Physiology

Protein C is a vitamin K-dependent glycoprotein that is synthesised in the liver. It circulates in an inactive form. It is activated by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C degrades the activated clotting factors Va and VIIIa. The actions of protein C are enhanced by the cofactor, protein S. Protein C also has anti-inflammatory and cytoprotective properties.

Aetiology

Protein C deficiency may be inherited or acquired.

Inherited protein C deficiency

Inherited protein C deficiency is classified into types I and II, although this classification is not clinically useful:

• Type I - decreased levels of protein C.
• Type II (less common) - decreased functional activity of protein C.

Genetics:

• There are many different mutations affecting protein C levels. The inheritance pattern is said to be autosomal dominant,^[2] although there are some autosomal recessive forms.^[3]
• Knowledge of the precise genetic variant does not seem to predict the degree of thrombotic risk.^[4] Even among families with the same genetic mutation, there may be differences in the thrombotic tendency.^[5]
• Patients who are homozygous for protein C deficiency (or who are 'compound heterozygotes') often have a severe form of thrombosis, neonatal purpura fulminans (NPF) - see below.^[5]

Note: inherited pro-thrombotic conditions are relatively common; co-existence of another pro-thrombotic condition will affect the clinical risk of thrombosis.

Acquired protein C deficiency

This may occur with:^[5]

• Severe infection, including meningococcal septicaemia.
• Disseminated intravascular coagulation.
• Liver disease.
• Vitamin K deficiency and warfarin therapy.
• Some chemotherapy agents - eg, L-asparaginase.
• Haemopoietic stem cell transplantation.

Epidemiology

• Protein C deficiency as measured in plasma affects between 1 in 200 and 1 in 500 people but many affected individuals remain asymptomatic.^[5]
• It is estimated that in a Caucasian population, protein C deficiency is found in 2-5% of patients with venous thromboembolism (VTE), in 5-10% of those with recurrent VTE and in 0.2-0.5% of the general population.^[2]
• Complete deficiency of protein C, causing NPF, is rare.^[2]
• The prevalence is probably similar in black and Asian populations.^[5]

Presentation^[2][5]

Many patients have no symptoms and no VTE episodes.

Venous thromboembolism

• Commonly, in the lower limb and/or lungs.
• It may also occur in rarer sites - eg, the mesenteric vein and cerebral sinus.
• VTE is usually absent until patients reach their early 20s, and rates increase towards the age of 50.
• Patients with severe deficiency (homozygotes or compound heterozygotes) may develop VTE in childhood or adolescence (if the deficiency is not already manifest in the neonatal period, see below).
• Of VTE cases with protein C deficiency, about 60-70% are unprovoked. The remainder are linked to a pro-thrombotic state - eg, pregnancy, immobilisation, etc.

Warfarin-induced skin necrosis^[5]

• WISN is a medical emergency. It is a rare complication of initiating warfarin therapy; protein C deficiency is a major risk factor.
• It probably arises from the different half-lives of the vitamin K-dependent proteins, ie protein C levels fall faster than the levels of vitamin K-dependent clotting factors. This creates a transient hypercoagulable state when warfarin therapy is started, particularly if large doses are used (eg, >10 mg daily).
• WISN presents with skin lesions on the extremities, torso, breasts and penis. They begin as erythematous macules and, if appropriate therapy is not initiated promptly, evolve to become purpuric and necrotic. There is ischaemic necrosis of the cutaneous tissue with cutaneous vessel thrombosis and surrounding haemorrhage.

Neonatal purpura fulminans^[5]

• Protein C can present in the immediate neonatal period.^[6]
• NPF is a life-threatening emergency which may occur in neonates who have severe protein C deficiency (homozygotes or compound heterozygotes for this condition).
• It usually presents in the first week of life with diffuse ecchymoses; there is thrombosis of cutaneous vessels.

Assessment and investigation^[4]

For any suspected thrombophilia:

• There are published guidelines for the investigation of thrombophilia; see separate article Thrombophilia.
• Assessment involves testing for various thrombophilic conditions. It is not advisable to test for one single condition in isolation.
• Take a full history and family history regarding VTE events.

Testing for protein C deficiency:

• Note:
  • Testing is best delayed until one month after finishing a course of anticoagulation, and after recovery from intercurrent illness, pregnancy, etc. If this is not possible, ensure the person interpreting the tests is aware of these factors.
  • Interpretation of the result requires an experienced clinician who is aware of all the patient's relevant factors.
  • Vitamin K deficiency and oral anticoagulants (warfarin) affect the protein C assay. Therefore, a baseline prothrombin time and drug history are essential when evaluating protein C. Ideally, test when the patient is not taking warfarin.
• The recommended assay for protein C is a functional one - this identifies both type I and type II deficiency. It uses a snake venom product to activate the protein C, which can then be quantified by either chromogenic or clotting methods. The chromogenic method is more reliable.
• Laboratories should establish their own reference ranges.
• There is generally no justification for tests to distinguish type I/type II deficiency (antigen assays) or for molecular tests to identify the genetic mutation, as these will not normally alter management.

