State-Of-The-Art Thrombosis Prevention and Treatment

FOREWORD

State-of-the-art thrombosis prevention and treatment

antagonists are used for longer periods of primary ‘Pulmonary embolism is a and secondary prophylaxis of thrombosis. leading cause of death in Heparins, especially unfractionated, have draw- cancer patients and the risk for backs, including the need for subcutaneous venous thromboembolism is injections and the risk for heparin-induced thrombocytopenia and osteoporosis on long- significantly increased in patients term use. The heparin derivatives requires bind- with solid tumors and ing to antithrombin in order to exert their anti- hematological malignancies.’ coagulant properties. Vitamin K antagonists have a narrow thera- Benjamin Brenner Thrombosis is the leading cause of death in peutic range that necessitates frequent monitoring Rambam Health Care developed countries, with arterial thrombosis of the prothrombin time. The pharmacogenetics Campus, Department of presenting as myocardial infarction, stroke or of the vitamin K epoxide reductase and CYP219 Hematology and Bone Marrow Transplantation, peripheral arterial occlusion. Venous thrombo- genes may be helpful to better define the dose and Haifa, Israel embolism (VTE) is a major cause of mortality the risk for bleeding on vitamin K antagonists [5]. Tel.: +972 4854 3520 worldwide, despite some variations in prevalence These limitations led to the development of Fax: +972 4854 3886 of the disease [1]. While the incidence of VTE numerous new antithrombotic agents during the E-mail: b_brenner@ rambam.health.gov.il increases with aging, it is the leading cause of past decade, and to an ongoing effort by the vascular morbidity in young adults. industry to develop novel anticoagulants with A multitude of risk factors can contribute to improved efficacy and safety profile and better presentation of VTE [2]. This includes transient tolerability for patients. Information gained risk factors such as trauma, surgery, immobiliza- from gene targeting in mice and animal models tion, long-haul flights, acute medical illness, hor- of thrombosis is useful for a better understand- monal therapy and pregnancy. Long-standing ing of the coagulation system and is detrimental risk factors include chronic conditions such as for the development of new drugs. congestive heart failure, chronic lung disease, The majority of these new anticoagulant inflammatory bowel disease and nephrotic syn- agents are directed either towards factor Xa or drome. The discovery of thrombophilic risk fac- factor IIa (thrombin), although a few agents are tors opened a new era of genetic assessment of directed toward the coagulation initiator tissue the predisposition for VTE with potential ability factor (TF), factor XI or factor XIa. for better definition of the risk associated with While there is an ongoing debate regarding transient risk factors. For example, hormonal which anticoagulant is theoretically better, the therapy in women with thrombophilic risk fac- direct anti-Xa or the direct antithrombin, these tors, such as Factor V Leiden and the pro- agents have not been compared in a clinical trial. thrombin gene polymorphism, multiply the risk The advantage of both classes include oral for VTE [3]. While testing for thrombophilia is administration, direct binding and inhibition of appealing, wider application has been hampered factor Xa or thrombin and no need for monitor- by equivocal cost-effectiveness analysis. A screen- ing. The most advanced agents are rivaroxaban ing test for thrombophilia would be useful, and and apixaban among the anti-Xa agents, and the global assays such as the Protein C Global have direct antithrombin dabigatran [6]. A potential been suggested in this regard [4]. disadvantage of these drugs is the lack of specific In general, VTE is preventable by application of antidote, which may pose a problem in case of prophylactic measures. Applying early mobiliza- bleeding, but in case there is an urgent need for tion and physical measures such as elastic stockings reversal, plasma transfusion can be applied. and external pneumatic compression devices is use- While clinical trials test the efficacy and safety ful. The current pharmacological approach is of new antithrombotics, data on venous throm- part of based on unfractionated, low-molecular-weight bosis in real life can be obtained from inter- heparins (LMWH) and fondaparinux. Vitamin K national multicenter registries, such as the

substantial information gained by the Registro that promotes angiogenesis and metastasis, has Informatizado de Pacientes con Enfermedad been shown to increase TF [10]. Tromboembólica Venosa en España (RIETE) Recent observations suggest that anti- registry [7]. coagulants, especially heparins and LMWHs, may affect survival in cancer patients, potentially ‘The majority of the new anticoagulant via a multitude of effects including anti-inflam- agents are directed either towards matory and anti-angiogenetic mechanisms as factor Xa or factor IIa (thrombin).’ well as their anticoagulant properties [11]. VTE is a major public health issue, as recently Venous thrombosis in the lower extremities declared by the Surgeon General’s Workshop [12] can be asymptomatic, as determined by radio- and therefore, patient and public education are of logical tests such as Doppler sonography and, the utmost importance. Worldwide efforts are particularly, venography, which still serves as the currently applied by a growing number of organi- gold standard in the diagnosis of asymptomatic zations with the aim of significantly decreasing the clots, as even quantitative Doppler sonography burden of venous thrombosis. fails to reveal several distal and, occasionally, even proximal clots. Whether distal clots should ‘Venous thromboembolism is a major be treated is still debatable [8]. The duration of public health issue, as recently declared anticoagulation after first VTE event depends by the Surgeon General’s Workshop, and on the combination of the type and strength of therefore, patient and public education risk factors and the severity of the first event. are of the utmost importance.’ D-dimer levels and the presence of residual thrombosis can contribute to assessment of the It is expected that the concentrated effort in risk for a recurrent event. basic studies and clinical science, together with Pulmonary embolism is a leading cause of patients and public education, will result in death in cancer patients and the risk for VTE is improved care of patients with thrombosis. significantly increased in patients with solid tumors and hematological malignancies. Mecha- Financial & competing interests disclosure nisms for increased thrombosis risk in cancer The author has no relevant affiliations or financial patients include procoagulant activity of tumor involvement with any organization or entity with a finan- cells, acquired activated protein C resistance, cial interest in or financial conflict with the subject matter effect of chemotherapy and immobilization and or materials discussed in the manuscript. This includes presence of indwelling central venous lines [9]. employment, consultancies, honoraria, stock ownership or TF plays a central role in cancer patients. options, expert testimony, grants or patents received or TF-bearing microparticles tend to be increased in pending or royalties. the plasma of patients with solid tumor and hema- No writing assistance was utilized in the production of tological malignancies. Heparanase, a key enzyme this manuscript.

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