cleave factors V and/or VIII. This protein C to cleave factors V and/or VIII. This may be hereditary or acquired. The best known may be hereditary or acquired. The best known and most common hereditary form is and most common hereditary form is Factor V LeidenFactor V Leiden. Acquired forms occur in the . Acquired forms occur in the presence of elevated Factor VIII concentrations.presence of elevated Factor VIII concentrations.

Warfarin necrosis is acquired protein C Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K deficiency due to treatment with the vitamin K inhibitor anticoagulant inhibitor anticoagulant warfarinwarfarin. In initial stages . In initial stages of action, inhibition of protein C may be stronger of action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to coagulation factors (II, VII, IX and X), leading to paradoxical (impossible) activation of paradoxical (impossible) activation of coagulation and coagulation and necrosisnecrosis of skin areas. of skin areas.

PathophysiologyPathophysiology The main function of The main function of protein Cprotein C is its anticoagulant is its anticoagulant

property as an inhibitor of coagulation factors property as an inhibitor of coagulation factors VV and and VIIIVIII. . There are two main types of protein C mutations that There are two main types of protein C mutations that

lead to protein C deficiency:lead to protein C deficiency: Type IType I: : QuantitativeQuantitative defects of protein C (low production defects of protein C (low production

or short protein half life) or short protein half life) Type IIType II: : QualitativeQualitative defects, in which interaction with defects, in which interaction with

other molecules is abnormal. Defects in interaction with other molecules is abnormal. Defects in interaction with thrombomodulinthrombomodulin, phospholipids, factors V/VIII and others , phospholipids, factors V/VIII and others have been described. have been described.

Homozygous protein C mutations often causes a severe Homozygous protein C mutations often causes a severe thrombotic disorder known as thrombotic disorder known as purpura fulminanspurpura fulminans..

protein c deficiency has only had 16 cases before 1999protein c deficiency has only had 16 cases before 1999

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 two In the circulation, Protein S exists in two forms: a free form and a complex form forms: a free form and a complex form bound to 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 associated with is a disorder associated with

increased risk of increased risk of venous thrombosisvenous thrombosis. . Protein S, a Protein S, a vitamin Kvitamin K-dependent physiological -dependent physiological

anticoagulant, acts as a nonenzymatic cofactor to anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of activated protein C in the proteolytic degradation of factor Vafactor Va and and factor VIIIafactor VIIIa. .

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

Protein S circulates in human plasma in two forms: Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement approximately 60 percent is bound to complement component C4b while the remaining 40 percent is free. component C4b while the remaining 40 percent is free.

Only free protein S has activated protein C cofactor Only free protein S has activated protein C cofactor activity.activity.

Types:Types: Hereditary and AcquiredHereditary and Acquired a) There are three types of hereditary protein S a) There are three types of hereditary protein S

deficiency.deficiency.

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 which

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

Systemic sex hormone therapy and pregnancySystemic sex hormone therapy and pregnancy Liver disease and certain chronic infections (for Liver disease and certain chronic infections (for

example HIV).example HIV).

Protein S deficiency is the underlying cause of a small Protein S deficiency is the underlying cause of a small proportion of cases of proportion of cases of disseminated intravascular coagulationdisseminated intravascular coagulation (DIC), (DIC), deep venous thrombosisdeep venous thrombosis (DVT) and (DVT) and pulmonary embolismpulmonary embolism (PE).(PE).

Hereditary PSD is an Hereditary PSD is an autosomal dominantautosomal dominant condition, condition, resulting in a 50 percent chance of passing the disease toresulting in a 50 percent chance of passing the disease to progenyprogeny. .

Less than half of those diagnosed with PSD will Less than half of those diagnosed with PSD will experience experience thrombosisthrombosis, and those who do usually are , and those who do usually are affected only from the age of the late teens onwards. affected only from the age of the late teens onwards.

Screening of young children is usually deferred because Screening of young children is usually deferred because early testing is often inaccurate, and it is better to wait early testing is often inaccurate, and it is better to wait until they are old enough to decide for themselves until they are old enough to decide for themselves whether they want to be tested.whether they want to be tested.

