Sickle cell disease: relation between procoagulant activity of red blood cells from different phenotypes and in vivo blood coagulation activation

Abstract

Summary.In the present study we examined if, among other mechanisms, the abnormal exposure of phosphatidylserine at the surface of sickle red blood cells (RBCs) contributes to the hypercoagulability which characterizes homozygous sickle cell disease (SCD). The question was addressed by comparison of the procoagulant properties of RBCs from subjects with various phenotypes (SS, SC and AS) that differ in clinical presentation. As previously reported, SS-RBCs accelerated the prothrombin activation by factor Xa, by decreasing the K m of the reaction compared to normal RBCs. SC-RBCs and AS-RBCs also promoted prothrombin activation although their procoagulant properties were milder compared to SS-RBCs. A significant increase of the thrombin-antithrombin complexes was observed in SS subjects. Prothrombin fragment 1þ2 (F1þ2) was elevated in half of the SS subjects, but the difference with controls did not reach significance. Elevated levels of thrombin-antithrombin complexes were observed in a number of SC (4/11) and AS (3/12) subjects, but the difference with controls was not significant. A significant correlation was observed between the plasma levels of thrombin-antithrombin complexes in the subjects with SS, AS and AA phenotypes, and the procoagulant properties of RBCs. Our results strongly suggest that the procoagulant properties which characterize SS-RBCs also affect SC-RBCs and AS-RBCs, and that exposure of phosphatidylserine by RBCs contributes to the hypercoagulable state observed in SCD.

Elevated hypercoagulability markers in hemoglobin SC disease

“…10,11,[13][14][15][16][19][20][21][22] In some of these studies, the authors described differences between Table 2. Tissue factor expression, markers of coagulation, endothelial and inflammation activation in controls, hemoglobin SC and sickle cell anemia patients.…”

“…It is important to emphasize that, since our study was focused specifically on HbSC disease, we included a large cohort of these patients (n=56), whereas only very small numbers were included in the previous studies (<18 cases). 10,11,19,21,22 Since we included a larger number of patients, we were able to evaluate associations of hyperoagulability markers with clinical complications in HbSC patients.…”

“…10,11,[19][20][21][22] Since the focus of these studies was not HbSC disease, only a few compared the HbSC patients with normal controls. 11,19,21,22 When this comparison was made, the results were variable and no conclusions could be drawn. It is important to emphasize that, since our study was focused specifically on HbSC disease, we included a large cohort of these patients (n=56), whereas only very small numbers were included in the previous studies (<18 cases).…”

Protein C and S and inflammation in sickle cell disease

“…sVCAM-1 thus most likely reflects vascular endothelial activation in sickle cell disease. A fundamental difference between the HbSS and HbSC genotypes is the lower concentration of sickle hemoglobin in red cells of HbSC patients with subsequently less in vivo sickling-desickling and red cell membrane changes, less exposure of the endothelium to reactive oxygen species, less circulating rigid irreversibly sickled erythrocytes, and a lower rate of hemolysis [12,[31][32][33]. Such factors can all activate and damage endothelial cells, and the fact that these occur to a greater extent in HbSS patients as compared to HbSC patients may explain the more profound serum sVCAM-1 enhancements in HbSS subjects as compared to HbSC patients (without increased vWF levels in this last group) [34][35][36][37].…”

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“…Previous studies have shown that a hypercoagulable state is present in patients with Hb SS and Hb SC [2,3] and in sickle cell trait [2] and that the changes in coagulation activity in Hb SS and Hb SC disease re¯ect the degree of disease severity of the hemoglobin disorder [3]. To further examine the extent to which increased coagulation activity occurs in individuals with sickle cell trait and to what degree the changes are comparable to the coagulation abnormalities observed in patients with Hb SS and Hb SC disease, we have made coagulation measurements in individuals with the trait and have compared results to controls, matched for age, gender, and race, and to previously described groups of patients with Hb SS and Hb SC disease [3].…”