By Lynn Malec, MD, MSc, and Janice Staber, MD
When one hematologic disorder begets another, unlocking the mystery of the mechanisms of disease is the first crucial step in identifying potential targets for future therapeutic modulation. It is known that hemolytic disorders are associated with increased risk of thrombosis; exactly how red cell turnover contributes to ab- normal clotting, however, is not fully understood. Chaired by Ingrid Pabinger, MD, of Medical University of Vienna, and Jeffrey Zwicker, MD, of Beth Israel Deaconess Medical Center, the Saturday and Sunday Scientific Program sessions, Hemolytic Disorders and Thrombosis: Mechanisms and Clinical Insights, highlighted emerging data regarding mechanisms of hypercoagulability in hemolytic anemia.
To begin the session, Sruti Shiva, PhD, of University of Pittsburgh, discussed the established clinical association between hemolysis and cell-free hemoglobin with platelet activation while acknowledging that the underlying mechanisms are not fully elucidated. It is known that mitochondria contribute to platelet homeostasis predominantly through ATP production and energy maintenance. Dr. Shiva explained, however, that platelet mitochondria also signal through the production of reactive oxygen species (ROS), which is closely linked to their energetic function. She discussed the mitochondrial function in models of hemolytic anemia including sickle cell disease (SCD). Using samples from individuals with SCD, her team demonstrated that mitochondrial oxidant production is the mechanistic link between hemolysis and platelet activation. She further illustrated that hemolysis-induced platelet mitochondrial dysfunction is likely relevant in hemolytic disorders beyond SCD. Understanding this pathway highlights the platelet mitochondrion as an “important signaling hub” linking hemolysis to potentially pathogenic platelet activation. Through in vitro data, Dr. Shiva emphasized that harnessing the mitochondrion as a potential therapeutic target could attenuate hemolysis-dependent platelet activation.
Wolfram Ruf, MD, of The Scripps Research Institute, has a longstanding research focus on the tissue factor (TF) –initiated coagulation pathway related to its critical role in cell signaling that drives inflammation, metastasis, and angiogenesis. During his session, he focused on mechanistic insights linking the complement cascade and thrombosis and high- lighted the contributions of complement to pathogenic TF signaling that is associated with thrombosis. Using an inferior vena cava flow restriction model, he demonstrated both the crucial role of complement component C3 in platelet activation and the requirement of complement for fibrin formation and thrombus generation. Additionally, Dr. Ruf discussed the role of complement activation and its contribution to antiphospholipid antibody syndrome. Specifically, the antiphospholipid antibodies directly interfere with TF regulatory mechanisms.
The final lecture in the session, ADAMTS13, an Anti-thrombotic Protein: Evidence Outside of Thrombotic Thrombocytopenic Purpura, was led by Simon De Meyer, PhD, of the University of Leuven in Belgium. Dr. De Meyer’s lab focuses on better under- standing the von Willebrand factor (vWF)/ADAMTS13/platelet access in hemostatic, thrombotic, and inflammatory processes. He began the ses- sion with a discussion of the role of vWF in normal hemostasis, including a review of the hemostatic activity of vWF being dependent on its multimer length. The role of vWF cleaving enzyme ADAMTS13 was next discussed in relation to its association with disease and the role of diminished ADAMTS13 activity leading to thrombotic thrombocytopenic purpura. Dr. De Meyer concluded the session with a discussion of the lesser known roles of ADAMTS13s anti-thrombotic and possibly thrombolytic effect in vari- ous other thrombotic diseases such as stroke and myocardial infarction.
This program illustrated what is currently known and highlighted areas for future discovery surrounding the link of red cell turnover to thrombosis.
Dr. Malec and Dr. Staber indicated no relevant conflicts of interest.