Weight-adjusted dalteparin for prevention of vascular thromboembolism in advanced pancreatic cancer patients decreases serum tissue factor and serum-mediated induction of cancer cell invasion

Abstract

The aim of the present study was to assess the role of tissue factor and serum-induced cell invasion in patients with advanced pancreatic cancer (APC). A cohort of 39 patients with APC, without thrombosis, receiving chemotherapy, were entered in a randomized controlled trial (ISRCTN = 76464767) of thromboprevention with weight-adjusted dalteparin (WAD). A total of 19 patients received WAD, the remaining 20 acting as a control group. Serum from baseline and week 8 was analysed for circulating-tissue factor antigen using ELISA. Circulating-tissue factor antigen rose from 324 pg/ml, [interquartile range (IQR) 282-347 pg/ml] to 356 pg/ml, (IQR 319-431 pg/ml) in controls (C), and decreased in the dalteparin-treated group (D) from 336 pg/ml (IQR 281-346 pg/ml) to 303 pg/ml (IQR 274-339 pg/ml). The difference in median percentage change between D and C was statistically significant [-4.0 (D) vs. 4.7 (C); P = 0.005, n = 39]. Serum-induced cellular invasion of MIA-Paca-2 cells in response to patient serum was studied using a Boyden chamber assay in 30 patients (14 WAD and 16 C). The median percentage change between C and D was significant [+54.9 (C) vs. -21.9 (D) P = 0.025, n = 30]. There was a weak correlation between BB-tissue factor reduction and cellular invasion reduction (Spearman) [0.384 (P = 0.037, n = 30)]. APC patients treated with WAD have lower tissue factor antigen levels and attenuated induction of cellular invasion in their blood. These assays may provide useful markers to guide appropriate dalteparin (and other low-molecular weight heparin) dosing schedules to optimize anticancer effects of dalteparin in APC.

Bone Marrow-Derived Mesenchymal Stem Cells Have Innate Procoagulant Activity and Cause Microvascular Obstruction Following Intracoronary Delivery: Amelioration by Antithrombin Therapy

“…Although heparin exerts its anticoagulant activity primarily through allosteric modification of ATIII , there are a number of possible alternative mechanisms by which heparin may improve MSC deliverability. Possible inhibition of TF expression by heparin has been examined in pancreatic cancer patients, in whom heparin caused reduction in the levels of circulating TF . In cancer cell lines, heparin downregulates TF mRNA expression suggesting that culture of MSC with heparin may be considered to reduce potential adverse procoagulant activity ab initio.…”

Tissue factor‐bearing microparticles and inflammation: a potential mechanism for the development of venous thromboembolism in cancer

“…The exact contribution of TF‐MPs to the development of VTE may therefore be highly variable between tumor types, and the association with pancreatic cancer may reflect the high level of TF expression relative to other cancer types and/or the late stage of disease presentation . Somewhat surprisingly, however, whereas ~ 80% of pancreatic cancer patients show increased TF levels, < 30% of these patients are found to develop thrombosis , indicating that elevated TF‐MP levels in isolation do not unequivocally trigger thrombosis, and raising the interesting question of why the clinically recorded thrombosis rate is so much lower. Intriguingly, the occurrence of a thromboembolic event in these patients is often accompanied by the presence of persistent inflammation.…”

Inhibitory effect of non-anticoagulant heparin (S-NACH) on pancreatic cancer cell adhesion and metastasis in human umbilical cord vessel segment and in mouse model

“…The potential anti-metastatic activity of heparin and LMWH that is independent of its antithrombotic effect is supported by data from many in vitro and in vivo studies [10][11][12][13][14][15][16][17][18][19][20][21]. Several clinical studies as well as meta-analyses have found significant improvement in 3-month and 6-month survival in cancer patients who are treated with LMWH compared to cancer patients treated with unfractionated heparin [9,[21][22][23][24][25][26].…”