Cancer increases the risk of venous thromboembolism (VTE). Here, we investigated the contribution of microparticle (MP)-dependent procoagulant activity to the prothrombotic state in these patients. In 43 cancer patients without VTE at study entry and 22 healthy volunteers, markers of in vivo and MP-dependent coagulation were measured and patients were prospectively followed for six months for the development of VTE. Procoagulant activity of MPs was measured in vitro using a tissue factor (TF)-independent phospholipid dependent test, a factor Xa-generation assay with and without anti-TF, and a fibrin generation test (FGT) with and without anti-factor VII(a). Markers of in vivo coagulation activation and total number of MPs at baseline were significantly elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/l, D-dimer 0.76 vs. 0.22 mg/l and 5.53 x 106 vs. 3.37 x 106 MPs/ml). Five patients (11.6%) developed VTE. Patients with VTE had comparable levels of coagulation activation markers and phospholipid-dependent MP pro-coagulant activity. However, median TF-mediated Xa-generation (0.82 vs. 0.21 pg/ml, p=0.016) and median VIIa-dependent FGT (13% vs. 0%, p=0.036) were higher in the VTE group compared with the non-VTE group. In this exploratory study the overall hypercoagulable state in cancer patients was not associated directly with the MP phospholipid-dependent procoagulant activity. However, in the patients who developed VTE within six months when compared to those who did not, an increased MP procoagulant activity was present already at baseline, suggesting this activity can be used to predict VTE.
Keywords
Cancer -
venous thromboembolism -
microparticle-dependent coagulant activity
References
1
Auwerda JJ,
Yuana Y,
Osanto S.
et al. Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma. Thromb Haemost 2011; 105: 14-20.
4
Buller HR,
van Doormaal FF,
van Sluis GL.
et al. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 05 (Suppl. 01) 246-254.
5
Davila M,
Amirkhosravi A,
Coll E.
et al. Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost 2008; 06: 1517-1524.
7
Dvorak HF,
Van DL Bitzer AM.
et al. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res 1983; 43: 4434-4442.
8
Falati S,
Liu Q,
Gross P.
et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585-1598.
9
Haas SL,
Jesnowski R,
Steiner M.
et al. Expression of tissue factor in pancreatic adenocarcinoma is associated with activation of coagulation. World J Gastroenterol 2006; 12: 4843-4849.
10
Hron G,
Kollars M,
Weber H.
et al. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007; 97: 119-123.
11
Kakkar AK,
DeRuvo N,
Chinswangwatanakul V.
et al. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 1004-1005.
12
Khorana AA,
Francis CW,
Menzies KE.
et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008; 06: 1983-1985.
14
Lee RD,
Barcel DA,
Williams JC.
et al. Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity. Thromb Res 2012; 129: 80-85.
15
Manly DA,
Wang J,
Glover SL.
et al. Increased microparticle tissue factor activity in cancer patients with Venous Thromboembolism. Thromb Res 2010; 125: 511-512.
16
Negaard HF,
Iversen PO,
Ostenstad B.
et al. Hypercoagulability in patients with haematological neoplasia: no apparent initiation by tissue factor. Thromb Haemost 2008; 99: 1040-1048.
18
Tesselaar ME,
Romijn FP,
van dL I.
et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?. J Thromb Haemost 2007; 05: 520-527.
19
Toth B,
Liebhardt S,
Steinig K.
et al. Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb Haemost 2008; 100: 663-669.
20
van Doormaal P,
Rousseau A,
Fontaine S.
et al. Clinical evaluation of a new functional test for detection of plasma procoagulant phospholipids. Blood Coagul Fibrinolysis 2009; 20: 494-502.
21
White RH,
Chew HK,
Zhou H.
et al. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med 2005; 165: 1782-1787.
22
Yu JL,
May L,
Lhotak V.
et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005; 105: 1734-1741.
24
Zwicker JI,
Kos CA,
Johnston KA.
et al. Cancer-associated thrombosis: tissue factor-bearing microparticles are associated with an increased risk of venous thromboembolic events in cancer patients. XXIst congress of the International Society on Thrombosis and Haemostasis, Geneva, July 2007. J Thromb Haemost. 2007 05. suppl. 2 =-M-005 (Abstract)
25
Zwicker JI,
Liebman HA,
Neuberg D.
et al. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 2009; 15: 6830-6840.
