Two Cases of Inherited Triple Deficiency in a Large Kindred with Thrombotic Diathesis and Deficiencies of Antithrombin III, Heparin Cofactor II, Protein C and Protein S^[*]

Summary

Thirty-three subjects, belonging to a large family with functional antithrombin III (ATIII) deficiency (type IIa) and recurrent thromboembolism, were investigated for ATIII, heparin cofactor II (HCII), protein C (PC) and protein S (PS). We report the exceptional finding of two cases of triple deficiency: ATIII combined with HCII and PC in the first case aged 15 and ATIII combined with HCII and PS in the second case aged 27. Interestingly, both are asymptomatic thus far. Twenty-five other deficient members were found, among which seven are affected with a double deficiency. Totally, the results of our study show 38 deficiencies of four distinct antithrombotic protein: ATIII (n = 9), HCII (n = 9), PC (n = 7) or PS (n = 13). Two types of HCII deficiency were observed and type I PC deficiency was found. Functional PS deficiency was characterized by reduced levels of cofactor activity for activated PC. Our report demonstrates that combined deficiencies should be sought in a family already known to be deficient in one antithrombotic protein.

• References

• 1 Rodgers GM, Shuman MA. Congenital thrombotic disorders. Am J Haematol 1986; 21: 419-30
• 2 Mannucci PM, Tripodi A. A laboratory screening of inherited thrombotic syndromes. Thromb Haemostas 1987; 57: 247-51
• 3 Conard J, Horellou MH, Samama M. Incidence of thromboembolism in association with congenital disorders in coagulation and fibrinolysis. Acta Chir Scand 1988; 543: 15-25 (suppl)
• 4 George AJ. The laboratory investigation of thrombotic disorders. In: Critical Factors in Haemostasis. Evaluation and Development.. Williams CE, Short PE, George AJ, Entwistle MBP. (eds) Ellis Horwood, Chichester,: 1988. pp 113-226
• 5 Grob JJ, Aillaud MF, Bonerandi JJ. L'enquête étiologique dans les thromboses veineuses récidivantes en 1988. Ann Dermatol Venereol 1988; 115: 753-7
• 6 Ashenhurst JB, Cooksey JA, Chediak J. Thrombotic tendency in combined deficiency of anti-thrombin III and plasminogen. Clin Res 1981; 29: A717 (abstr)
• 7 Bauer KA, Ashenhurst JB, Chediak J, Rosenberg RD. Antithrombin "Chicago": A functionally abnormal molecule with increased heparin affinity causing familial thrombophilia. Blood 1983; 62: 1242-50
• 8 Manabe S, Matsuda M. Homozygous protein C deficiency combined with heterozygous dysplasminogenemia found in a 21-year-old thrombophilic male. Thromb Res 1985; 39: 333-41
• 9 Andersson TR, Larsen ML, Abildgaard U. Low heparin cofactor II associated with abnormal crossed immunoelectrophoresis pattern in two Norwegian families. Thromb Res 1987; 47: 243-8
• 10 Al-Mondhiry H, Galanakis D. Dysfibrinogenemia and lupus anticoagulant in a patient with recurrent thrombosis. J Lab Clin Med 1987; 110: 726-38
• 11 Maurin N, Schunkert H, Sieberth HG. Thrombophilia with a combination of antithrombin III and factor XII deficiency. Thromb Haemostas 1988; 60: 127
• 12 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou MH, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-26
• 13 Gandrille S, Priollet P, Capron L, Roncato M, Fiessinger N, Aiach M. Association of hereditary dysfibrinogenaemia and protein C deficiency in two unrelated families. Br J Haematol 1988; 68: 329-37
• 14 Haire WD, Newland JR. Protein C deficiency and anticardiolipin antibodies in a family with premature stroke. Am J Haematol 1990; 33: 61-3
• 15 Odegard OR, Lie M, Abildgaard U. Heparin cofactor activity measured with an amidolytic method. Thromb Res 1975; 6: 287-94
• 16 Abildgaard U, Larsen ML. Assay of dermatan sulfate cofactor (heparin cofactor II) activity in human plasma. Thromb Res 1985; 35: 257-66
• 17 Nakhleh R, Vogt JM, Edson JR. Heparin cofactor assay. Elimination of heparin and antithrombin III effects. Am J Clin Pathol 1988; 89: 353-8
• 18 Suzuki K, Nishioka J. Plasma protein S activity measured using Protac, a snake venom derived activator of protein C. Thromb Res 1988; 49: 241-51
• 19 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
• 20 Sas G. Classification of antithrombin III deficiencies. Has a new tower of Babel been built? Thromb Haemostas 1988; 60: 530-1
• 21 Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. New Engl J Med 1987; 317: 991-6
• 22 Mannucci PM, Valsecchi C, Krachmalnicoff A, Faioni EM, Tripodi A. Familial dysfunction of protein S. Thromb Haemostas 1989; 62: 763-6
• 23 Bertina RM, van der Linden IK, Engesser L, Muller HP, Brommer EJP. Hereditary heparin cofactor II deficiency and the risk of development of thrombosis. Thromb Haemostas 1987; 57: 196-200