A worldwide survey to assess the current approach to the treatment of patients with cancer and venous thromboembolism.

Low-molecular-weight heparin (LWMH) is recommended as the preferred anticoagulant treatment over vitamin K antagonists (VKA) for venous thromboembolism (VTE) in patients with cancer. However, there is uncertainty about the duration and dose of LMWH treatment. Therefore, we designed this multinational survey to assess the current approach to the treatment of patients with cancer and VTE. An electronic survey tool was used to disseminate a survey containing 49 questions on different aspects of the treatment of patients with cancer and VTE, among both thrombosis and non-thrombosis specialists. A total of 229 invitations were sent, and 141 completed the survey (60% of the total). Fifty-eight percent of the respondents were from Europe, 35% from the US and the remaining 7% from other countries. Respondent's specialties included haematology (23%), oncology (18%), pulmonology (15%) and general internal medicine (15%). LMWH was indicated as the first choice for the long-term treatment by 82% of the respondents, of whom 60% used full therapeutic doses and 40% chose a dose reduction. When continuing anticoagulants after the long-term treatment period, 44% of respondents preferred LMWH, 10% VKA, while the remaining 45% chose per individual patient for either LMWH or VKA. In conclusion, we observed a relatively high observance rate of the guidelines with respect to the use of LMWH for the long-term treatment of VTE in cancer. In contrast, the dose of LMWH and the type of anticoagulant chosen after the initial 3-12 months varied substantially, probably reflecting the limited available evidence.

Competing events in patients with malignant disease who are at risk for recurrent venous thromboembolism.

Patients with malignant disease enrolled in trials of thrombotic disorders may experience competing events such as death. The occurrence of a competing event may prevent the thrombotic event from being observed. Standard survival analysis techniques ignore competing risks, resulting in possible bias and distorted inferences. To assess the impact of competing events on the results of a previously reported trial comparing low molecular weight heparin (LMWH) with oral anticoagulant (OAC) therapy for the prevention of recurrent venous thromboembolism (VTE) in patients with advanced cancer, we compare the results from standard survival analysis with those from competing risk techniques which are based on the cumulative incidence function (CIF) and Gray's test. The Kaplan-Meier method overestimates the risk of recurrent VTE (17.2% in the OAC group and 8.7% in the LMWH group). Risk of recurrence using the CIF is 12.0% and 6.0% in the OAC and LMWH groups, respectively. Both the log-rank test (p=0.002) and Gray's test (p=0.006) suggest evidence in favor of LMWH. The overestimation of risk is 30% in each treatment group, resulting in a similar relative treatment effect; using the Cox model the hazard ratio (HR) is 0.48 (95% confidence interval [CI], 0.30 to 0.78) and HR=0.47 (95% CI, 0.29 to 0.74) using the CIF model. Failing to account for competing risks may lead to incorrect interpretations of the probability of recurrent VTE. However, when the distribution of competing risks is similar within each treatment group, standard and competing risk methods yield comparable relative treatment effects.

Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia.

We studied the pathogenesis of the bleeding disorder in acute promyelocytic leukemia by measuring procoagulant, profibrinolytic, and proinflammatory mediators in peripheral blood and bone marrow cells from 25 previously untreated patients. Patients were induced with either all-trans retinoic acid (ATRA) or chemotherapy. Plasma levels of fibrinopeptide A (FPA), fibrin d-dimer, thrombin antithrombin (TAT) complex, prothrombin fragment 1.2 (F1.2), urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (t-PA) and plasminogen activator-inhibitor 1 (PAI-1) were measured before and after therapy, as was the cellular expression of the genes for tissue factor (TF) and interleukin-1 beta (IL-1 beta). The mean plasma levels of fibrin d-dimer, F1.2, TAT and FPA were markedly elevated prior to therapy and declined during the first 30 days of treatment with either ATRA or chemotherapy, but more rapidly and to a greater extent in patients treated with ATRA. ATRA treatment was associated with a significant decrease in TF gene expression in bone marrow cells during the first 30 days of treatment, whereas IL-1 beta gene expression, which decreased in the cells of six patients treated with either chemotherapy or ATRA, actually increased in the remaining six patients treated with either chemotherapy or ATRA. In patients with APL, treatment with either chemotherapy or ATRA rapidly ameliorates the coagulopathy, as indicated by an abrupt decline in markers of clotting activation. An increase in cytokine gene expression (e.g. IL-1 beta) may provide an explanation for the persistent hypercoagulability observed in some patients with APL, regardless of therapeutic approach. Our data confirms and extends earlier observations by others that ATRA is more effective than chemotherapy alone in rapidly reducing the procoagulant burden of APL tumor cells. However, our data also suggests that cytokine expression in some patients may be accelerated by either chemotherapy or ATRA. The implications of this observation for understanding the retinoic acid syndrome will require further studies.

