The Risk of Thromboembolism in Asymptomatic Patients with Protein C and Protein S Deficiency: A Prospective Cohort Study

Summary

Background: Prospective studies on the incidence of thrombosis in asymptomatic individuals with hereditary protein C- or protein S deficiency have not been performed so far.

Objective: We have carried out a prospective cohort study in 44 asymptomatic protein C- and protein S deficient subjects and in 49 asymptomatic non-deficient relatives (age at study entry > 14 years) of symptomatic deficient patients.

Methods: 20 asymptomatic protein C deficient (median age 20 years) and 24 asymptomatic protein S deficient patients (median age 21.5 years) were prospectively followed and compared with 20 asymptomatic non-deficient relatives (median age 25 years) of protein C- and 29 (median age 27 years) of protein S deficient patients. The total observation period was 118.8 patient years for protein C deficient and 92.8 for protein S deficient patients. Patients were not on anticoagulants except for short duration in case of high risk situations.

Results: Eight thromboembolic events (1 pulmonary embolism, 1 deep vein thrombosis + pulmonary embolism, 3 deep vein thrombosis, 1 caval vein thrombosis and 2 superficial vein thrombosis) occurred in 6 deficient patients. The incidence of thromboembolism was 2.5% per patient year for protein C deficient and 3.5% per patient year for protein S deficient patients. 4 events occurred spontaneously, in 2 patients thromboembolic events were triggered by high risk situations (caesarean section, minor trauma). In the controls no thromboembolic events occurred. The probability for thromboembolism was significantly higher in protein C and protein S deficient patients compared to the control group (Wilcoxon test, p = 0.002, log rank test, p = 0.001). One major and 5 minor uneventful surgeries were carried out in the deficient patients using heparin prophylaxis. 1/8 pregnancies was complicated by superficial vein thrombosis during the second trimester despite prophylactic heparin administration. The same pregnancy was complicated by pulmonary embolism 5 weeks after delivery after discontinuation of heparin.

Conclusions: Asymptomatic deficient relatives of symptomatic patients with protein C or protein S deficiency are at an increased risk of thrombosis compared to nondeficient individuals. Prophylactic treatment seems to be highly effective in high risk situations.

• References

• 1 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-3
• 2 Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study in three Dutch families. N Engl J Med 1983; 309: 340-4
• 3 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1298-300
• 4 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8
• 5 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-7
• 6 Engesser L, Broekmans AW, Briet E, Brommer EJP, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Intern Med 1987; 106: 677-82
• 7 Pabinger I, Kyrle PA, Speiser W, Stoffels U, Jung M, Lechner K. Diagnosis of protein C deficiency in patients an oral anticoagulant treatment: comparison of three different functional protein C assays. Thromb Haemostas 1990; 63: 407-12
• 8 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-8
• 9 Tripodi A, Bertina RM, Conard J, Pabinger I, Sala N, Mannucci PM. Multicenter evaluation of three commercial methods for measuring protein S antigen. Thromb Haemostas 1992; 68: 149-54
• 10 Pabinger I, Briicker S, Kyrle PA, Schneider B, Kominger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagulation Fibrinolysis 1992; 3: 547-53
• 11 Pabinger I, Allaart CF, Hermans J, Briet E, Bertina RM. and the Protein C Transmitter Study Group. Hereditary protein C deficiency: laboratory values in transmitters and guidelines for the diagnostic procedure. Report on a study of the SSC Subcommittee on Protein C and Protein S. Thromb Haemostas 1992; 68: 470-4
• 12 Poort SR, Pabinger-Fasching I, Mannhalter C, Reitsma PH, Bertina RM. Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency. Blood Coagulation Fibrinolysis 1993; 4: 273-80
• 13 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-8
• 14 Mustafa S, Pabinger I, Mannhalter C. A mutation in the protein S gene results in cryptic splicing and leads to hereditary protein S deficiency. Submitted.
• 15 Broekmans AW, Conard J. Hereditary protein C deficiency. In: Protein C and related proteins Bertina RM. (ed). New York: Churchill Livingstone; 1988: 160-81
• 16 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-6
• 17 Caro JJ, Groome PA, Flegel KM. Atrial fibrillation and anticoagulation: from randomised trials to practice. Lancet 1993; 341: 1381-4