In situ localization of tissue factor in human thrombi

Abstract

Drach and colleagues report that thalidomide in combination with a variety of cytotoxic drugs is associated with the increased risk of deep-vein thrombosis (DVT) in malignant disorders. The development of thrombosis in cancer patients is multifactorial, and the role of these different factors in the thromboembolic events of patients treated with thalidomide is difficult to dissect. The incidence of DVT in myeloma patients treated with multiagent chemotherapy without thalidomide is approximately 10%. 1 When thalidomide was introduced as a single agent for refractory myeloma, no significant increase in thromboembolic events was noted. 2 Because of its minimal myelosuppressive effect and its activity in chemotherapy-refractory myeloma, the drug was combined with chemotherapy; in that setting an increased incidence of DVT was observed which could not be explained by other known prothrombogenic factors. 3 The highest incidence was observed when thalidomide was given with vincristine, adriamycin, dexamethasone (VAD) or other regimens containing anthracyclines. 2,4 We have treated more than 70 patients with multiple cycles of cytoxan, dexamethansone, etoposide, platinum (CDEP) plus thalidomide, and the observed incidence of DVT has been below 15%. Many factors can contribute to the development of thromboembolism in cancer patients, including age, performance status, presence of a central-vein catheter, history of previous DVT, recent surgery, hereditary hypercoagulable states, and as recently reported by our group, non-Factor V Leiden activated protein C resistance. 5 All of these factors need to be taken into consideration before reaching any conclusion. Drach and colleagues report frequent thromboembolic episodes in mantle cell lymphoma patients treated with cyclophosphamide, vincristine, and prednisone (CHOP), thalidomide, and rituximab. Rituximab as a single agent has also been associated with DVT in non-Hodgkin lymphoma patients. 6 Therefore, the contribution of thalidomide to the development of DVT is not clear. Moreover, this regimen is a combination of thalidomide with an anthracycline and a corticosteroid. These findings therefore do not support the conclusions reached by Drach and colleagues that thalidomide is the main offender in the development of DVT in malignancies.

Increased Vascular Wall Thrombogenicity Combined With Reduced Blood Flow Promotes Occlusive Thrombus Formation in Rabbit Femoral Artery

“…Himber et al 33 have revealed that active TF is localized in human thrombi, where it was associated with platelets, fibrin, monocytes, and polymorphonuclear leukocytes. Our results support this observation.…”

The role of leukocytes in thrombosis

“…Studies evaluating the composition of venous thrombi from humans demonstrated the presence of TF-expressing leukocytes and NETs. 89,90 These processes increase the localized concentration of leukocyte-derived procoagulant activity and potentially forms the nidus upon which the thrombus develops.…”

Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall

“…7,8 Although the cellular origin of circulating TF remains elusive, substantial evidence from in vitro studies favors leukocytes, or microparticles derived from leukocytes, as the major source. 7,14,15 Nevertheless, existing data have shown primarily an association of circulating TF with leukocytes, without a clear demonstration of its functional significance. Our data do not support the hypothesis that leukocyte-derived TF is a key determinant of the thrombotic response to macrovascular injury because a selective and marked reduction in the BM-derived pool of TF had no apparent effect on arterial or venous thrombus formation in mice with normal vessel wall TF expression.…”

“…12,13 Leukocyte-associated TF is present in clots formed in vitro and in human thrombi in situ. 7,14 Furthermore, TF can be transferred from leukocytes to platelets in vitro via an interaction involving CD15-expressing membrane microparticles and P-selectin. 15 Thus, based on in vitro studies, coupled with the observation of increased levels of circulating TF ϩ leukocyte-derived microparticles in various thrombotic diseases, 16-19 a growing body of evidence favors a role for leukocyte-derived TF in thrombosis.…”