Exchange Plasmapheresis Is Effective In Removing Procoagulant Microparticles and Has Additional Therapeutic Benefit In The Treatment Of TTP

Abstract

IntroductionIn thrombotic thrombocytopenic purpura (TTP), autoantibodies bind and deplete ADAMTS13, a vWF cleaving protease, leading to accumulation of large molecular weight vWF multimers, excessive platelet adhesion and aggregation in microvasculature, formation of platelet rich thrombi and disruption of microcirculation. This results in microangiopathic hemolytic anemia, severe thrombocytopenia and multi-organ dysfunction. Under higher shear stress, red cells undergo shape changes, fragmentation and release of red cell microparticles (RMP). Similarly, MP are released from activated platelets (PMP) and endothelium (EMP). It is now well established that cell derived MP play an important role in hemostasis and thrombosis. Roles of circulating MP in TTP are not well elucidated. Exchange plasmapheresis and infusion of FFP is now a standard therapy for TTP. It is assumed that plasmapheresis removes autoantibodies against ADAMTS 13 and plasma infusion supplies the deficient protease to resume normal hemostasis. It is possible that plasmapheresis also removes procoagulant MP, contributing to remission. We studied MP profiles in patients with acute TTP and investigated efficacy of exchange plasmapheresis to remove procoagulant MP. MethodsThree patients presenting acute TTP were admitted for exchange plasmapheresis. In addition to routine CBC, platelet counts, reticulocyte counts, blood chemistry, LDH, special assays of MP derived from platelets (PMP), red cells (RMP), leukocytes (LMP) and endothelium (EMP) were performed daily and before and after each exchange plasmapheresis. Samples were drawn immediately before and immediately after plasmapheresis into citrated vacutainer tubes. Microparticles were assayed by flow cytometry using fluorophore conjugated mAb's specific to endothelial, platelet, leukocyte, or erythrocyte lineage. Thromboelastography (TEG) was employed to study thrombus formation in vitroand correlate microparticles and clinical parameters. Results1) Effects of plasmapheresis on MP levels: Circulating RMP and PMP levels fell rapidly following ExPh. Each round of plasmapheresis reduced RMP by 45% (p=0.001) from starting baselines. Repeated plasmapheresis over one week removed 74% of RMP from the peak level (p<0.01). By day 6, RMP were, on average, reduced from 4111/μL to a normal level of 1100/μL. Each round of plasmapheresis also reduced PMP by 53% from baseline (p=0.001). Over one week period, PMP were reduced by 69% from peak levels.2) Effects of plasmapheresis on LDH, HGB, and platelets: LDH was reduced by 30% on average over a week period, from 845 ±211U/L to 545 ±33U/L, but this represented only 45% normalization. Platelet count normalized completely, increasing almost fivefold from an average of 46 ±22 to 219 ±68 after seven days (p<0.05). HGB fell an average of 10% over the course of treatment but this result was not significant.3) Effect of plasmapheresis on TEG parameters: Exchange plasmaphresis tended to prolong the R time (8.4 ±2.2 minutes pre vs. 10.9 ±6.1 minutes post). It also increased K time by 38% and reduced CI by 42%. Although these changes did not reach statistical significance due to high degree of variation in the post-plasmapheresis group, the trend indicated plasmapheresis reduced procoagulance and hypercoagulability. ConclusionExchange plasmapheresis is very effective in reducing procoagulant and proinflammatory RMP and PMP. Clearance of microparticles resulted in improved TEG parameters and reduced hypercoagulability in TTP. Benefits were pronounced even in the first round of plasmapheresis. Exchange plasmaphresis has additional therapeutic benefit in the treatment of TTP by removing procoagulant microparticles and reducing hypercoagulability in TTP. Disclosures:No relevant conflicts of interest to declare.