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 , cannot be inactivated by activated protein C. Factor V Leiden is the most protein C. Factor V Leiden is the most common hereditary hypercoagulability common hereditary hypercoagulability disorder amongst Eurasians.disorder amongst Eurasians.

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 an Factor V Leiden is an autosomal dominantautosomal dominant condition in which the coagulation factor cannot condition in which the coagulation factor cannot be destroyed by aPC. be destroyed by aPC.

MutationMutation of the of the genegene encoding factor V—a single encoding factor V—a single nucleotidenucleotide substitution substitution —changes the —changes the proteinprotein's 506th 's 506th amino acidamino acid from from argininearginine to to glutamineglutamine. .

Since this amino acid is normally the cleavage site for aPC, the mutation Since this amino acid is normally the cleavage site for aPC, the mutation prevents efficient inactivation of factor V. prevents efficient inactivation of factor V.

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

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

If the venous clots break off, these clots can travel through the If the venous clots break off, these clots can travel through the heartheart to to the the lunglung, where they block a , where they block a pulmonary blood vesselpulmonary blood vessel and cause a and cause a pulmonary embolismpulmonary embolism..

Women with the disorder have an increased risk of miscarriage and Women with the disorder have an increased risk of miscarriage and stillbirth. stillbirth.

Studies have found that about 5% of caucasians in North America have Studies have found that about 5% of caucasians in North America have factor V Leiden. factor V Leiden.

Up to 30% of patients who present with Up to 30% of patients who present with vein thrombosisvein thrombosis have this have this condition.condition.

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

The presence of acquired risk factors for The presence of acquired risk factors for venous thrombosis -- including venous thrombosis -- including smokingsmoking, , use of estrogen-containing (combined) use of estrogen-containing (combined) forms of forms of hormonal contraceptionhormonal contraception use, and use, and recent recent surgerysurgery -- further increase the -- further increase the chance that an individual with the factor V chance that an individual with the factor V Leiden mutation will develop DVT.Leiden mutation will develop DVT.

Women with Factor V Leiden have a Women with Factor V Leiden have a substantially increased risk of clotting in substantially increased risk of clotting in pregnancypregnancy (and on (and on estrogenestrogen containing containing birth control pills or hormone replacement) birth control pills or hormone replacement) in the form of deep vein thrombosis and in the form of deep vein thrombosis and pulmonary embolism. pulmonary embolism.

They also have an increased risk of They also have an increased risk of preeclampsia, as well as miscarriage and preeclampsia, as well as miscarriage and stillbirth due to clotting in the placenta, stillbirth due to clotting in the placenta, umbilical cord, or the fetus.umbilical cord, or the fetus.

Heterozygote patients have 5 folds Heterozygote patients have 5 folds increased risk of thrombosis.increased risk of thrombosis.

Homozygote patients have around 50-Homozygote patients have around 50-folds risk of thrombosisfolds risk of thrombosis

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 thrombotic event should be considered in any white patient below the age of 45, or in any any white patient below the age of 45, or in any person with a family history of venous person with a family history of venous thrombosis.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 increases the aPTT. normal patient, adding APC increases 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 will fail to prolong plasma of Factor V leiden will fail to prolong APTT. 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 molecule that (AT) is a small protein molecule that inactivates several enzymes of the inactivates several enzymes of the coagulationcoagulation system. system.

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

FunctionFunction The physiological target of antithrombin are those of the The physiological target of antithrombin are those of the

contact activation pathwaycontact activation pathway (formerly known as the intrinsic (formerly known as the intrinsic pathway), namely the activated forms of pathway), 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 (XIIa) and Factor II (thrombin) (IIa) and also the activated form of Factor VII II (thrombin) (IIa) and also the activated form of Factor VII (VIIa) from the (VIIa) from the tissue factor pathwaytissue factor pathway (formerly known as the (formerly known as the extrinsic pathway).[7]extrinsic pathway).[7]

Pathology:Pathology:Autosomal Dominant inheritance.Autosomal Dominant inheritance.Antithrombin (AT) deficiency usually Antithrombin (AT) deficiency usually

causes recurrent venous thrombosis causes recurrent venous thrombosis usually start early in adult live.usually start early in adult live.

