Jeffrey I. Zwicker

Tumor-Derived Tissue Factor–Bearing Microparticles Are Associated With Venous Thromboembolic Events in Malignancy

Purpose: Despite the strong association between malignant disease and thromboembolic disorders, the molecular and cellular basis of this relationship remains uncertain. We evaluated the hypothesis that tumor-derived tissue factorbearing microparticles in plasma contribute to cancer-associated thrombosis. Experimental Design: We developed impedance-based flow cytometry to detect, quantitate, and size microparticles in platelet-poor plasma. We evaluated the number of tissue factorbearing microparticles in a cohort of cancer patients of different histologies (N = 96) and conducted a case-control study of 30 cancer patients diagnosed with an acute venous thromboembolic event (VTE) compared with 60 cancer patients of similar age, stage, sex, and diagnosis without known VTE, as well as 22 patients with an idiopathic VTE. Results: Tissue factorbearing microparticles were detected in patients with advanced malignancy, including two thirds of patients with pancreatic carcinoma. Elevated levels of tissue factorbearing microparticles were associated VTE in cancer patients (adjusted odds ratio, 3.72; 95 confidence interval, 1.18-11.76; P = 0.01). In cancer patients without VTE, a retrospective analysis revealed a 1-year cumulative incidence of VTE of 34.8 in patients with tissue factorbearing microparticles versus 0 in those without detectable tissue factorbearing microparticles (Gray test P = 0.002).The median number of tissue factorbearing microparticles in the cancer VTE cohort (7.1 104 microparticles/L) was significantly greater than both the idiopathic VTE and cancerno VTE groups (P = 0.002 and P = 0.03, respectively). Pancreatectomy in three patients eliminated or nearly eliminated these microparticles which coexpressed the epithelial tumor antigen, MUC-1. Conclusion: We conclude that tumor-derived tissue factorbearing microparticles are associated with VTE in cancer patients and may be central to the pathogenesis of cancer-associated thrombosis. (Clin Cancer Res 2009;15(22):683040)

Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia.

Summary.  The natural history of heparin‐induced thrombocytopenia (HIT) in the absence of thrombosis was previously established using functional assays for confirmation of diagnosis (e.g. 14C serotonin release assay). An enzyme‐linked immunosorbent assay (ELISA) that detects the presence of antibodies directed against the heparin–platelet factor‐4 (PF4) complex has largely replaced functional assays in many medical centers. Although the ELISA is highly sensitive for detecting HIT antibodies, its usefulness for predicting thrombotic outcomes has not been clearly established. We performed a retrospective chart review of all hospitalized patients at a university hospital who tested seropositive for HIT by a commercial ELISA during 2001 and 2002. A total of 63 inpatients were identified as HIT positive by ELISA. Forty‐eight patients had no apparent HIT‐associated thrombosis at the time of HIT seropositivity (i.e. isolated HIT) and only one was treated prophylactically with a direct thrombin inhibitor. The 30‐day thrombosis rate for patients with isolated HIT was 17% (eight of 48). Higher ELISA optical density (OD) measurements correlated significantly with thrombosis (1.41 ± 0.87 vs. 0.79 ± 0.46, P < 0.001). Patients with isolated HIT and an OD measurement of ≥ 1.0 demonstrated nearly a 6‐fold increased risk of thrombosis compared with those with OD values between 0.4 and 0.99 (odds ratio 5.74, 95% confidence interval 1.73, 19.0; absolute rate of thrombosis, 36% vs. 9%, respectively, P = 0.07). We conclude that in hospitalized patients with isolated HIT, the presence of heparin–PF4 antibodies detected by ELISA was associated with a significant risk of subsequent thrombosis and higher ELISA values were observed among patients suffering thrombotic events.

Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis

Objectives To evaluate the risk of venous thromboembolic events associated with the use of progestin-only contraception and whether that risk differs with the mode of drug delivery (oral, intrauterine, or depot injection). Design Systematic review and meta-analysis of randomised controlled trials and observational studies. Data sources Pubmed, Embase, Cochrane Library, and reference lists of relevant reviews. Study selection Randomised controlled trials and case-control, cohort, and cross sectional studies with venous thromboembolic outcome for progestin-only contraception reported relative to a non-hormone comparator group. Data extraction Data were extracted by two independent investigators, and consensus for inclusion was reached after assessment by additional investigators. Results Among the 2022 unique references identified by all searches, eight observational studies fulfilled inclusion criteria. A total of 147 women across all studies were diagnosed with a venous thromboembolic event while taking progestin-only contraception, and the summary measure for the adjusted relative risk of a venous thromboembolic episode for users versus non-users of a progestin-only contraceptive was, based on the random effects model, 1.03 (95% CI 0.76 to 1.39). Subgroup analysis confirmed there was no association between venous thromboembolic risk and progestin-only pills (relative risk 0.90 (0.57 to 1.45)) or a progestin intrauterine device (0.61 (0.24 to 1.53)). The relative risk of a venous thromboembolic event for users of an injectable progestin versus non-users was 2.67 (1.29 to 5.53). Conclusions Published data assessing the risk of venous thromboembolism in women prescribed progestin-only contraception are limited. In this meta-analysis of eight observational studies, the use of progestin-only contraception was not associated with an increased risk of venous thromboembolism compared with non-users of hormonal contraception. The potential association between injectable progestins and thrombosis requires further study.

Tissue Factor–Bearing Microparticles and Thrombus Formation

Blood microparticles are vesicular structures with a diameter of 100 to 1000 nm that are present in the blood of normal subjects and in patients with various diseases. These microparticles are derived from cells that circulate in the blood and cells associated with the blood vessel wall. Microparticle membranes retain the protein receptors of their parent cells and may retain RNAs and other cytosolic content. On the basis of surface protein expression, microparticles are known to be derived from platelets, granulocytes, monocytes, endothelial cells, smooth muscle cells, and tumor cells. Only a subpopulation of these microparticles expresses tissue factor.

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Background Low‐molecular‐weight heparin is the standard treatment for cancer‐associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. Methods In this open‐label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low‐molecular‐weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. Results Of the 1050 patients who underwent randomization, 1046 were included in the modified intention‐to‐treat analysis. A primary‐outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, ‐3.4 percentage points; 95% CI, ‐7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). Conclusions Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682.)

Management of challenging cases of patients with cancer‐associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH

M. CARR IER ,* A . A . KHORANA,† J . I . ZWICKER ,‡ S . NOBLE ,§ A. Y . Y . LEE ¶ and ON BEHALF OF THE SUBCOMMITTEE ON HAEMOSTAS I S AND MAL IGNANCY FOR THE SSC OF THE ISTH *Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada; †Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; ‡Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; §Royal Gwent Hospital, Newport, UK; and ¶Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

PREDICTION AND PREVENTION OF THROMBOEMBOLIC EVENTS WITH ENOXAPARIN IN CANCER PATIENTS WITH ELEVATED TISSUE FACTOR-BEARING MICROPARTICLES: A RANDOMIZED-CONTROLLED PHASE II TRIAL (THE MICROTEC STUDY)

Elevated levels of circulating tissue factor‐bearing microparticles (TFMP) have been associated with an increased risk of developing venous thromboembolism (VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (N = 23) was 5·6% while the higher TFMP group observation arm (N = 11) was 27·3% (Gray test P = 0·06). The cumulative incidence of VTE in the low TFMP was 7·2% (N = 32). No major haemorrhages were observed in the enoxaparin arm. The median survival for patients with higher levels of TFMP followed by observation was 11·8 months compared with 17·8 months on enoxaparin (P = 0·58). In a prospective randomized trial, increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE. Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP, with an overall rate of VTE similar in magnitude to the lower TFMP group.