Epidemiology of thrombosis in cancer.

We have utilized epidemiological data to address three questions in patients with cancer and venous thromboembolism (VTE): (1) What is the risk for occult cancer in patients with idiopathic versus secondary VTE? (2) What is the risk for thrombosis in patients with cancer (vs. noncancer patients)? (3) What is the risk of recurrent VTE in cancer patients with an initial episode of VTE compared to noncancer patients? The risk for a new cancer diagnosis within 6-12 months of the diagnosis of idiopathic VTE (including pulmonary embolism) is well supported by retrospective analyses of large numbers of unselected patients, population-based retrospective cohort analyses from large registries and prospective studies. The odds ratios for these studies are in the range of 4- to 7-fold increased risk. In surgical patients with known cancer the odds ratio for an episode of postoperative VTE is approximately 2, when compared to a control group of noncancer patients subjected to the same procedures. A similar odds ratio of approximately 2 exists for the relative risk for recurrence of VTE in the first 3 months after an initial episode in cancer patients treated with heparin and warfarin (Coumadin) compared to noncancer patients. Therefore, patients with idiopathic VTE are at increased risk for occult cancer and cancer patients are at increased risk for VTE. Appropriate studies are underway to determine the best strategies for anticoagulant management of these patients.

Molecular basis for the relationship between thrombosis and cancer.

Cancer patients are highly susceptible to thromboembolic complications, which some have estimated accounts for a significant percentage of the morbidity and mortality of the disease. Not all of the mechanisms for the production of the hypercoagulable state characteristic of cancer are entirely understood. Those that are known seem to interdigitate the biology of cancer with the major regulatory pathways that mediate blood coagulation, platelet-vessel wall interaction, fibrinolysis and inflammatory cytokine production. In other words, the events responsible for thrombosis in cancer appears to be a result of an over exuberant host response in an attempt to delimit tumor growth. In this brief review, therefore, we attempt to put into the context of tumor growth, angiogenesis and metastasis the current information about the pathogenesis of venous thromboembolism (VTE).

The role of the hemostatic system in tumor growth, metastasis, and angiogenesis: tissue factor is a bifunctional molecule capable of inducing both fibrin deposition and angiogenesis in cancer.

Cancer patients are prone to venous thromboembolism (VTE), and this hypercoagulability favors tumor growth and metastasis. After a brief review of the clinical aspects of VTE and cancer, we discuss the pathogenesis of hypercoagulability with an emphasis on the role of tissue factor (TF). The discovery that, in addition to tumor cells, TF is expressed by tumor-associated macrophages and tumor-associated endothelial cells led to studies of the role of TF in the regulation of tumor angiogenesis. In human lung cancer, melanoma, and breast cancer, TF and vascular endothelial growth factor (VEGF) co-localize in tumor cells; a close correlation exists between TF and VEGF synthesis (P = .001) in tumor cell lines and with angiogenesis in vivo in a severe, combined immunodeficient mouse model. Transfection of a TF/VEGF low-producing human tumor cell line with full length TF complementary DNA (cDNA) results in conversion to a high producer of TF and VEGF; transfection of a deletion-mutant TF cDNA lacking cytoplasmic serine residues restores full TF procoagulant activity but not VEGF synthesis to the cells. These results suggest that the cytoplasmic tail of TF is necessary for tumor cell VEGF synthesis. Targeting of TF in tumors and tumor-associated blood vessels is discussed as a strategy for drug delivery and rational anti-cancer and anti-angiogenesis drug design.

Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients.

