Thrombosis Research

Arterial events in cancer patients treated with apixaban for venous thrombosis

In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·10 In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

Disseminated intravascular coagulation with hyperfibrinolysis induced by a degenerating uterine leiomyoma: A rare case report

Disseminated intravascular coagulation (DIC) is typically associated with malignancy, sepsis, or obstetric complications. Its occurrence in benign tumors, particularly uterine leiomyomas, is extremely rare. We report a case of a 49-year-old woman with two months of menorrhagia. Laboratory tests revealed anemia, prolonged clotting times, hypofibrinogenemia, and markedly elevated D-dimer and fibrin degradation products (FDP) levels. Coagulation factor activities (V, VIII, XII) were reduced. Thrombin-antithrombin complex (TAT) and plasmin-α2-plasmin inhibitor complex (PIC) were elevated, and thromboelastography (TEG) indicated hypocoagulability with hyperfibrinolysis. Image revealed a large degenerating uterine fibroid. Comprehensive workup excluded autoimmune, neoplastic, and inherited causes. After perioperative antifibrinolytic and coagulation management, hysterectomy was performed. Pathology confirmed extensive intratumoral thrombosis. Coagulation parameters normalized postoperatively without requiring transfusion, and no thrombotic events were observed. This case highlights a rare but important cause of DIC with hyperfibrinolysis secondary to a benign uterine tumor. It underscores the value of TEG and molecular markers in diagnosis and management, and the need to consider benign tumors in the differential diagnosis of unexplained coagulopathy.

Chemotherapy alters thrombomodulin and factor VIIIc expression resulting in acquired activated protein C resistance and enhanced thrombin generation in cancer associated thrombosis

Tumour type, treatment and patient related factors contribute to cancer associated venous thromboembolism (VTE), however, the role of each factor and the mechanisms involved are not understood. To assess the role of the tumour, and of chemotherapy, in mediating the procoagulant response associated with VTE in gynaecological cancer patients. Gynaecological cancer patients who developed VTE during follow-up (n = 59) (VTE+) were matched with treatment naïve(treatment (-)(VTE-)(n = 120) and chemotherapy treated patients(treatment (+)(VTE-) (n = 57)). Thrombin generation, Factor V(FV), VIIIc(FVIIIc), Tissue Factor Pathway Inhibitor(TFPI), soluble Thrombomodulin(sTM), Protein S(PS), C(PC) endothelial protein C receptor(EPCR) and fibrinogen were compared in each group. EPCR and TM expression was assessed in EA.hy926 cells in vitro following addition of chemotherapy agents. mRNA expression of coagulation genes was measured in tumour biopsies. Thrombin generation was increased in treatment(-)VTE(+) compared with treatment(-)VTE(-) controls but not in the treatment(+)VTE(+) patients. Using the TM modified assay, thrombin generation was increased in the treatment (+)VTE(-) group compared with treatment(-)(VTE-) with a further increase in the treatment (+) VTE(+) group. Reduced levels of sTM in treatment (+) VTE(+) patients correlated with thrombin generation. TM expression was reduced in vitro by carboplatin and paclitaxel. FVIIIc was increased in both VTE groups and was predictive of VTE. F5 mRNA levels were lower in tumours from VTE(+) patients compared with controls. Chemotherapy alters sTM and confers an acquired activated Protein C(aPC) resistance which may be implicated in cancer associated VTE in gynaecological cancer patients. FVIIIc may be a useful predictive marker for VTE in cancer patients in this setting.

Multitarget strategy of GATA3 and high-grade serous ovarian carcinoma: Where are we now?

Ovarian vein thrombosis after gynecological malignant tumor surgery with adnexectomy: Clinical features and outcomes

Procoagulant activity in high grade serous ovarian cancer patients following neoadjuvant chemotherapy-The role of the activated protein C pathway

Ovarian cancer patients are at high risk of thrombosis particularly during chemotherapy treatment however the mechanism is not understood. The aim of this study is to investigate the role of the activated protein C (aPC) pathway in the procoagulant activity observed in ovarian cancer patients undergoing neoadjuvant chemotherapy. Thrombin generation was determined before and after addition of thrombomodulin (TM) in high grade serous ovarian cancer (HGSOC) patients treated with neoadjuvant chemotherapy (n = 29) compared with HGSOC patients who were chemo naïve (n = 23) and patients with benign tumours (n = 29). Plasma expression of proteins from the aPC pathway was analysed. mRNA expression was determined in endothelial (EA.hy926) and ovarian (OAW42) cell lines following addition of carboplatin and paclitaxel. Lower levels of ETP (p < 0.007; p < 0.003) and peak thrombin (p < 0.0008; p < 0.0018) were found in the neoadjuvant group compared with both chemo naïve and benign groups. Following addition of TM, ETP (p < 0.0005) and peak thrombin (p < 0.0049) were higher in the neoadjuvant group compared with the benign controls indicating an increase in aPC resistance. Increased TM and lower levels of protein S were found in the neoadjuvant group compared with benign controls (p < 0.05; p < 0.003). Factor V levels were increased in the neoadjuvant group compared with the chemo naïve group (p < 0.05). Carboplatin and paclitaxel altered the expression of EPCR and thrombomodulin in OAW42 cells with a modest effect on EA.hy926 cells. Chemotherapy induced procoagulant activity in HGSOC is associated with an alteration in expression of key members of the aPC pathway. This acquired aPC resistance may explain the procoagulant phenotype associated with ovarian cancer patients undergoing chemotherapy.

Incidence and risk factors of preoperative venous thromboembolism and pulmonary embolism in patients with ovarian cancer

To determine the incidence and predisposing factors of preoperative venous thromboembolism (VTE), especially pulmonary embolism (PE) in patients with ovarian cancer. This retrospective study included 387 patients with primary ovarian cancer, whose preoperative work up included both ultrasonography of lower extremity vein and spiral computed tomography pulmonary angiogram, from September 2013 to November 2016. SPSS 22 was used for statistical analyses. The incidence of preoperative VTE and PE was 13.4% (52 patients), 9.3%(36 patients), respectively. Both the univariate and multivariate analyses revealed that D-dimer (DDI) level, age, and massive ascites were associated with preoperative VTE. Moreover, DDI level (odds ratio [OR] 3.133, 95% confidence interval [CI] 1.193-8.225, p = .02), massive ascites (OR 9.972, 95% CI 3.687-26.968, p 5 μg/ml, the incidence of preoperative VTE and PE were 18.4% and 14.2% respectively. Moreover, DDI value was significantly correlated with preoperative PE volume (r = 0.746, p < .001). Preoperative VTE and PE are common events in patients with ovarian cancer. DDI level is a useful parameter for diagnosing and evaluating preoperative VTE and PE.