Protein C Deficiency

Protein C is one of the major inhibitors of the coagulation system^[1] . Protein C deficiency is a heritable or acquired risk factor for thrombophilia. Presentation varies from asymptomatic to venous thromboembolism to neonatal purpura fulminans.

Hereditary protein C deficiency is caused by mutation in the PC (PROC) gene located on chromosome 2q14.3. Heterozygous and acquired protein C deficiencies are more common than homozygous deficiency^[2] .

Physiology^[3]

Protein C and protein S are vitamin K-dependent glycoproteins that act as natural anticoagulants. The proteolytic activation of protein C by thrombin occurs on the surface of endothelial cells and involves thrombomodulin and endothelial protein C receptor. In the presence of protein S, phospholipids and calcium, activated PC inactivates membrane-bound factors Va and VIIIa. Protein C also has anti-inflammatory and cytoprotective properties.

Aetiology

Protein C deficiency may be inherited or acquired.

Inherited protein C deficiency^[4]

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

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:

• 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

• Severe protein C deficiency (homozygous or compound heterozygous forms) is extremely rare (1 in 500 000 to 1 in 750 000 births), but partial deficiencies (heterozygous forms) are much more frequent (1 in 200 to 1 in 500)^[2] .
• However, genetic predisposition of thromboembolism depends on the racial background. Factor V Leiden and factor II mutation are the leading causes of inherited thrombophilias in white people but are not found in Asian ancestries. Protein S, protein C and antithrombin activity are reportedly low in 65% of adult Japanese patients with deep vein thrombosis^[6] .
• Complete deficiency of protein C, causing neonatal purpura fulminans (see below) is rare.

Presentation

Many patients have no symptoms and no VTE episodes.

Venous thromboembolism (VTE)

• 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; 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, most cases are unprovoked. The remainder are linked to a pro-thrombotic state - eg, pregnancy, immobilisation, etc.

Warfarin-induced skin necrosis (WISN)^[7]

• WISN is a rare complication (less than 0.1%) of warfarin therapy.
• Necrosis occurs more often in females. It can occur in the limbs and adipose tissue, including the breast, buttocks and penis, with an onset usually within several days of initiation of therapy.
• In addition to the inhibition of the coagulation factors II, VII, IX, and X, warfarin also inhibits the anticoagulant proteins C and S.
• Current treatment options include the following, depending on the extent of the necrosis:
• Immediate discontinuation of warfarin to prevent further necrosis.
• Reversal of warfarin effects with the administration of vitamin K.
• Possible administration of fresh frozen plasma and protein C concentrate to replace coagulation and anticoagulation factors, respectively^[8] .
• Wound care with possible amputation.
• Anticoagulation should be continued with a parenteral agent once appropriate.

Neonatal purpura fulminans (NPF)^{[9, 10]}

• Protein C can present in the immediate neonatal period.
• 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.
• 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.
• Long-term subcutaneous protein C replacement has also been used in neonatal severe protein C deficiency^[11] .

Assessment and investigation^[5]

For any suspected thrombophilia:

• There are published guidelines for the investigation of thrombophilia; see the separate Thrombophilia article.
• 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

VTE

Acute VTE^[12]
The standard anticoagulation regimen is normally used. See the separate Deep Vein Thrombosis and Pulmonary Embolism articles). It is essential to begin anticoagulation with heparin, during induction of oral anticoagulation. This is to prevent an initial pro-coagulant state and WISN.

VTE prophylaxis
All patients:

• See the separate Prevention of Venous Thromboembolism article.

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

• Long-term primary prophylaxis (anticoagulants) is not indicated (the risk of haemorrhage outweighs the benefits).
• If there is a family history of VTE, 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.
• Whether long-term prophylaxis (anticoagulation) should be used is uncertain:
  • Protein C deficiency is rare and the evidence regarding recurrent VTE rates is conflicting.
  • Take into account the circumstances of the VTE - whether there were any provoking factors and whether they still apply.
  • Take into account the number of VTE events. Patients with ≥2 spontaneous VTEs normally require long-term anticoagulant prophylaxis.
• NB: 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^[13] :

• 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.
• 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)^[5] .
• Women with previous VTE should be screened for inherited and acquired thrombophilia ideally before pregnancy.
• Recommendations (summarised) are:
  • 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.

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^[5] .
• WISN and NPF are serious or life-threatening emergencies.

Protein C deficiency does NOT appear to cause arterial thrombosis^[5] .

Prognosis

• There is a 10- to 15-fold risk of VTE, and a marked increase risk of recurrent VTE^[5] . 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.
• 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^[13] .