Protein C Deficiency

Updated: Jan 21, 2016
  • Author: Adam Cuker, MD, MS; Chief Editor: Perumal Thiagarajan, MD  more...
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Overview

Background

Protein C deficiency is a congenital or acquired condition that leads to increased risk for thrombosis. Congenital protein C deficiency is one of several inherited thrombophilias, which are a heterogeneous group of genetic disorders associated with an elevated risk of venous thromboembolism. Other inherited thrombophilias include the factor V Leiden mutation, the prothrombin gene mutation, dysfibrinogenemia, protein S deficiency, and antithrombin deficiency.

This article will focus on the pathophysiology, prevalence, clinical manifestations, diagnosis, and treatment of hereditary protein C deficiency. Causes of acquired protein C deficiency are also addressed (see Causes).

For patient education information, see the Deep Vein Thrombosis Health Center, as well as Pulmonary Embolism.

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Pathophysiology

The protein C pathway

Protein C is a 62-kD, vitamin K-dependent glycoprotein synthesized in the liver. It circulates in the blood as an inactive zymogen at a concentration of 4 μg/mL. Its activation into the serine-protease-like enzyme, activated protein C (aPC), is catalyzed by thrombin when it is bound to the endothelial proteoglycan thrombomodulin. [1, 2] The protein C pathway is illustrated in the image below.

The protein C pathway. APC = activated protein C; The protein C pathway. APC = activated protein C; PC = protein C; S= protein S; T = thrombin; TM = thrombomodulin; Va = factor Va; VIII = factor VIIIa.

Activated protein C (aPC) exerts its anticoagulant activity primarily through inactivation of coagulation factors Va and VIIIa, which are required for factor X activation and thrombin generation. The catalytic activity of activated protein C (aPC) is greatly enhanced by the vitamin K-dependent cofactor protein S. [3]

Aside from its role in coagulation, aPC subserves anti-inflammatory and cytoprotective functions, which are mediated through the endothelial protein C receptor and the protease-activated receptor-1 (PAR-1). [4, 5]

A deficiency of activated protein C (aPC) disturbs the delicate balance between procoagulant and anticoagulant proteins and engenders a prothrombotic environment. The role of activated protein C (aPC) and other anticoagulant proteins in this balance appears to be especially important in the slow-flowing venous circulation, in which there is prolonged exposure of procoagulant proteins and platelet phospholipids to the vessel wall. This may explain, in part, why protein C deficiency appears to be associated primarily with venous thrombosis.

Genetics of protein C deficiency

Heterozygous protein C deficiency is inherited in an autosomal dominant fashion. The gene for protein C is located on the long arm of chromosome 2 and nearly 200 pathogenic mutations of this gene have been described. [6, 7] These mutations are divided into 2 types — type I and type II — on the basis of whether they cause a quantitative (type I) or functional (type II) deficiency of protein C.

Type I deficiency

Type I protein C deficiency refers to a quantitative deficiency in the plasma protein C concentration. Heterozygous individuals typically demonstrate protein C antigen and activity levels that are approximately one half that of normal patient plasma. A range of causative genetic alterations within the protein C promoter region and splice sites as well as in the coding sequence of the protein C gene itself have been reported. [6]

There is marked phenotypic variation among families with heterozygous type I protein C deficiency. Some families exhibit a severe thrombotic tendency, whereas others remain asymptomatic. [8, 9, 10] Interestingly, this variability is seen even among different pedigrees that harbor the same protein C mutation, suggesting that the mutation itself does not fully explain the phenotypic variability. [11] The presence of a second thrombophilic mutation such as factor V Leiden has been associated with a more severe phenotype in some protein C-deficient kindreds. [12]

Type II deficiency

Type II protein C deficiency is less common than type I disease, and is associated with decreased functional activity and normal immunologic levels of protein C. A number of point mutations within the protein C gene giving rise to this disorder have been described. [6]

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Epidemiology

Frequency

United States

The frequency of protein C deficiency in the United States is similar to that found internationally.

International

Protein C deficiency by plasma level alone is found in 1 in 200 to 1 in 500 persons in the general population. [13, 14] However, many affected individuals remain asymptomatic throughout life. Protein C deficiency is present in approximately 2-5% of patients presenting with VTE. [15, 16, 17] Severe homozygous or compound heterozygous protein C deficiency occurs in approximately 1 in 500,000 to 1 in 750,000 live births.

Mortality/Morbidity

Clinical manifestations of heterozygous protein C deficiency include VTE and warfarin-induced skin necrosis (WISN). Whether the risk of pregnancy loss is increased in this disorder is controversial. Heterozygous protein C deficiency does not appear to be associated with an elevated risk of arterial thrombosis.

Homozygous and compound heterozygous protein C deficiency are classically associated with neonatal purpura fulminans (NPF); intracranial thromboembolism may also occur in neonates. [18]     Occasionally, patients present with VTE in childhood or adolescence.

Venous thromboembolism

The cardinal clinical manifestation of heterozygous protein C deficiency is VTE. The risk of VTE in this population is roughly seven-fold over that of the general population. [19, 20] Approximately 40% of patients with VTE have one of the usual thrombotic risk factors, such as pregnancy, the postpartum state, hormonal therapy, surgery, or immobilization. [21] The remaining 60% present with unprovoked VTE.

