NDT Advance Access originally published online on May 17, 2005
Nephrology Dialysis Transplantation 2005 20(7):1515-1516; doi:10.1093/ndt/gfh886
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High clotting factor activities and enhanced platelet-related haemostasis in a patient with recurrent episodes of thrombotic–thrombocytopenic purpura: additional risk factors for onset and recurrence?
Sir,Thrombotic–thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by microvascular thrombi, mainly in arterioles and capillaries, low platelet count, haemolysis and neurological deficits [1]. Impaired activity of the von Willebrand factor (vWF) cleaving protease ADAMTS 13, leading to the accumulation of ultralarge vWF multimers, was found to play a major role in the pathogenesis of TTP [2]. Consequently, plasma exchange became the therapy of choice supplying ADAMTS 13 and/or removing anti-ADAMTS 13 autoantibodies and unusually large vWF multimers [3]. Remarkably, in a recent analysis of 142 patients suffering from TTP, only 13% had a severe ADAMTS 13 deficiency, defined as <1% activity [4]. Thus, a low activity of ADAMTS 13 does not identify all patients affected [5]. In addition, the protease activity was found to correlate weakly with the severity and recurrence of TTP [2]. These observations suggest the involvement of additional factors contributing to the pathogenesis of this thrombotic disorder, probably including risk factors for venous and arterial thrombosis.
Here, we report on a 35-year-old woman who was first diagnosed with TTP at the age of 25 years. The diagnosis was based on neurological symptoms in association with low platelet count, haemolysis and persistently reduced ADAMTS 13 activity. After the first episode, she suffered from at least six recurrences, all characterized by neurological symptoms and thrombocytopenia. The actual assessment of haemostasis was performed >2 years after the most recent plasma exchange therapy at complete clinical remission. ADAMTS 13 activity was severely reduced (residual activity <2.5%) due to the presence of antibodies. Evaluation of plasmic haemostasis showed a massively shortened partial thromboplastin time of 19 s (reference range 29–33) and a shortened prothrombin time (INR 0.7). These results were explained by markedly elevated activities of coagulation factors II [177%, reference range (SD) 114±22], V (246%, reference range 108±25), VIII:C (260%, reference range 127±28), X (170%, reference range 118±23) and XI (167%, reference range 95±20). All these coagulation factor activities were above the 95th percentile determined from 120 women below 45 years of age. Thrombin–antithrombin complexes (11.1 µg/l, reference values <4.1 µg/l), prothrombin fragments F1 + F2 (1.13 nmol/l, reference values <1 mmol/l) and fibrin monomers (1.8 mg/dl, reference values <1.45 mg/dl) were elevated, indicating activation of haemostasis. In addition, platelet-related haemostasis was enhanced revealed by remarkably shortened closure times below the 1% percentile with epinephrine/collagen (77 s) and ADP/collagen cartridges (52 s) determined with a platelet function analyser (100). Platelet receptor polymorphisms associated with increased thrombogenicity, particularly the HPA-1b/1b phenotype and the GP Ia 807 TT phenotype, were not found. The patient was negative for the prothrombotic G1691A mutation of the factor V gene (factor V Leiden), the G20210A mutation of the prothrombin gene and the MTHFR 677TT genotype. Two months after these examinations were performed, the patient developed the next episode of TTP and was effectively treated with plasma separation and immunosuppression.
Elevated activities of coagulation factors II, V, VIII:C, X and XI have been identified as risk factors for venous [6] and arterial thrombosis [7]. In addition, elevated activities of coagulation factors VIII:C and increased d-dimer levels have been found to be associated with recurrent events in patients with a history of previous venous thrombosis [8,9]. The relevance of enhanced platelet-related haemostasis, e.g. reflected by shortened closure times determined with a platelet function analyser as risk factor for thrombotic events is less well established. Our findings suggest a potential pathogenetic role for enhanced plasmic and platelet-related haemostasis in the pathogenesis of TTP and illustrate that factors other than ADAMTS 13 deficiency might be involved in the pathogenesis of this thrombotic disorder. Although it remains unclear whether the haemostatic abnormalities observed in our patient are a cause or rather a consequence of this thrombotic disorder, these factors modulate the thrombogenicity and, thus, might predispose not only to the development, but also to the recurrence of TTP. We speculate that reduction of clotting factor activities by oral anticoagulants and inhibition of platelet function might reduce the risk for further episodes of TTP in selected patients. The identification and evaluation of abnormalities of haemostatic components as additional risk factors for TTP should be assessed in further studies.
Conflict of interest statement. None declared.
1 Department of Hemostasis and Transfusion Medicine2 Department of Nephrology Heinrich Heine University Medical Center Duesseldorf Germany Email: sucker{at}med.uni-duesseldorf.de
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[Abstract/Free Full Text]
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