We report our experience with the incidence of adverse events during the use of Stimate brand intranasal desmopressin acetate (IN DDAVP) for patients with haemophilia A (HA) or von Willebrand disease (vWD) after noting two severe adverse events in one adult patient. All patients with documented vWD (type 1 or 2 A) or haemophilia A (mild, moderate or symptomatic carrier) from the Emory Comprehensive Hemophilia Center who had IN DDAVP challenge testing or were using Stimate for treatment of bleeding were evaluated for adverse events by patient report or nursing observation of clinical signs and symptoms. Forty patients were studied. Sixty-eight per cent (27/40) experienced clinical signs and/or symptoms. The majority of these symptoms were mild, however several patients reported moderate to severe side-effects and one adult patient required medical intervention for symptomatic hyponatraemia. In our experience, two-thirds of patients tested experienced adverse signs and/or symptoms with the use of Stimate; considerably higher than that reported from preliminary results in the literature. Young age did not correlate positively with adverse reactions. Severe adverse events requiring medical intervention were rare, however symptoms such as moderate to severe headache, nausea, vomiting and weakness may necessitate evaluation for hyponatraemia. This is the first report of symptomatic hyponatraemia in an adult patient with recommended dosing of Stimate. Side-effects may be minimized if patients adhere to instructions regarding fluid intake and composition while using IN DDAVP.

Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor.

Tissue factor (TF), a transmembrane receptor for coagulation factor VII/VIIa, is aberrantly expressed in human cancers. We demonstrated a significant correlation between TF and vascular endothelial growth factor (VEGF) production in 13 human malignant melanoma cell lines (r(2) = 0.869, P < 0.0001). Two of these cell lines, RPMI-7951, a high TF and VEGF producer, and WM-115, a low TF and VEGF producer, were grown s.c. in severe combined immunodeficient mice. The high-producer cell line generated solid tumors characterized by intense vascularity, whereas the low producer generated relatively avascular tumors, as determined by immunohistologic staining of tumor vascular endothelial cells with anti-von Willebrand factor antibody. To investigate the structure-function relationship of TF and VEGF, a low-producer melanoma cell line (HT144) was transfected with a TF cDNA containing the full-length sequence, a cytoplasmic deletion mutant lacking the coding sequence for the distal three serine residues (potential substrates for protein kinase C), or an extracellular domain mutant, which has markedly diminished function for activation of factor X. Cells transfected with the full-length sequence produced increased levels of both TF and VEGF. Transfectants with the full-length sequence and the extracellular domain mutant produced approximately equal levels of VEGF mRNA. However, cells transfected with the cytoplasmic deletion mutant construct produced increased levels of TF, but little or no VEGF. Thus, the cytoplasmic tail of TF plays a role in the regulation of VEGF expression in some tumor cells.

Pathophysiology of the thrombophilic state in the cancer patient.

The "hypercoagulable state" of malignancy is due to a complex interaction of tumor cells and their products with host cells, leading to various degrees of impairment of the normal defense mechanisms that ordinarily protect the host against thrombogenesis. Tumor cells can activate directly the blood clotting cascade and cause thrombosis or can induce procoagulant properties and inhibit anticoagulant properties of vascular endothelial cells, platelets, and monocytes and macrophages. In the setting of the local and systemic effects of cancer (e.g., stasis induced by prolonged bed rest and/or vascular invasion by tumor), together with iatrogenic complications of the treatment of cancer (e.g., the use of central vein catheters and angiopathic chemotherapy), this basic pathophysiology conspires to make cancer perhaps the best example of "acquired thrombophilia." In this brief review, we have attempted to describe what is currently known about the mechanisms for the hypercoagulable state of cancer and provide a summary of the evidence that indicates the many levels of defects in patients with malignancies that predispose them to thrombosis. A better understanding of the pathophysiology of thrombophilia in cancer should provide clinicians with an improved rationale for more aggressive and specific anticoagulant strategies in selected patients.

Research priorities in hereditary hemochromatosis.

The Working Group on Research Priorities used a formal nominal group technique to identify and prioritize the specific aims of applied research needed to provide the scientific basis for population screening for iron overload disorders. The most important applied research goal was characterization of the natural history of the relation between genotype and phenotype in hereditary hemochromatosis and other iron overload disorders. Three other important research objectives were development of an optimal approach to screening for iron overload; analyses of the cost-effectiveness of screening; and assessment of the ethical, legal, and social implications of screening. To achieve these specific aims, two research studies were recommended as being of the highest priority: a multicenter, cross-sectional, population-based study of the natural history of iron overload and a multicenter, case-control study of patients with disease manifestations potentially attributable to hereditary hemochromatosis in primary care and subspecialty clinics.

Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.

Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer pro-coagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.

Venous thromboembolism in malignancy and malignancy in venous thromboembolism.

