Natural inhibitors of coagulation and markers of coagulation activation: the hypercoagulable state in sickle cell disease

ABSTRACT

This study was designed to clarify abnormalities of the natural coagulation inhibitors and of the markers of thrombin generation in patients with homozygous sickle cell disease [HbSS] in the steady-state, and to evaluate their role in the contribution of the increased thrombotic risk in these patients that could result in new therapeutic interventions. This study was carried out on 50 subjects. They were divided into two groups. Group [A] included 30 patients with homozygous sickle cell disease [HbSS]. Group [B] included 20 apparently healthy age- and sex-matched control subjects; with normal baseline hematologic parameters and haemoglobin electrophoresis as well as no apparent increased thrombotic risk. All patients were tested during steady-state phase with no symptoms or signs of crises or infection for at least 8 weeks and had not had any blood transfusion during the preceding two weeks. They were not on medications other than folic acid 5mg tablets. HbSS was diagnosed by family studies and haemoglobin electrophoresis on cellulose-acetate at pH 8.6. Both patients and control groups were subjected to initial laboratory investigations including complete blood count [CBC], bleeding time [BT], prothrombin time [PT] and INR, activated partial thromboplastin time [aPTT] and haemoglobin electrophoresis. Then, both groups were tested for [1] Natural coagulation inhibitors including Protein C [antigen and activity], Protein S [total and free levels], Antithrombin-III activity, Heparin cofactor II level, and Tissue factor pathway inhibitor [TFPI] and [2] Markers of coagulation activation; Prothrombin fragments 12 [Fl.2] and Thrombin-antithrombin complex [TAT]. HbSS patients had significantly higher leukocytic count [x 10 [3]/cmm] than control subjects [10.4 +/- 2.8 compared to 6.2 +/- 2.4, p < 0.01]. There was no significant difference between both groups regarding platelet count, bleeding time, prothrombin time [and INR] and activated partial prothrombin time. HbSS patients had significantly lower values than the control group regarding the level of protein C antigen, protein C activity, protein S total and protein S free as well as heparin cofactor TI [p < 0.001, each]. Although FIbSS had lower antithrombin-III activity and tissue factor pathway inhibitor than the control group, the difference was not significant. On the other hand, markers of coagulation activation [namely prothrombin fragments 1.2 and thrombin-antithrombin complex] were significantly higher in HbSS patients compared to the control group [p < 0.001, each]. Comparative studies showed no significant correlation between the level of haemoglobin SS and any of the studied coagulation inhibitors or markers of activation. These data shows that steady state SCD is associated with significant reduced level and/or function of the majority of naturally occurring anticoagulants as well as increased markers of thrombin generation denoting a state of chronic hypercoagulability with increased thrombotic and vasoocclusive tendency. Such changes might justify the prophylactic use of low dose coumadin and/or antiplatelet drugs in HbSS