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 ... 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.
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, ... 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.
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. ... 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.
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 ... 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.