Thrombophilia Due To Protein C Deficiency, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant thrombophilia due to protein C deficiency (THPH3) is caused by heterozygous mutation in the PROC gene (612283) on chromosome 2q14.

See also autosomal recessive thrombophilia due to protein C deficiency (THPH4; 612304), a more severe disorder caused by homozygous mutation in the PROC gene.

Description

Heterozygous protein C deficiency is characterized by recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic (Millar et al., 2000). Individuals with decreased amounts of protein C are classically referred to as having type I deficiency and those with normal amounts of a functionally defective protein as having type II deficiency (Bertina et al., 1984).

Acquired protein C deficiency is a clinically similar disorder caused by development of an antibody against protein C. Clouse and Comp (1986) reviewed the structural and functional properties of protein C and discussed both hereditary and acquired deficiency of protein C.

Clinical Features

Griffin et al. (1981) reported a 22-year-old Caucasian man with recurrent thrombophlebitis complicated by pulmonary embolism. His 56-year-old father had thrombophlebitis with pulmonary embolism following a minor leg injury at age 24, a cerebrovascular accident at age 43, and a myocardial infarction at age 45. A paternal uncle had thrombophlebitis and recurrent pulmonary emboli dating from age 20. The paternal grandfather died abruptly at age 45 after developing pulmonary infiltrates while confined to bed due to a leg injury in a fall from a horse. The paternal great-grandfather died unexpectedly of a cerebrovascular accident at age 61. The propositus, his father, and his paternal uncle showed decreased levels of plasma protein C antigen, determined immunologically by the Laurell rocket technique, that were 38 to 49% of normal values. Clinically unaffected members of the kindred had normal levels.

Bertina et al. (1984) and Barbui et al. (1984) reported families with a discrepancy between normal protein C antigen levels and low functional activity of protein C. The proband in the latter report was a man with myocardial infarction at age 28 and severe thrombotic episodes thereafter, including cerebral thrombophlebitis, and both superficial and deep venous thrombosis of the leg. Although no other member of the family had a history of thromboses, the father also was found to have decreased functional activity of protein C. Immunoelectrophoretic studies showed an abnormal migration pattern of the protein, which the authors termed 'protein C Bergamo.'

Using an immunologic and a functional assay, Horellou et al. (1984) identified 22 patients from 9 French families with protein C deficiency. Six were asymptomatic, 15 had a history of venous thromboembolism, and 1 had a history of arterial thromboembolism. The first thrombotic episode occurred at a mean age of 24.1 years. Five patients (56%) had absence of a precipitating condition. One patient with severe protein C deficiency developed skin necrosis soon after starting oral anticoagulant treatment. Family history suggested autosomal dominant transmission of the defect.

Israels and Seshia (1987) described stroke in a 17-month-old girl with heterozygous protein C deficiency.

In a large New England kindred, Bovill et al. (1989) found a strong statistical correlation between thromboembolic disease and heterozygous protein C deficiency. On the other hand, they found no thromboembolic manifestations in many protein C-deficient family members, indicating that some factors other than heterozygous protein C deficiency must play an important role in the clinical expression.

Berdeaux et al. (1993) described 11 subjects from 3 families with dysfunctional protein C, or type II deficiency, characterized by a disproportionate decrease in protein C activity compared to the amount of antigen. In their own series, 4 of the 11 patients were symptomatic. They compared the findings in these subjects with those in 67 reported patients, including 39 symptomatic and 28 asymptomatic, with dysfunctional protein C deficiency.

In a study in the Netherlands, Allaart et al. (1993) found a significant difference in the thrombosis-free survival of 77 heterozygotes and 84 controls in the same families: by age 45, 50% of the heterozygotes and 10% of normal relatives had a manifestation of venous thromboembolism. Thrombotic events occurred more often in years in which the patient had been immobile for more than a week or had had surgery. There was no predisposing event such as surgery or pregnancy in 50% of all first episodes and 65% of recurrences of venous thromboembolism in the heterozygotes.

Acquired Protein C Deficiency

Using an electroimmunoassay, Mannucci and Vigano (1982) evaluated acquired protein C deficiency in conditions associated with an increased tendency to thrombosis.

Mitchell et al. (1987) described a fatal thrombophilia associated with the development of an antibody to protein C. Acquired nonmendelian autoimmune phenocopies are known for several other disorders, including dystrophic epidermolysis bullosa (226600), hemophilia A (306700), hereditary angioedema (106100), and von Willebrand disease (see 193400).

Gruppo et al. (2000) reported a 20-month-old child with acquired protein C deficiency who had a stroke while receiving valproic acid for a seizure disorder. They studied 20 children on valproic acid therapy and 20 children receiving other anticonvulsants and found that protein C levels were reduced to less than 5% of normal in up to 45% of the children receiving valproic acid.

Other Features

Pabinger et al. (1986) described coumarin-associated hemorrhagic skin necrosis of the toes in a patient with heterozygous protein C deficiency. The complication occurred on the 4th day of coumarin treatment overlapping with effective intravenous anticoagulation with heparin. Family studies revealed protein C deficiency in 2 sisters of the proposita without a history of thromboembolic disease. Pabinger et al. (1986) noted 3 earlier reports of this complication.