Differential diagnosis

• Other causes of heritable thrombophilia (which may co-exist).
• Other conditions causing a thrombophilic state - eg, myeloproliferative disorders, malignancy.

Management

Venous thromboembolism

Acute VTE^[7]
The standard anticoagulation regimen is normally used (see separate articles Deep Vein Thrombosis and Pulmonary Embolism). It is essential to begin anticoagulation with heparin, during induction of warfarin therapy. This is to prevent an initial pro-coagulant state and WISN.

VTE prophylaxis
All patients:

• See separate article Prevention of Venous Thromboembolism.

Asymptomatic patients with protein C deficiency, ie those without VTE:

• Long-term primary prophylaxis (anticoagulants) are not indicated (the risk of haemorrhage outweighs the benefits).
• If there is a family history of VTE, then consider prophylaxis to cover periods of increased thrombotic risk - eg, pregnancy, surgery, trauma or immobilisation).

Patients with protein C deficiency AND a previous VTE:

• Consider short-term prophylaxis to cover periods of increased thrombotic risk.
• Should long-term prophylaxis (anticoagulation) be used? This is uncertain:
  • Protein C deficiency is rare and the evidence regarding recurrent VTE rates is conflicting.
  • Take into account the circumstances of the VTE - were there any provoking factors, and do they still apply?
  • Take into account the number of VTE events. Patients with ≥2 spontaneous VTEs normally require long-term anticoagulant prophylaxis.
• Note: long-term anticoagulation is required for patients with protein C deficiency who are homozygotes and compound heterozygotes for this condition. These patients would normally be identified and treated already, because of NPF or a childhood VTE.

Pregnancy and postnatal period:

• Pregnancy and the puerperium are risk factors for VTE (pregnancy carries a ten-fold increase compared with non-pregnant women). Protein C deficiency and previous VTE are additional risk factors.^[8]
• Women who are heterozygous for protein C deficiency are considered at 'moderately' increased risk of pregnancy-associated VTE (on a scale of mild/moderate/severe).^[4]
• Women with previous VTE should be screened for inherited and acquired thrombophilia ideally before pregnancy.
• Recommendations (summarised) are:^[8]
  • Avoid immobilisation and dehydration.
  • Wear graduated compression stockings throughout the pregnancy.
  • Seek haematology advice; however, in general:
    • Women with previous VTE and thrombophilia should be offered thromboprophylaxis with low molecular weight heparin antenatally and for at least six weeks postpartum.
    • Women with thrombophilia and no previous VTE should be stratified according to the level of risk associated with their thrombophilia. Consider using thromboprophylaxis antenatally and postpartum.

Warfarin-induced skin necrosis^[5]

• Stop warfarin and give vitamin K.
• Give heparin in therapeutic doses.
• For protein C-deficient patients, give protein C to normalise protein C activity (as protein C concentrate or as fresh frozen plasma).^[9]

Neonatal purpura fulminans^[5]

• After initial treatment with fresh frozen plasma, protein C must be given to normalise protein C activity (using intravenous protein C concentrate).^[10] 
• After the acute phase, patients need lifelong anticoagulation. Warfarin is suitable, but protein C must be given while initiating warfarin therapy.
• Protein C can be used if there is breakthrough thrombosis despite anticoagulation.

Complications

Possible complications include:

• Complications of VTE.
• Risk of bleeding from anticoagulation, if used.
• With heritable thrombophilias, there is probably an increased risk of fetal loss.^[4]
• Protein C deficiency does NOT appear to cause arterial thrombosis.^[4]
• WISN and NPF are serious or life-threatening emergencies.

Prognosis

• There is a 10- to 15-fold risk of VTE.^[4] However, there is a marked variation in risk among families with protein C deficiency, that cannot be explained by the genetic defect itself. Any co-existing thrombophilic disorders are also important.^[2]
• With a known VTE event, the risk of recurrent VTE may be up to 60%.^[5] A recent study found a recurrence rate of 38% over 10 years.^[11]
• Pregnancy - pregnant women with protein C deficiency have an increased risk of VTE, but most events occur postpartum. The risk also depends on whether the woman or her close family has had a previous VTE.^[8]