Clonal mutations and Coagulopathy

About This Grant

PROJECT SUMMARY/ ABSTRACT Coagulopathy manifesting as disseminated intravascular coagulation (DIC) with associated bleeding and venous thromboembolism (VTE) is a common complication in patients with acute myeloid leukemia (AML), occurring in 10-20% patients at diagnosis and within the first 30 days of treatment. With improvements in supportive care, the overall survival of AML patients has improved, but early mortality from DIC remains a major challenge. While DIC is extensively studied in acute promyelocytic leukemia (APL), which is a small and distinct subgroup of AML, mechanisms of DIC and subsequent bleeding and VTE risk are not clearly understood in non-APL AML (referred to as AML from here on). Majority of the studies examining DIC in AML have focused on the tissue factor pathway and there is limited understanding of the role of endothelial dysfunction and the contact pathway of coagulation in coagulopathy of AML. Examining novel biomarkers in these pathways may explain the mechanisms of bleeding, and high VTE risk due to central venous catheters in AML patients. Clonal hematopoiesis (CH) refers to the acquisition of somatic mutations in driver genes in the hematopoietic stem cells that lead to increased risk of leukemia, cardiovascular disease including venous thromboembolism (VTE) and hemorrhagic stroke in the general population. A select group of mutations known as “adverse risk clonal mutations” (ACMs) in TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 genes are associated with poor prognosis in AML. DIC is often observed in patients with high-risk AML, which is characterized by high white count, lactate dehydrogenase and blast%; these features are also seen in individuals who harbor FLT3-ITD mutation and other ACMs. The overall objectives of this proposal are to harness the resources from the University of Alabama at Birmingham (UAB) AML cohort (PI: Dr. Gangaraju) of 761 patients that have next generation sequencing data for clonal mutations to: (1) Examine the association between ACMs and DIC at AML diagnosis, and between ACMs and 30-day bleeding and VTE risk, and (2) Identify novel biomarkers of endothelial dysfunction and contact pathway of coagulation associated with ACMs at AML diagnosis and with 30-day bleeding and VTE risk in AML. This cohort has rich phenotypic data on demographics, comorbidities, labs at AML diagnosis and validated outcomes of interest including bleeding and VTE. A sub- group of patients provided plasma samples for biomarker studies, and the study team has expertise in measurement of the biomarkers proposed in this application. Investigating the mechanistic pathways of DIC, VTE and bleeding risk in AML aligns with NHLBI’s mission to understand the mechanisms of these complications in cancer. This will be the first step towards achieving my long-term goal of identifying AML patients at increased risk of bleeding and VTE, and examining strategies to provide safer and efficacious anticoagulation in these complex patients.