The most common sites of thrombosis are the deep veins of the lower extremities, although an elevated risk of mesenteric vein and cerebral sinus thrombosis is also well-documented. [22, 23, 24] Approximately 40% of patients with protein C deficiency present with evidence of pulmonary embolism, and roughly 60% suffer recurrent thrombosis if anticoagulation is discontinued. [21] The risk of VTE increases with age and, among heterozygotes, thrombosis is unusual before age 20 years. Rare homozygotes and compound heterozygotes who do not manifest NPF in infancy may present with VTE later in childhood or adolescence. [25]

Warfarin-induced skin necrosis

WISN is a potentially catastrophic complication of warfarin therapy that arises as a consequence of the different half-lives of the vitamin K-dependent proteins. One day after initiation of usual doses of warfarin, protein C activity is reduced by approximately 50%. Owing to their longer half-lives, the levels of the vitamin K-dependent clotting factors II, IX, and X decline more slowly (factor VII activity declines at approximately the same rate as protein C). The reduced level of protein C activity relative to these other procoagulant molecules creates a transient hypercoagulable state. This effect is more pronounced when large loading doses of warfarin are administered. Indeed, WISN typically occurs during the first few days of warfarin therapy, often when daily doses in excess of 10 mg are administered. [26, 27]

The skin lesions of WISN arise 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 (see image below). Dermal biopsy demonstrates ischemic necrosis of the cutaneous tissue with cutaneous vessel thrombosis and surrounding interstitial hemorrhage. [28]

A patient with warfarin-induced skin necrosis. A patient with warfarin-induced skin necrosis.

Although protein C deficiency is a strong risk factor for the development of WISN, approximately two thirds of patients with WISN do not have underlying hereditary protein C deficiency. [29] Other conditions reported in association with WISN include acquired protein C deficiency (see Causes) [30] and heterozygous protein S deficiency. [31]

See Deterrence/Prevention for the discussion of prevention and treatment of WISN.

Pregnancy loss

Protein C deficiency may be weakly associated with late and recurrent pregnancy loss. In the European Prospective Cohort on Thrombophilia, the odds ratio (OR) for stillbirth (defined as pregnancy loss at >28 weeks' gestation) among women with an inherited thrombophilia was 3.6 (95% confidence interval [CI] 1.4-9.4), whereas the risk of miscarriage before 28 weeks' gestation in this cohort was not significantly different than that of nonthrombophilic women. [32] Among the subgroup of thrombophilia subjects with congenital protein C deficiency, the OR of stillbirth was 2.3 (95% CI 0.6-8.3). [33, 32] In a meta-analysis of 633 subjects with hereditary protein C deficiency, the association with recurrent fetal loss was likewise nonsignificant (OR 1.57; 95% CI 0.23-10.54). [34]

Arterial thrombosis

There are several case reports of arterial stroke [35, 36] and myocardial infarction [37] occurring in young adults with congenital protein C deficiency. However, the results of larger studies are conflicting [38, 39, 40, 41, 42] and the existence of an association between protein C deficiency and arterial thrombosis remains controversial.

Peripheral arterial disease

In a study of 106 patients with peripheral arterial disease (PAD) and 44 with abdominal aortic aneurysm (AAA), Komai and colleagues found that the incidences of protein C deficiency was 4.7% in patients with PAD and 4.% in patients with AAA — higher rates than those observed in the general population. Protein C activity levels were significantly lower in PAD patients with critical limb ischemia than in those with intermittent claudication. In multivariate logistic regression analysis, lower protein C activity and female gender were determinant factors of critical limb ischemia. [43]

Neonatal purpura fulminans

NPF is a life-threatening condition that occurs in newborns with homozygous or compound heterozygous protein C deficiency, usually during the first several days of life. Affected neonates present with diffuse ecchymoses (see image below). Skin biopsy demonstrates extensive thrombosis of cutaneous venous and arterial channels, much as is observed in WISN. [44, 45] Laboratory testing reveals severe deficiency (< 1% of normal) of immunologic protein C levels. [46] Expeditious treatment with an exogenous source of protein C, discussed below in Treatment, Medical Care, is paramount.

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Race

Congenital protein C deficiency is recognized as a cause of thrombophilia around the world. Studies in blacks and Asians suggest that its prevalence in these populations is on par with its frequency of occurrence in whites. [47, 48] In contrast, the factor V Leiden and prothrombin gene mutations (see Hypercoagulability: Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli) occur with substantially greater frequency in white than in nonwhite populations.

Sex

As would be expected for an autosomal genetic disorder, the prevalence of hereditary protein C deficiency is similar in men and women. However, pregnancy, the postpartum state, and estrogen-containing hormonal therapy are important risk factors for the development of VTE that are unique to women.

Age

Preterm infants have protein C levels approximately 10-15% of normal adult levels; neonates, approximately 35%; and adolescents, 80%. Protein C levels increase approximately 4% per decade in adulthood [49, 50] ; nonetheless, the risk of thrombosis in individuals with heterozygous protein C deficiency increases with age. The median age at onset of VTE in heterozygous individuals is 30-40 years, and thrombosis is rare before age 20 years. [51]

In contrast, homozygous or compound heterozygous protein C deficiency classically manifests as NPF in the first several hours to days of life. Rare patients with homozygous or compound heterozygous deficiency may present with VTE during childhood or adolescence. [25]

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