Occasionally causes arterial thrombosis.Occasionally causes arterial thrombosis.Many molecular variants of AT are known Many molecular variants of AT are known

and are associated with varying degree of and are associated with varying degree of thrombosis.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.

It leads to increased prothrombin levels.It leads to increased prothrombin levels. It increases the risk of thrombosis by at It increases the risk of thrombosis by at

least 2-folds.least 2-folds.Such mutation + high concentrations of Such mutation + high concentrations of

factor VII, IX and XI will lead to sustained factor VII, IX and XI will lead to sustained generation of thrombin which will lead generation of thrombin which will lead reduction in the regulation of fibrinolysis reduction in the regulation of fibrinolysis and finally to thrombosis.and finally to thrombosis.

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

Supplementation with pyridoxine, folic acid, Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the concentration of homocysteine in the bloodstream.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 large condition characterized by an abnormally large level of homocysteine in the blood.level of homocysteine in the blood.

Classical Hyperhomocysteinemia:Classical Hyperhomocysteinemia: Is a rare autosomal recessive disorderIs a rare autosomal recessive disorder Vascular disease and thrombosis are major features of Vascular disease and thrombosis are major features of

the disease.the disease. Higher levels can be genetic or acquired.Higher levels can be genetic or acquired. Such Higher levels are associated with increased risk of Such Higher levels are associated with increased risk of

both venous and arterial thrombosis.both venous and arterial thrombosis.Acquired risk factors:Acquired 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 men and The risk is increased with age and it is higher in men and

menopausal women.menopausal women.

Hypercoagulable stateHypercoagulable state.. Definition of Hypercoagulable state:Definition of Hypercoagulable state: A hypercoagulable state is the medical term for A hypercoagulable state is the medical term for

a condition in which there is an abnormally a condition in which there is an abnormally increased tendency toward blood clotting increased tendency toward blood clotting (coagulation). (coagulation).

Hypercoagulation disorders may be acquired or Hypercoagulation disorders may be acquired or hereditary.hereditary.

Some of the primary or hereditary disorders that Some of the primary or hereditary disorders that lead to hypercoagulation are: lead to hypercoagulation are:

Abnormal clotting factor V. Abnormal clotting factor V. Variations in fibrinogen. Variations in fibrinogen. Deficiencies in proteins C and S. Deficiencies in proteins C and S.

Other body system diseases may also lead Other body system diseases may also lead to these disorders, includingto these disorders, including Diabetes.Diabetes.Sickle cell anemia, Sickle cell anemia, Congenital heart disease, Congenital heart disease, Lupus. Lupus. Thalassemia, Thalassemia, Polycythemia rubra vera, and others. Polycythemia rubra vera, and others. Antithrombin III deficiency.Antithrombin III deficiency.

Secondary or acquired hypercoagulable Secondary or acquired hypercoagulable states are acquired during life, usually in an states are acquired during life, usually in an individual who is unwell or immobile.individual who is unwell or immobile.

The common causes of a secondary The common causes of a secondary hypercoagulable state fall into three main hypercoagulable state fall into three main categories:categories:

Venous stasis caused by: Venous stasis caused by: Immobility Immobility Obesity Obesity Congestive cardiac failure Congestive cardiac failure Posteroperative bedrestPosteroperative bedrest

Coagulation factor activation caused by: Coagulation factor activation caused by: Malignant disease Malignant disease Pregnancy Pregnancy Oestrogen and oral contraceptive use Oestrogen and oral contraceptive use Nephrotic syndrome Nephrotic syndrome Antiphospholipid syndromeAntiphospholipid syndrome

platelet activation caused by: platelet activation caused by: Myeloproliferative disorders Myeloproliferative disorders Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura

Commonly an acute thrombotic episode Commonly an acute thrombotic episode results in an individual who acquires a results in an individual who acquires a hypercoagulable state on the background hypercoagulable state on the background of a primary hypercoagulability.of a primary hypercoagulability.