Lenalidomide enhances anti-myeloma cellular immunity

Lenalidomide is an effective therapeutic agent for multiple myeloma that exhibits immunomodulatory properties including the activation of T and NK cells. The use of lenalidomide to reverse tumor-mediated immune suppression and amplify myeloma-specific immunity is currently being explored. In the present study, we examined the effect of lenalidomide on T-cell activation and its ability to amplify responses to a dendritic cell-based myeloma vaccine. We demonstrate that exposure to lenalidomide in the context of T-cell expansion with direct ligation of CD3/CD28 complex results in polarization toward a Th1 phenotype characterized by increased IFN-γ, but not IL-10 expression. In vitro exposure to lenalidomide resulted in decreased levels of regulatory T cells and a decrease in T-cell expression of the inhibitory marker, PD-1. Lenalidomide also enhanced T-cell proliferative responses to allogeneic DCs. Most significantly, lenalidomide treatment potentiated responses to the dendritic cell/myeloma fusion vaccine, which were characterized by increased production of inflammatory cytokines and increased cytotoxic lymphocyte-mediated lysis of autologous myeloma targets. These findings indicate that lenalidomide enhances the immunologic milieu in patients with myeloma by promoting T-cell proliferation and suppressing inhibitory factors, and thereby augmenting responses to a myeloma-specific tumor vaccine.

Lack of Evidence to Support Thromboprophylaxis in Hospitalized Medical Patients with Cancer

BACKGROUND The administration of anticoagulant thromboprophylaxis for all patients with cancer who are hospitalized for acute medical illness is considered standard practice and strongly recommended in clinical guidelines. These recommendations are extrapolated from randomized controlled prophylaxis trials not specifically conducted in cancer cohorts. Because hospitalized patients with cancer constitute a unique population with increased risk of venous thromboembolic events and major hemorrhage, validation of the efficacy and safety of primary thromboprophylaxis in this population is critical. We sought to summarize the rates of venous thromboembolic events and major bleeding episodes among hospitalized patients with cancer who were receiving anticoagulant therapy compared with placebo. METHODS A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. Two reviewers independently extracted data onto standardized forms. The primary end points were all venous thromboembolic events. Secondary end points included major bleeding episodes and symptomatic venous thromboembolic events. Pooled analysis with relative risk using a random effect model was used as the primary measurement. RESULTS A total of 242 citations were identified by the literature search. Of these, 3 placebo-controlled randomized trials included venous thromboembolic events as a primary outcome and were analyzed according to cancer subgroups. The pooled relative risk of venous thromboembolic events was 0.91 (95% confidence interval, 0.21-4.0; I(2): 68%) among hospitalized patients with cancer who were receiving thromboprophylaxis compared with placebo. None of the trials reported the rates of symptomatic venous thromboembolic events or major bleeding episodes according to cancer status. CONCLUSIONS The risks and benefits of primary thromboprophylaxis with anticoagulant therapy in hospitalized patients with cancer are not known. This is especially relevant because numerous Medicare-type pay-for-performance incentives mandate prophylaxis specifically in patients with cancer.

Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study

Venous thromboembolism occurs frequently in patients with cancer who have brain metastases, but there is limited evidence supporting the safety of therapeutic anticoagulation. To assess the risk for intracranial hemorrhage associated with the administration of therapeutic doses of low-molecular-weight heparin, we performed a matched, retrospective cohort study of 293 patients with cancer with brain metastases (104 with therapeutic enoxaparin and 189 controls). A blinded review of radiographic imaging was performed, and intracranial hemorrhages were categorized as trace, measurable, and significant. There were no differences observed in the cumulative incidence of intracranial hemorrhage at 1 year in the enoxaparin and control cohorts for measurable (19% vs 21%; Gray test, P = .97; hazard ratio, 1.02; 90% confidence interval [CI], 0.66-1.59), significant (21% vs 22%; P = .87), and total (44% vs 37%; P = .13) intracranial hemorrhages. The risk for intracranial hemorrhage was fourfold higher (adjusted hazard ratio, 3.98; 90% CI, 2.41-6.57; P < .001) in patients with melanoma or renal cell carcinoma (N = 60) than lung cancer (N = 153), but the risk was not influenced by the administration of enoxaparin. Overall survival was similar for the enoxaparin and control cohorts (8.4 vs 9.7 months; Log-rank, P = .65). We conclude that intracranial hemorrhage is frequently observed in patients with brain metastases, but that therapeutic anticoagulation does not increase the risk for intracranial hemorrhage.