OC-14 - Baseline D-dimer levels are predictive of recurrent venous thromboembolism (VTE) at 6 months in cancer patients with VTE treated with tinzaparin.

INTRODUCTION: VTE is a major complication in cancer patients. Despite treatment with low molecular weight heparin (LMWH), 9% will have recurrent VTE within 6 months. Measurement of plasma biomarkers in cancer patients receiving LMWH may be predictive of recurrent VTE or overall survival (OS). AIM: We conducted a single arm phase 2 study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis of VTE in cancer patients. The study included a prospective analysis of plasma biomarkers D-dimer and IL-6 to assess whether these were predictive of recurrent VTE or OS. MATERIALS AND METHODS: Consecutive patients with active cancer diagnosed with a pulmonary embolism (PE) and/or proximal deep venous thrombosis (DVT) at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles County Medical Center, or New York Presbyterian - Weill Cornell Medical Center were invited to participate in this study with a target enrollment of 100 patients. Key eligibility criteria included: age ≥18, ECOG score ≤2, adequate organ function, and ≥6 month estimated survival. Patients were treated with daily subcutaneously tinzaparin 175 U/kg for 6 months on study. Tinzaparin could be continued ≤1 year at the discretion of the treating physician. All patients who received ≥1 dose were evaluable for efficacy and safety. Primary study endpoints were recurrent VTE or major bleeding. Secondary outcome measures included OS and plasma biomarkers. Biomarkers were measured at baseline, 7 days, 1 month and 6 months after tinzaparin initiation. Patients who had baseline and 1 week or 1 month samples collected were included in the biomarker analysis. RESULTS: 97 patients were enrolled. 2 patients were ineligible. 8 patients did not have baseline or follow-up biomarkers completed. 87 patients were included in the analysis. 28 (32%) of patients completed≥6 months of tinzaparin. Major bleeding occurred in 2 patients. 11 patients had recurrent VTE at 6 months (3 PE, 7 DVT, 1 central venous thrombosis not associated with a catheter). Median baseline D-dimer level was 2759 ng/mL (range: 375-37,591). Median baseline IL-6 level was 9.4 pg/mL (range: 0.8-20.9). Baseline D-dimer>median was predictive of VTE recurrence at 6 months (p=.006). Baseline IL-6>median was not predictive of VTE recurrence at 6 months. Neither 1 month D-dimer or IL-6 levels were predictive of VTE recurrence at 6 months. D-dimer and IL-6 at baseline and at 1 month were not predictive of OS. CONCLUSIONS: In patients with active cancer and VTE treated with tinzaparin, baseline D-dimer levels above the median value were predictive of VTE recurrence at 6 months.

Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden.

BACKGROUND: Thromboembolic events are well recognized complications of cancers and their treatment. Tamoxifen, an antiestrogen used in the treatment of breast carcinoma and other malignancies, has been associated with thrombotic events. Activated protein C resistance due to Factor V Leiden is the most prevalent inherited prothrombotic defect in populations of European descent and has been reported as a major cofactor in the development of thrombosis in women receiving estrogens. METHODS: The authors report three patients who developed thromboembolic complications while receiving tamoxifen. These patients were studied for the presence of activated protein C resistance by coagulation assay and the presence of Factor V Leiden by molecular analysis. RESULTS: All three patients had resistance to activated protein C by coagulation assay and were determined to be heterozygous for Factor V Leiden by molecular analysis. CONCLUSIONS: The authors propose that inheritance of Factor V Leiden significantly increases the risk of thrombosis in patients who receive tamoxifen therapy. All patients prescribed tamoxifen should be carefully questioned regarding personal and family histories of thrombosis and, when indicated, screened for Factor V Leiden.

Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: a critical review.

Des-gamma-carboxyprothrombin (DCP) appears to be a useful tumor marker for the evaluation of patients with HCC. DCP is produced by the malignant hepatocyte and appears to result from an acquired posttranslational defect in the vitamin K-dependent carboxylase system. DCP production is independent of vitamin K deficiency, although pharmacological doses of vitamin K can transiently suppress DCP production in some tumors. DCP levels greater than 0.1 AU/ml (100 ng/ml) on ELISA are highly suggestive of HCC or tumor recurrence. Normalization of DCP levels correlates well with successful tumor resection and appears to be an excellent marker of tumor activity. Plasma DCP does not correlate with AFP levels. However, when used together, DCP and AFP assays increase the sensitivity to HCC in more than 85% of patients. The specificity of the DCP assay appears to be superior to that of AFP; fewer than 5% of patients with nonmalignant liver disorders have DCP levels in excess of 100 ng/ml. In patients with medium to large HCC, DCP levels do correlate with tumor size. In tumors of less than 3 cm, DCP levels are increased in only 20% of patients. However, the diagnostic threshold for the DCP assay may be improved by newer assays that can detect partially carboxylated DCP species not measured by the monoclonal antibody-based ELISA.

Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.

Severe bleeding resulting from excessive fibrinolysis has been observed in patients with primary amyloidosis. The authors studied a patient with this hemostatic disorder before and during therapy with epsilon-aminocaproic acid. Excessive fibrinolysis was associated with depressed plasma concentrations of coagulation Factors XII, XI, high-molecular-weight kininogen, and Factors VIII and V; and plasminogen and alpha-2-plasmin inhibitor. These deficiencies were corrected with treatment. The functional and antigenic concentrations of tissue plasminogen activator and plasminogen activator inhibitor in the patient's plasma were normal. Urokinase-type activator activity and antigen were three to five times elevated in the patient's plasma. Results of immunoprecipitation showed that single-chain urokinase-type activator was the primary urokinase-type activator species in the patient's plasma. Excessive fibrinolysis in patients with amyloidosis results from increased plasma single-chain urokinase-type activator activity.