The activation of coagulation in patients with cancer contributes significantly to morbidity and mortality rates and may play a fundamental role in the host response to growing tumours. Patients with cancer are clearly at high risk for the development of venous thromboembolism (VTE), particularly during chemotherapy and surgery. This situation is aggravated by the use of venous access catheters and possibly growth factors. Data derived from large, randomized, controlled trials have been used to determine the true incidence of this complication of cancer and its treatment. The incidence based on the analyses of these randomized controlled trials varies from 1% for limited stage patients with breast cancer treated with tamoxifen to 60% for patients with any type of cancer who are subjected to orthopaedic surgery and do not receive prophylactic therapy. In view of the morbidity and mortality attributable to VTE in cancer, widespread utilization of prophylactic anticoagulation therapy, which has proven safe and effective in a variety of situations, should be considered. While migratory thrombophlebitis is a clear indicator of an underlying neoplasm, the risk of cancer in patients with the more typical form of VTE has been the subject of intense debate over recent years. Some investigators have suggested that the relative risk of being diagnosed with an occult cancer within 6 months of an episode of VTE (particularly recurrent VTE) could be up to 10-fold. However, the cost-effectiveness of aggressive screening for cancer in patients with VTE has not yet been defined adequately.

Treatment of venous thromboembolism in cancer patients.

The occurrence of venous thromboembolism complicates the management of the patient with malignant disease because of the need for anticoagulant therapy. Cancer patients have an ongoing thrombotic stimulus due to the underlying cancer and its associated treatments, but are also considered to be at increased risk for anticoagulant-related bleeding. In recent years, the results of clinical trials have demonstrated the safety and efficacy of bodyweight-adjusted subcutaneous low-molecular-weight heparin administered at home for patients with acute deep vein thrombosis. This approach is particularly attractive in patients with cancer, in whom quality of life is an important consideration. There are no trials to date which specifically address the question of the duration of oral anticoagulant therapy in cancer patients. However, data can be extrapolated from trials evaluating the duration of oral anticoagulant therapy in other high-risk patients. Hence, cancer patients should continue oral anticoagulant therapy for as long the cancer remains active (usually at least 6 months). There remain a number of unanswered questions regarding the clinical management of thromboembolism in the cancer patient.

Fibrin induction of tissue factor expression in human vascular endothelial cells.

BACKGROUND: For the present study, we hypothesized that fibrin is an inducer of tissue factor (TF) expression in vascular endothelial cells in vitro and in vivo. METHODS AND RESULTS: To test the in vitro aspect of this hypothesis, human umbilical vein endothelial cells (HUVECs) were cocultured with physiologically relevant concentrations of fibrin (0.03 to 1.0 mg fibrin/mL) for various times (0.5 to 24 hours), and TF expression was compared with that in unstimulated HUVECs (media control). Results demonstrated that fibrin induced a time- and dose-dependent increase in TF antigen expression, functional TF procoagulant activity, and TF mRNA in HUVECs. CONCLUSIONS: These studies demonstrate that fibrin can directly regulate TF expression in HUVECs in vitro.

Molecular mechanisms linking thrombosis and angiogenesis in cancer.

In this brief review, the authors concentrate on selected issues related to the newly described role of tissue factor (TF), the major activator of mammalian blood coagulation, as a regulator of angiogenesis and of tumor growth and metastasis. Previously, TF had been considered strictly as the primary activator of the coagulation cascade; however, it has recently been demonstrated that overexpression of the TF gene in murine tumor cells leads to increased transcription of the gene for vascular permeability factor/vascular endothelial growth factor (VEGF), a proangiogenic factor, and decreased transcription of the gene for thrombospondin (TSP), an antiangiogenic factor. Conversely, underexpression of TF leads to decreased VEGF and increased TSP transcription. When grown in mice and compared with low TF-producing tumor cells, high TF-producing tumor cells stimulate angiogenesis by approximately twofold. This effect of TF appears to be independent of its clot-promoting procoagulant activity (PCA) and suggests that TF regulates the angiogenic properties of tumor cells by altering the production of growth regulatory molecules (for example, VEGF) that can act on vascular endothelial cells (VECs). There is substantial preliminary evidence that the regulation of tumor angiogenesis can be mediated by TF via both fibrin clotting-dependent and fibrin clotting-independent mechanisms. (Trends Cardiovasc Med 1997;7:52-59). © 1997, Elsevier Science Inc.