Role of tumor-derived tissue factor in cancer-associated thrombosis
Cancer is commonly associated with an increased risk of thrombosis. In fact, thrombosis is often the first symptom of cancer, and may also contribute to morbidity and mortality in cancer patients.
Tissue factor (TF) is the protein that normally initiates blood coagulation in response to an injury. TF has been found in the blood of cancer patients and is thought to be implicated in cancer-associated thrombosis. We have recently shown that TF can circulate in the blood attached to tiny fragments – known as microparticles – that are shed from the surface of the cancer cells.
In a core research effort involving all our scientists, we are aggressively studying the role that TF plays in several types of cancer, including ovarian and breast cancers, pancreatic cancer, high grade malignant brain cancers, melanoma, and certain types of leukemia.
We anticipate that our studies will yield information about the role of TF in cancer growth and spread, and help us better predict the possibility of thrombosis in cancer patients. Ultimately, we hope to point the way towards novel therapies, and improved laboratory detection of cancer-associated hypercoagulability.
Effects of therapeutic monoclonal antibodies on platelet activation
The Center for Thrombosis Research is currently conducting research aimed at better understanding the mechanism by which monoclonal antibodies used in cancer treatment may cause thrombosis in some patients. We have shown that such therapeutic antibodies may assemble into immune complexes in circulating blood, and that these immune complexes can directly activate blood platelets – a potential cause of dangerous thrombosis.
We have also identified several other antibodies that are in preclinical development that may potently activate platelets. We are currently collaborating with the University of Central Florida and several pharmaceutical companies to ensure that these antibodies are "platelet-safe" before they enter human trials. This research promises both short term and long term benefits for patients, and has led to new ways of thinking about ways to improve cancer therapy.
Detection and significance of auto-antibodies against CD40 and CD40-ligand
CD40-CD40-ligand (CD40L) interactions, classically known to be of critical importance in adaptive immunity, may also have roles in platelet function. We have previously shown that a monoclonal antibody to CD40L, which was withdrawn from clinical trials in Lupus patients due to the occurrence of fatal thrombosis, is a potent activator of human platelets. Since patients with autoimmune disorders such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) have a high incidence of thrombosis associated with auto-antibody formation, we hypothesized that such patients may produce antibodies against CD40L.
Scientists at the Center for Thrombosis Research have developed a laboratory assay for CD40L auto-antibodies and are currently assessing the clinical significance of these antibodies in a variety of clinical situations. The development of a marker to identify those APS and SLE patients who are at risk of a thrombotic complication would allow the implementation of preventive treatment, significantly improving their management and clinical outcomes.
Development and application of thrombin generation assays
Thrombin is the terminal enzyme in the coagulation system. The amount of thrombin generated in a blood sample holds the key to whether a patient may bleed or clot abnormally. Thus, the measurement of a patient’s capacity to generate thrombin may be diagnostically useful in a wide variety of clinical situations.
The thrombin generation assay (TGA) is the only global assay that describes the overall capacity of a patient to generate thrombin. Scientists at the Center for Thrombosis Research have further developed and standardized this sophisticated method through extensive work over the last two years. Our method now represents a fully validated, state-of-the-art way to study procoagulant activity in plasma, cancer cells and suspensions of cellular microparticles. We are also working to validate the thrombin generation assay in whole blood samples, and to establish a method for the measurement of microparticles in the blood of cancer patients. This research will contribute to our understanding of cancer-associated hypercoagulability, and could ultimately provide a critical tool for hematologists and oncologists alike, with distinct ramifications for improved patient care.
Heparin-Induced thrombocytopenia (HIT)
HIT continues to be a focus of scientific activity at the Florida Hospital Center for Thrombosis Research. Our interests include the mechanisms of platelet activation by heparin-associated antibodies, laboratory testing for HIT and the effects of heparin-platelet factor 4 antibodies on patient outcome following cardiovascular surgery. Our laboratory also acts as a core facility for pharmaceutical companies involved with clinical trials of anticoagulant therapy in HIT patients.