Abstract
Familial Mediterranean fever (FMF) patients in clinical remission are reported to have increased baseline inflammation. Normal function of the natural anticoagulant pathways is particularly needed in diminishing inflammatory responses. In the presence of subclinical inflammation, natural anticoagulant response may be exaggerated. We aimed to observe the anticoagulant–procoagulant status in attack-free FMF patients. Twenty-seven FMF patients diagnosed in accordance with Tel-Hashomer criteria, and 26 healthy controls were included. All patients were attack-free under regular colchicine treatment. Amyloidosis, autoimmunity, accompanying liver and renal disease, and vasculitis were excluded. Predisposing factors for thrombosis were not present. Acute phase reactants (APRs), anticardiolipin antibody positivity, prothrombin time (PT), activated prothrombin time, thrombin time (TT) and d-dimer, protein C activity, activated protein C resistance, free protein S, antithrombin, lupus anticoagulant, human prothrombin fragment F 1 + 2, and human thrombin/antithrombin III complex were analyzed for all subjects. APRs were comparable with controls. Autoimmune markers were negative in all. Anti-streptolysin titers were significantly different than the control group. PT, TT, protein C activity, and F 1 + 2 levels were significantly different from those of healthy controls. Shortened PT and TT, decreased protein C activity vs increased levels of F 1 + 2 suggested a hypercoagulable state in our patients. The hypercoagulable state detected in FMF patients suggests that screening with abnormal coagulation tests may be beneficial for tracing the future consequences of subclinical inflammation in these patients. Studies covering larger groups of patients are needed to verify the currently observed hypercoagulable status in FMF.
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References
The International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807
The French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31
Kastner DL (1998) FMF: the genetics of inflammation. Hosp Prac 33:131–158
Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL (1998) FMF at the millennium: clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine 77:268–297
McDermott MF, Aksentijevich I (2002) The autoinflammatory syndromes. Curr Opin Allergy Clin Immunol 2:511–516
Ozen S (1999) Vasculopathy, Behcet’s syndrome, and familial Mediterranean fever. Curr Opin Rheumatol 11:393–398
Yalcinkaya F, Ince E, Ucar T, Ozkaya N, Tekin M, Elhan AH, Tutar E, Guriz DH, Aysev D, Gokdemir R, Dogru U, Tumer N (2002) Antistreptococcal response is exaggerated in children with familial Mediterranean fever. Clin Rheumatol 21:378–381
Tekin M, Yalcinkaya F, Tumer N, Cakar N, Kocak H (1999) Familial Mediterranean fever and acute rheumatic fever: a pathogenetic relationship? Clin Rheumatol 18:446–449
Bauer KA (2003) Management of thrombophilia. J Thromb Haemost 1:1429–1434
Gathof BS, Picker SM, Rojo J (2004) Epidemiology, etiology and diagnosis of venous thrombosis. Eur J Med Res 9:95–103
Flick MJ, Du X, Witte DP, Jirouskova M, Soloviev DA, Busuttil SJ, Plow EF, Degen JL (2004) Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest113:1596–1606
Esmon CT (2004) Crosstalk between inflammation and thrombosis. Maturitas 47:305–314
Opal SM (2003) Interactions between coagulation and inflammation. Scand J Infect Dis 35:545–554
Esmon CT (2001) Role of coagulation inhibitors in inflammation. Thromb Haemost 86:51–56
Gil W (2001) Inflammo-coagulatory response, extrinsic pathway thrombin generation and a new theory of activated clotting time interpretation. Perfusion 16:27–35
Hooper WC, Phillips DJ, Renshaw MA, Evatt BL, Benson JM (1998) The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. J Immunol 161:2567–2573
Johnson K, Choi Y, DeGroot E, Samuels I, Creasey A, Aarden L (1998) Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 160:5130–5135
Drake WT, Lopes NN, Fenton JW 2nd, Issekutz AC (1992) Thrombin enhancement of interleukin-1 and tumor necrosis factor-alpha induced polymorphonuclear leukocyte migration. Lab Invest 67:617–627
Duzova A, Bakkaloglu A, Besbas N, Topaloglu R, Ozen S, Ozaltin F, Bassoy Y, Yilmaz E (2003) Role of A-SAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin Exp Rheumatol 21:509–514
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879–1885
Ruiz N, Wang B, Pentland A, Caparon M (1998) Streptolysin O and adherence synergistically modulate proinflammatory responses of keratinocytes to group A streptococci. Mol Microbiol 2:337–346
Fukumori T, Ohta H, Okubo A, Hino M, Ohta K, Yamane T, Tatsumi N (2002) New compact-type latex photometric immunoassay system for hemoglobin and three acute inflammation markers: neutrophil count, C-reactive protein, and anti-streptolysin O. J Clin Lab Anal 16:95–102
Stassen M, Muller C, Richter C, Neudorfl C, Hultner L, Bhakdi S, Walev I, Schmitt E (2003) The streptococcal exotoxin streptolysin O activates mast cells to produce tumor necrosis factor alpha by p38 mitogen-activated protein kinase- and protein kinase C-dependent pathways. Infect Immun 71:6171–6177
Courillon-Mallet A, Bevilacqua M, Wautier JL, Dervichian M, Cattan D, Caen J (1986) Increased procoagulant response of monocytes from patients with familial Mediterranean fever. Thromb Haemost 56:211–213
Mosesson MW, Wautier JL, Amrani DL, Dervichian M, Cattan D (1982) Evidence for circulating fibrin in familial Mediterranean fever. J Lab Clin Med 99:559–567
Disdier P, Swiader L, Aillaud MF, Harle JR, Weiller PJ (1996) Familial Mediterranean fever crisis and lupus anticoagulant. Lancet 348:1321–1322
Greaves M, Cohen H, MacHin SJ, Mackie I (2000) Guidelines on the investigation and management of the antiphospholipid syndrome. Br J Haematol 109:704–715
Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM, O’Shea JJ, Rosenberg HF, Malech HL, Kastner DL (2000) The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95:3223–3231
Kearon C, Crowther M, Hirsh J (2000) Management of patients with hereditary hypercoagulable disorders. Annu Rev Med 51:169–185
Akar N, Akar E, Dalgin G, Sozuoz A, Omurlu K, Cin S (1997) Frequency of Factor V (1691 G→A) mutation in Turkish population. Thromb Haemost 78:1527–1528
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Aksu, G., Ozturk, C., Kavakli, K. et al. Hypercoagulability: interaction between inflammation and coagulation in familial Mediterranean fever. Clin Rheumatol 26, 366–370 (2007). https://doi.org/10.1007/s10067-006-0334-y
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DOI: https://doi.org/10.1007/s10067-006-0334-y