Serdal UĞURLU, Erhan ATAHAN, Cihat ŞARKIŞ, Erkan ÇAĞLAR

Venöz tromboemboli ve kalıtsal trombofili

Kalıtsal trombofili venöz tromboembolizme genetik yatkınlıktır. Genel toplumda koagülasyon anormallikleri yaygındır ve bazı bireylerde herhangi bir risk faktörü olmadan spontan olarak da görülebilmektedir. Ailede tromboz öyküsü olanlarda, mutasyon bulunma olasılığı yüksektir. Tromboz için en sık görülen kalıtsal risk faktörleri olan faktör V Leiden ve protrombin G20210A gen mutasyonu venöz tromboembolim açısından yüksek risk taşırlar. Bu trombofili nedenleri, tekrarlayan venöz tromboemboli ataklarını artırmaktadır. Geriye kalan olguların çoğunda trombofili nedeni; protein C, protein S ve antitrombin-III eksikliğidir. Kalıtsal trombofiliden şüphe edilmesi gereken klinik tablolar; idiyopatik tromboz, genç yaşta geçirilen tromboz, tekrarlayan trombotik olaylar ve nadir olarak etkilenen damarlarda tromboembolik olayların ortaya çıkması şeklinde sıralanabilir. Kalıtsal trombofilinin çeşitli nedenlerinin varlığını test etmek açısından güvenilir testler bulunmaktadır.

Venous thromboembolism and inherited thrombophilia

Inherited thrombophilia is a genetic tendency to venous thromboembolism. Coagulation abnormalities are common in the general population and therefore will present spontaneously in some individuals. Patients with a family history of thrombosis are at an increased risk for a mutation. Factor V Leiden and the prothrombin, G20210A mutation the commonest inherited risk factors for thrombosis, are associated with an increased risk of venous thromboembolism. These causes of thrombophilia increase the risk of venous thromboembolism recurrence. Deficiencies in protein C, protein S, and antithrombin-III account for most of the remaining cases of thrombophilia. Inherited thrombophilia should be suspected in patients with one or more of the following clinical features: idiopathic thrombosis, thrombosis at a young age, recurrent thrombosis, and thrombosis at an unusual site. Reliable assays are now available to test for the presence of the various causes of inherited thrombophilia.

