Protein C Deficiency

Etiology

Protein C deficiency may be acquired or congenital. Congenital protein C deficiency results from mutations in the PROC gene. More than 160 PROC mutations have been described and may result in reduced levels of protein C (Type I) or the production of an altered protein C molecule with decreasing levels of activity (Type II).[1] Protein C deficiency is an autosomal dominant condition. Mutations in a single copy in heterozygous individuals cause mild protein C deficiency, whereas individuals with homozygous mutations present with severe protein C deficiency.

Epidemiology

Estimates of the incidence of mild protein C deficiency are between 1 in 200 to 1 in 500 individuals.[2] The incidence of clinically substantial protein C deficiency is estimated to be 1 in 20000 people. Severe protein C deficiency is rare and is predicted to occur in 1 in 4 million infants.[3] The rarity of observed severe protein C deficiency may be attributable to underdiagnosis or under-reporting.

Pathophysiology

Protein C is a vitamin K-dependent protease circulating in plasma at low concentrations and serves a critical role in the regulation of thrombin.[4] Levels of protein C mature later than many other coagulation proteins, with levels increasing from birth until 6 months and into puberty. Protein C becomes activated to form activated protein C (APC) via interactions with thrombin. APC acts to downregulate coagulation by cleaving and inactivating clotting factors V and VIII. A deficiency of protein C, and thus APC activity, leads to an inability to inactivate clotting factors and control thrombin production.

Protein C is also known to have a role in the regulation of inflammation and sepsis, with demonstrated cytoprotective functions.[4]

History and Physical

Severe protein C deficiency resulting from congenital homozygous mutations presents in neonates soon after birth and characteristically presents as disseminated intravascular coagulation (DIC) and purpura fulminans (PF). Affected individuals experience recurrent episodes of PF, which may be triggered by infection, trauma, or surgery.[5]

Patients with moderately severe protein C deficiency may not present until adolescence and often experience recurrent venous thrombotic events (VTE), including deep vein thrombosis (DVT), pulmonary emboli (PE), parenchymal thrombi and a tendency for DIC.

Individuals with heterozygous protein C deficiency and mild deficiency in protein C activity can range in symptom severity from asymptomatic to experiencing recurrent thromboses leading to post-thrombotic syndrome. In addition to DVT and PE, these patients may develop sequelae including ischemic arterial stroke and pregnancy-associated thrombosis.[6] The variability in risk of thrombotic events in carriers of protein C mutations may be due to incomplete gene penetrance, environmental or genetic influences.

Evaluation

Diagnostic testing for protein C deficiency is performed using functional assays including clotting assays, enzyme-linked immunosorbent assays (ELISA), and chromogenic tests to determine levels of protein C activity. Mutational analysis of the PROC gene is also available.[7]

The mean plasma concentration of protein C in a normal term infant is 40 IU dL-1, increasing to approximately 60 IU dL-1 at 6 months old. The normal range of protein C activity in healthy adults is between 65 to 135 IU dL-1. Patients with mild protein C deficiency have activity levels between 20 IU dL-1 and the lower limit of normal values, as determined by age. Moderately severe protein C deficiency is activity levels between 1–20 IU dL-1 and severe deficiency for activity demonstrates levels less than 1 IU dL-1. The relative level of protein C activity may also be expressed as functional percentages.

Treatment / Management

There are few standardized guidelines for the treatment of protein C deficiency. There have been few large studies and evidence is mostly based on case studies and anecdotal experience. Protein C deficiency is treatable by replacement with protein C concentrate. Neonatal PF is controllable with protein C replacement from fresh frozen plasma (FFP) or human plasma-derived, viral inactivated protein C concentrate.[8] Other than in episodes of PF, DIC, or acute VTE events, neonatal patients have been managed using long-term protein C replacement applied as prophylactic treatment. Anticoagulation treatments, such as high-intensity warfarin or low-molecular-weight heparin are also options.[9] Protein C replacement can be costly, leading to the use of anticoagulation therapies in specific settings such as VTEs occurring in children.[10](B3)

Differential Diagnosis

Patients who present with thrombophilia without other risk factors may suffer from protein C deficiency. Alternative causes of thrombophilia include other congenital coagulation abnormalities or a combination of protein C deficiency with other risk factors. The other congenital coagulation abnormalities include factor V Leiden mutation, protein S deficiency, antithrombin deficiency, and prothrombin G20210A mutation. Protein C deficiency may also be an acquired condition, rather than congenital, as a result of conditions including warfarin therapy, vitamin K deficiency, severe hepatic dysfunction, and bacterial infections in children.

Prognosis

Neonates presenting with severe protein C deficiency have a poor prognosis. Complications from frequent infusions of plasma, such as fluid overload contribute to a high rate of infant death. There is limited data available regarding the long-term outcome of patients with severe congenital protein C deficiency.[3]

Patients with mild protein C deficiency are prone to recurrent episodes of VTEs, including DVT. These events may lead to post-thrombotic syndrome and conditions such as venous stasis ulcers. The development of recurrent thrombotic events in individuals with thrombophilia can come under the influence of factors such as family history, obesity, underlying inflammatory disorders, and the presence of multiple thrombophilia qualities.[3]

Complications

Fresh frozen plasma (FFP) therapy can result in fluid overload, leading to the high levels of infant mortality observed in severe protein C deficiency. This is due to the volume of plasma that requires replacing during FFP. Furthermore, viral-inactivated FFP is not accessible in all settings. There is an additional risk of viral infections resulting from frequent transfusions. As with all transfusion therapies, there is a hazard of adverse immune reactions to donor molecules present in FFP. There is less risk of viral contamination and allergic reactions associated with the use of protein C concentrate. Long-term protein C replacement in neonates often necessitates the insertion of devices to access the central venous system, resulting in complications including thrombotic events and infections.

In adolescents and adults, long-term anticoagulation therapy increases the cumulative likelihood of severe bleeding complications such as ruptured ovarian cysts with resultant pelvic hemorrhage in female patients. Unless protein C deficiency is being sufficiently replaced, the use of traditional suppressive therapy with estrogens is contraindicated in these patients.[11] Replacement by protein C concentrate is also used to managed hemorrhage and thromboembolic complications during certain surgical interventions. The effectiveness of screening at-risk patients is under investigation and requires further evidence.[12]