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
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
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