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1) Perry DJ. Antithrombin and its inherited deficiencies. Blood Rev 1994;8:37-55.
2) Bayston T, Lane D. Antithrombin mutation database. Available from: http://www1.imperial.ac.uk/medicine/about/ divisions/is/haemo/coag/antithrombin/ Access date; June 5, 2007.
3) Meade TW, Dyer S, Howarth DJ, Imeson JD, Stirling Y. Antithrombin III and procoagulant activity: sex differences and effects of the menopause. Br J Haematol 1990; 74:77-81.
4) Tait RC, Walker ID, Perry DJ, Carrell RW, Islam SIA, McCall F, et al. Prevalence of antithrombin III deficiency subtypes in 4000 healthy blood donors. Thromb Haemost 1992;65:839.
5) Tait RC, Walker ID, Perry DJ, Islam SI, Daly ME, McCall F, et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994;87:106-12.
6) Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases. Thromb Haemost 1987; 58:1094.
7) Thaler, E, Lechner, K. Antithrombin III deficiency and thromboembolism. In: Prentice CRM, editor. Clinics in haematology. Vol. 10, London: W. B. Saunders; 1981. p. 369-90.
8) Walker ID. Congenital thrombophilia. Baillieres Clin Obstet Gynaecol 1997;11:431-45.
9) Bick RL, Kaplan H. Syndromes of thrombosis and hypercoagulability. Congenital and acquired causes of thrombosis. Med Clin North Am 1998;82:409-58.
10) Hultin MB. Antithrombin III Assays. In: Beutler E, Lichtman MA, Coller BS, Kipps TS, editors. Williams hematology. 5th ed. New York: McGraw Hill Inc; 1995. p. 101-9.
11) Damus PS, Wallace GA. Immunologic measurement of antithrombin III-heparin cofactor and alpha2 macroglobulin in disseminated intravascular coagulation and hepatic failure coagulopathy. Thromb Res 1975;6:27-38.
12) Mammen EF. Antithrombin: its physiological importance and role in DIC. Semin Thromb Hemost 1998;24:19-25.
13) Panicucci F, Sagripanti A, Conte B, Pinori E, Vispi M, Lecchini L. Antithrombin III, heparin cofactor and antifactor Xa in relation to age, sex and pathological condition. Haemostasis 1980;9:297-302.
14) Weenink GH, Kahlé LH, Lamping RJ, ten Cate JW, Treffers PE. Antithrombin III in oral contraceptive users and during normotensive pregnancy. Acta Obstet Gynecol Scand 1984; 63:57-61.
15) Weenink GH, Treffers PE, Vijn P, Smorenberg-Schoorl ME, Ten Cate JW. Antithrombin III levels in preeclampsia correlate with maternal and fetal morbidity. Am J Obstet Gynecol 1984;148:1092-7.
16) Raya-Sánchez JM, González-Reimers E, Rodríguez-Martín JM, Santolaria Fernández F, Molina-Pérez M, Rodríguez- Moreno F, et al. Coagulation inhibitors in alcoholic liver cirrhosis. Alcohol 1998;15:19-23.
17) Segal H, Cottam S, Potter D, Hunt BJ. Coagulation and fibrinolysis in primary biliary cirrhosis compared with other liver disease and during orthotopic liver transplantation. Hepatology 1997;25:683-8.
18) Pirisi M, Fabris C, Ceriello A, Soardo G, Giacomello R, Toniutto P, et al. Deficient antithrombin III activity and enhanced fibrinolysis in patients with liver disease: evidence against a cause-effect relationship. Acta Gastroenterol Belg 1995;58:230-7.
19) Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166:729-36.
20) Vink R, Kraaijenhagen RA, Levi M, Büller HR. Individualized duration of oral anticoagulant therapy for deep vein thrombosis based on a decision model. J Thromb Haemost 2003; 1:2523-30.
21) Marchetti M, Pistorio A, Barosi G. Extended anticoagulation for prevention of recurrent venous thromboembolism in carriers of factor V Leiden-cost-effectiveness analysis. Thromb Haemost 2000;84:752-7.
22) Emmerich J, Rosendaal FR, Cattaneo M, Margaglione M, De Stefano V, Cumming T, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost 2001;86:809-16.
23) Lalouschek W, Schillinger M, Hsieh K, Endler G, Tentschert S, Lang W, et al. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke 2005;36:1405-9.
24) Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT Jr, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817-21.
25) Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;100:3-10.
26) Lindahl TL, Lundahl TH, Nilsson L, Andersson CA. APCresistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee-a prospective study. Thromb Haemost 1999;81:18-21.
27) De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996;87:3531-44.
28) Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, et al. Inherited thrombophilia: Part 2. Thromb Haemost 1996;76:824-34.
29) Simioni P, Prandoni P, Lensing AW, Manfrin D, Tormene D, Gavasso S, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000;96:3329-33.
30) Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost 1999;81:684-9.
31) Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999;353:1167-73.
32) Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3�-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-703.
33) Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042-50.
34) D�Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997;90:1-11.
35) Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987;317:991-6.
36) Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995;73:87-93.
37) Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism-results of the Spanish Multicentric Study on Thrombophilia (EMETStudy). Thromb Haemost 1997;77:444-51.
38) Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988;59:18-22.
39) Heijboer H, Brandjes DP, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990;323:1512-6.
40) Broekmans AW, Bertina RM. Protein C. In: Poller L, editor. Recent advances in blood coagulation. Vol. 4 New York: Churchill Livingstone; 1985,. p. 117-30.
41) Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913-6.
42) Makris M, Rosendaal FR, Preston FE. Familial thrombophilia: genetic risk factors and management. J Intern Med Suppl 1997;740:9-15.
43) Comp PC. Protein C and protein S. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams hematology. 5th ed. New York: McGraw Hill; 1995. p. 99-105.
44) Bauer KA. The hypercoagulable state. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams hematology. 5th ed. New York: McGraw-Hill; 1995. p. 1531-50.
45. Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, et al. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997;350:1590-3.
46) Fourrier F, Lestavel P, Chopin C, Marey A, Goudemand J, Rime A, et al. Meningococcemia and purpura fulminans in adults: acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates. Intensive Care Med 1990;16:121-4.
47) Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 1993;91:418-22.
48) Allaart CF, Aronson DC, Ruys T, Rosendaal FR, van Bockel JH, Bertina RM, et al. Hereditary protein S deficiency in young adults with arterial occlusive disease. Thromb Haemost 1990;64:206-10.
49) Douay X, Lucas C, Caron C, Goudemand J, Leys D. Antithrombin, protein C and protein S levels in 127 consecutive young adults with ischemic stroke. Acta Neurol Scand 1998;98:124-7.
50) Munts AG, van Genderen PJ, Dippel DW, van Kooten F, Koudstaal PJ. Coagulation disorders in young adults with acute cerebral ischaemia. J Neurol 1998;245:21-5.
51) Heeb MJ, Mosher D, Griffin JH. Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation. Blood 1989;73:455-61.
52) D�Angelo A, Vigano-D�Angelo S, Esmon CT, Comp PC. Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation. J Clin Invest 1988;81:1445-54.
53) Stahl CP, Wideman CS, Spira TJ, Haff EC, Hixon GJ, Evatt BL. Protein S deficiency in men with long-term human immunodeficiency virus infection. Blood 1993;81:1801-7.
54) Vigano-D�Angelo S, D�Angelo A, Kaufman CE Jr, Sholer C, Esmon CT, Comp PC. Protein S deficiency occurs in the nephrotic syndrome. Ann Intern Med 1987;107:42-7.
55) Gouault-Heilmann M, Gadelha-Parente T, Levent M, Intrator L, Rostoker G, Lagrue G. Total and free protein S in nephrotic syndrome. Thromb Res 1988;49:37-42.
56) Pui CH, Chesney CM, Bergum PW, Jackson CW, Rapaport SI. Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia. Br J Haematol 1986;64:283-90.
57) D�Angelo A, Della Valle P, Crippa L, Pattarini E, Grimaldi LM, Viganò D�Angelo S. Brief report: autoimmune protein S deficiency in a boy with severe thromboembolic disease. N Engl J Med 1993;328:1753-7.
58) Bernardi F, Legnani C, Micheletti F, Lunghi B, Ferraresi P, Palareti G, et al. A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects. Thromb Haemost 1996;76:505-9.
59) Tait RC, Walker ID, Conkie JA, Islam SI, McCall F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis. Thromb Haemost 1996;76:1004-8.
60) Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol 1997;4:357-65.
61) Schorer AE, Singh J, Basara ML. Dysfibrinogenemia: a case with thrombosis (fibrinogen Richfield) and an overview of the clinical and laboratory spectrum. Am J Hematol 1995; 50:200-8.
62) Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983;62:248-55.
63) Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345:152-5.
64) O�Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77:825-8.
65) Kraaijenhagen RA, in�t Anker PS, Koopman MM, Reitsma PH, Prins MH, van den Ende A, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000;83:5-9.
66) Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Tracy RP, Aleksic N, et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002;113:636-42.
67) Bombeli T, de Conno E, Jutzi M, Fehr J. In patients symptomatic for deep-vein thrombosis factor VIII elevation is found twice as frequent as in patients symptomatic for pulmonary embolism. Thromb Haemost 2003;89: 198-200.
68) Bloemenkamp KW, Helmerhorst FM, Rosendaal FR, Vandenbroucke JP. Venous thrombosis, oral contraceptives and high factor VIII levels. Thromb Haemost 1999; 82:1024-7.
69) Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457-62.
70) Cristina L, Benilde C, Michela C, Mirella F, Giuliana G, Gualtiero P. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 2004;124:504-10.
71) OSullivan GJ, Semba CP, Bittner CA, Kee ST, Razavi MK, Sze DY, et al. Endovascular management of iliac vein compression (May-Thurner) syndrome. J Vasc Interv Radiol 2000;11:823-36.
72) Patel NH, Stookey KR, Ketcham DB, Cragg AH. Endovascular management of acute extensive iliofemoral deep venous thrombosis caused by May-Thurner syndrome. J Vasc Interv Radiol 2000;11:1297-302.
73) Sharaf M. Recurrent left-leg venous thrombosis in a woman despite a therapeutic international normalized ratio. CMAJ 2005;173:1032.
74) Lamont JP, Pearl GJ, Patetsios P, Warner MT, Gable DR, Garrett W, et al. Prospective evaluation of endoluminal venous stents in the treatment of the May-Thurner syndrome. Ann Vasc Surg 2002;16:61-4.
75) Chee YL, Culligan DJ, Watson HG. Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young. Br J Haematol 2001;114:878-80.
76) Ruggeri M, Tosetto A, Castaman G, Rodeghiero F. Congenital absence of the inferior vena cava: a rare risk factor for idiopathic deep-vein thrombosis. Lancet 2001;357:441.
77) Hamoud S, Nitecky S, Engel A, Goldsher D, Hayek T. Hypoplasia of the inferior vena cava with azygous continuation presenting as recurrent leg deep vein thrombosis. Am J Med Sci 2000;319:414-6.
78) Motwani J, Rose PE, Shatwell W. An unusual case of venous thromboembolism. Br J Haematol 2005;128:1.