Conlan et al. (1988) described a family with type II protein C deficiency in which the proband had the simultaneous development of warfarin-induced skin necrosis and bilateral adrenal hemorrhage. The adrenal hemorrhage was manifested by abdominal pain, hypotension, and hyponatremia, and was confirmed by abdominal ultrasonography.

Among 8 patients with Legg-Perthes disease (150600), Glueck et al. (1994) found 3 instances of protein C deficiency; the patients came from kindreds with previously undiagnosed protein C deficiency. In 1 of these 3 kindreds, there were 6 protein C-deficient family members, 4 of whom had thrombotic events as adults. Protein S deficiency (612336) was found in 1 of the 8 patients; his brother had sustained mesenteric vein thrombosis at age 43. The other 4 patients had normal protein C, protein S, and antithrombin III, but 1 of them had hypofibrinolysis, failing to elevate tissue plasminogen activator activity (PLAT; 173370) after 10 minutes of venous occlusion at 100 mm Hg. Beyond their Legg-Perthes disease, none of the 8 patients had evidence of venous thrombosis. Glueck et al. (1994) suggested that thrombophilia contributed to thrombotic venous occlusion in the femoral head with subsequent venous hypertension and bone death that characterize Legg-Perthes disease.

Debus et al. (1998) found that 6 of 24 children with porencephaly (see 175780) had protein C deficiency, 1 of whom had a positive family history of thrombosis. Ten children had other prothrombotic conditions, including factor V Leiden (188055), protein S deficiency, and familial elevated serum Lp(a) concentration (152200). The authors concluded that protein C deficiency plays an important role in the etiology of congenital brain cysts but that other putative interacting factors, such as perinatal infection, placental insufficiency, and fetal cardiac arrhythmias, should also be considered.

Biochemical Features

Iijima et al. (1991) identified an abnormal protein C in a 60-year-old man with recurrent thrombosis. The anticoagulant protein C activity was reduced to nearly half of normal, but the total antigen protein levels were in the normal range. Immunoelectrophoretic studies showed an abnormal pattern. Further studies indicated that a half population of protein C in the patient's plasma was dysfunctional in the gamma-carboxyglutamic acid (Gla)-domain or its related structures. Four other family members were found to have the same abnormality of protein C but all were asymptomatic. The protein was designated 'protein C Yonago.'

Mapping

By studies of 11 heterozygotes with partial protein C deficiency Rocchi et al. (1985, 1986) found linkage to chromosome 2.

Molecular Genetics

In affected members of 2 unrelated families with protein C deficiency, Romeo et al. (1987) identified 2 different heterozygous mutations in the PROC gene (612283.0001 and 612283.0002), respectively. Affected individuals showed 50% reduction of both enzymatic and antigen levels of protein C.

Reitsma et al. (1993) provided a listing of mutations causing protein C deficiency, including a total of 67 different single basepair substitutions. Of these, 29 (43%) occurred in CpG dinucleotides and were C-to-T or G-to-A transitions compatible with a model of methylation-mediated deamination. A 1995 update on PROC mutations was provided by Reitsma et al. (1995). Reitsma (1996) stated that the 1995 update of the database comprised 331 entries describing 160 unique mutation events.

Genotype/Phenotype Correlations

Koeleman et al. (1994) found that heterozygous carriers of both the factor V Leiden mutation (R506Q; 612309.0001) and a mutation in the protein C gene were at higher risk of thrombosis compared to patients with either defect alone. Among 120 unrelated Swedish/Danish patients with protein C deficiency, Hallam et al. (1995) found a significantly increased frequency of the factor V Leiden allele compared to healthy controls; however, this was not found in a British population with protein C deficiency. Hallam et al. (1995) concluded that coinheritance of factor V Leiden was unlikely to be the sole determinant of whether a person with protein C deficiency will come to clinical attention.

Gandrille et al. (1995) detected the factor V R506Q mutation in 15 (14%) of 113 patients with protein C deficiency and in 1 (1%) of 113 healthy controls. There was a significant difference in the allele frequency of the R506Q mutation between heterozygous protein C-deficient patients and protein C-deficient patients with no identified mutation in the PROC gene. The results demonstrated that a significant subset of thrombophilic patients have multiple genetic risk factors, although additional secondary genetic risk factors remained to be identified in a majority of symptomatic protein C-deficient patients. The authors concluded that the factor V gene abnormality could help account for clinical expression of protein C deficiency in approximately 14% of the patients.

Population Genetics

Rocchi et al. (1986) quoted a frequency of 1/5000 for thrombophilia due to protein C deficiency in the Netherlands.

Animal Model

Lay et al. (2005) generated mouse models expressing 1 to 18% of normal protein C levels. The mice developed thrombosis and inflammation, the onset and severity of which varied significantly and were strongly dependent on plasma protein C levels. Maternal protein C was vital for sustaining pregnancy beyond 7.5 days postcoitum; Lay et al. (2005) suggested that protein C may regulate the balance of coagulation and inflammation during trophoblast invasion.