Consortium Linking Oncology with Thrombosis (CLOT)

The purpose of the CLOT Program UO1 grant is: 1) encourage studies in selected cancer types that expand mechanistic investigation into the intersection between cancer and thrombotic pathways; and 2) apply mechanistic insights towards the identification and development of biomarkers of thrombotic risk or cancer progression and new strategies for preventing or treating the deleterious interplay between cancer, cancer therapy, and hemostasis/thrombosis.

Background and Objectives

Venous thromboembolism (VTE) is a common complication of malignant disease, representing a major cause of morbidity and mortality in cancer patients. The association between cancer and thrombosis is well established. However, despite the accumulation of a considerable volume of epidemiologic data since the first observation made as early as the 1820’s by Boulliard and further developed by Trousseau in the 1860’s, the pathophysiology remains poorly understood. Rates of pulmonary embolism (PE) and deep vein thrombosis (DVT) are increased four- to seven- fold in cancer patients compared with those without cancer. Patients undergoing surgery for cancer have a three times higher risk of postoperative DVT than those having surgery for nonmalignant diseases. Furthermore, the risk of VTE recurrence after a first episode of VTE is higher in cancer patients than in those without underlying malignancy. Finally, individuals presenting with an unprovoked episode of VTE are more likely to have an underlying cancer than those with a VTE associated with an identifiable risk factor for thrombosis. More than 10% of persons presenting with unprovoked VTE are subsequently diagnosed with cancer over 5 to 10 years, and the diagnosis is established within the first year of presentation of DVT in >75% of cases.

Cancer patients who experience VTE fare worse with respect to major bleeding and death, compared with those who do not have VTE, and VTE is a leading cause of death among patients undergoing chemotherapy. Beyond chemotherapies, other cancer treatments such as antiangiogenics, hormonal therapies, and radiotherapy can elevate thrombotic risk.

The relationship between cancers and thrombosis are bidirectional: cancer-associated factors contribute to thrombosis and components of the hemostatic/thrombotic pathways influence the development and progression of cancer.

Advances in thrombosis and hemostasis research have not been rapidly adapted as treatment and prophylaxis modalities to this population. In addition, recent research has identified new common factors that play significant roles in the progression of both thrombosis and cancer, such as neutrophil extracellular traps (NETs), platelet microparticles, cell-free DNA, factor XII activation and histones. Rates of VTE are known to vary widely between different groups of cancer patients. Multiple factors, including clinical characteristics (e.g., site of cancer, tumor type, clinical stage, therapy) and individual patient characteristics (e.g., sex, race, age, previous VTE history, immobilization, and obesity) contribute to the risk of VTE in cancer patients.

Translational studies that further expand these mechanistic investigations may substantially advance our understanding and approach to treatment and prevention of cancer related thrombosis.


Research Activities Supported By NIH/NHLBI

The proposed program will focus on translation of the research advances in thrombosis into novel therapeutic modalities, as well as into further identification and development of novel biomarkers and risk assessment models to stratify cancer patients by thrombotic risk in selected oncological diseases, and patient populations that might benefit from thromboprophylaxis.

A cooperative agreement multi-PI approach (U01) with hematologists and oncologists working together will provide complementary multidisciplinary expertise to cover the multifaceted problems of these patient populations. This approach, coupled with a collaborative consortium structure and access to samples and phenotypic data from existing biorepositories and ongoing clinical studies, will create unique opportunities for investigators to conduct much needed translational research through a strong emphasis on team science.