Hypercoagulability in Ovarian Cancer Revisited: A Prospective Analysis of Coagulation and Platelet Activation Markers.
Authors: Amirkhosravi Ali , Bigsby Glenn , Desai Hina , Amaya Mildred , Coll Enriqueta , Robles Liza , Faust Patricia , Langer Florian , Drexler Alane , Reyes Edward , Francis John L. 
Published: October 2019

Abstract
Coagulation and platelet activation occurs in patients with ovarian cancer, and several factors underlying such hypercoagulability have been implicated in tumor growth and metastasis. The incidence of venous thromboembolism throughout the course of ovarian cancer is high, and identification of hypercoagulable patients may be important not only for effective thromboprophylaxis, but also for future anti-hemostatic treatment strategies targeting disease progression. The purpose of this prospective study was therefore, first, to characterize in more detail, the hypercoagulable state in patients with ovarian tumors and, second, to define markers of coagulation or platelet activation that specifically identify patients with malignant disease. Thirty nine patients presenting to our institution with an ovarian mass of unknown type (41–69 yrs) and 32 age-matched controls were included in the study. Pre- and postoperative (7–14 days) blood samples were collected, and all whole blood (WB) analyses were performed and plasmas prepared and frozen within 2 hours thereafter. WB thrombelastography (TEG) served for global coagulation assessment. D-Dimer and prothrombin fragment F1+2 were used as markers of coagulation activation. Soluble CD40 ligand (sCD40L), soluble P-selectin, platelet-monocyte conjugates, and platelet-derived microparticles (PMP) were measured to assess in vivo platelet activation. Tissue factor (TF) antigen and TF+ microparticles were quantified in plasma by ELISA and flow cytometry, respectively. Compared to controls, mean values for TEG-R, a measure of clotting time, and TEG-MA, a measure of clot strength, were significantly decreased (10.1 vs. 7.3 min, P<0.05) and increased (63 vs. 68 mm, P<0.001), respectively, in preoperative samples. Median levels of TF antigen (88 vs. 28 pg/ml, P<0.01), D-Dimer (255 vs. 133 ng/ml, P<0.01), and sCD40L (223 vs. 162 pg/ml, P<0.01) as well as platelet-monocyte conjugates (66 vs. 45%, P<0.001) and plasma PMP (10.2 vs. 5.7x106/ml, P=0.01) were significantly higher in preoperative samples than in controls. Interestingly, no correlation was found between plasma TF antigen levels and absolute numbers of TF+ microparticles. Moreover, while we found significant correlations between the various markers of platelet activation, there was no obvious association between the two TF indices and any of the hemostatic parameters analyzed. D-Dimer values (1310 vs. 255 ng/ml, P<0.001) and TEG-MA (73 vs. 68 mm, P<0.05) were significantly elevated in postoperative as compared to preoperative samples, indicating further and prolonged coagulation activation by the surgical trauma. Furthermore, when compared to patients with benign tumors (n=31), values for D-Dimer (215 vs. 2329 ng/ml, P=0.009) and TEG-MA (66.9 vs. 72.6 mm, P=0.007) were significantly elevated in those with histologically proven ovarian cancer (n=8). Importantly, two of three patients with metastatic disease had the highest D-Dimer and TEG-MA values of the entire patient cohort. In summary, our results demonstrate significant coagulation and platelet activation in women presenting with an ovarian mass. In addition, plasma D-Dimer and WB TEG may be helpful in identifying individuals at high risk for perioperative thromboembolic complications and metastatic malignant disease.