Thrombogenesis in sickle cell disease

Thirty-three subjects with sickle cell disease (SCD), 11 during episodes of pain and 22 during periods without pain, were evaluated for in vivo thrombogenic activities as compared with 10 normal black control subjects. Measurements were performed for (1) platelet surface activation, assessing flow cytometric expression of activated integrin α_IIbβ₃ receptor (GPIIb/IIIa, CD41a) and P-selectin (CD62p); (2) platelet and erythrocyte surface procoagulant activities, measuring flow cytometric binding of activated factor (FVa) and annexin V; (3) plasma levels of platelet-specific secreted proteins platelet factor 4 (PF4) and β-thromboglobulin (βTG); (4) plasma markers of thrombin generation, prothrombin activation fragment (F_1.2), and thrombin: antithrombin complex (TAT); and (5) plasma markers of fibrinolysis, D-dimer, and plasmin:antiplasmin complex (PAP). As compared with control subjects, asymptomatic subjects with SCD demonstrated significantly increased platelet activation (P < .01 for P-selectin and annexin V binding), elevated plasma levels of PF4 and βTG (P < .01 and P < .03, respectively), and increased plasma concentrations of F_1.2, TAT, PAP, and D-dimer (P < .05 in all cases). During episodes of SCD pain, platelet activation was increased as compared with periods without pain (P < .01 for expression of activated integrin α_IIbβ₃ receptor and P-selectin and binding of FVa and annexin V), erythrocytes expressed procoagulant activities (P < .01 for FVa and annexin V binding), and platelet microparticles appeared in the circulation (3% to 30%; P < .001). SCD pain episodes were associated with elevated plasma levels of F_1.2, TAT, PAP, and D-dimer (P < .05 as compared with asymptomatic intervals). The frequency of pain episodes correlated with enhanced platelet procoagulant activity (r = 0.61, P < .05) and elevated plasma fibrinolytic activity (r = 0.74, P < .01) measured during periods without pain. Plasma fibrinolytic activity was inversely correlated with time to the next pain episode (r = -0.50, P < .05). Thus, asymptomatic subjects with SCD exhibit ongoing platelet activation, thrombin generation, and fibrinolysis that increases during episodes of pain. These changes are predictive of frequency of pain and interval to next pain episode, thereby implicating thrombogenic activity in the development of SCD pain episodes.