In Surgical Colon Cancer Patients Extended-Duration Thromboprophylaxis (30 days) with the Highest Dose of Tinzaparin (4,500 IU s.c./q.d.) Normalizes the Postoperative VEGF Levels

Abstract

Background/Purpose: In colon cancer (CC) patients preoperative (pre-op) levels of VEGF-A165 (VEGF) is a strong predictor for disease recurrence. Elevated postoperative (post-op) VEGF levels could have undesirable effects by enhancing tumor growth and metastasis formation. It has been suggested that thromboprophylaxis with a Low Molecular Weight Heparin (LMWH) in surgical cancer patients, further to thromboembolic protection, may exert some anti-neoplastic properties, as well. The aim of our study was to assess the potential impact of the LMWH Tinzaparin (Innohep® - Leo Pharma, Copenhagen, Denmark), given at different doses and for different perioperative (peri-op) periods, upon the post-op variability of serum VEGF levels in surgical CC patients.Methods: A total of 54 consecutive CC patients who underwent a curative resection were randomized in four groups according to their peri-op thromboprophylaxis scheme, which was based on administrating Tinzaparin in different doses and at different periods, as follows: group I: 3,500 IU for 10 days, group II: 3,500 IU for 30 days, group III: 4,500 IU for 10 days and group IV: 4,500 IU for 30 days. Serum VEGF concentrations were evaluated on the pre-op day (Day 0) and on the 10th and 30th post-op days (Day 10 and Day 30, respectively). For statistical analyses the mixed design ANOVA was used. P < 0.05 was considered significant.Results: On Day 0, VEGF didn't differ between groups I, II, III and IV (p>0.05, for every comparison). On Day 10, VEGF was increased in all groups. Between Day 10 and Day 30, VEGF remained stable in groups I (p=0.031) and II (p=1.000) and increased significantly in group III (p=0.005). On the contrary, VEGF decreased significantly in group IV (p<0.001). The most remarkable finding was observed when we compared VEGF between Day 0 and Day 30: while in groups I, II and III, VEGF remained significantly higher compared to Day 0 (p<0.001, p=0.041 and p<0.001, respectively), on the contrary, in group IV (extended-duration with the highest dose of 4,500 IU of tinzaparin) it was comparable to Day 0 (p=1.000).Conclusions: In surgical CC patients only the recommended thromboprophylaxis scheme with the highest prophylactic dose of Tinzaparin (4,500 IU) for extended-duration (30 days) normalizes VEGF levels at the end of the first post-op month by reducing them to the pre-op levels.

The Antineoplastic Effect of Heparin on Colorectal Cancer: A Review of the Literature

“…Four studies investigated the antitumor effects of heparin in a total of 1000 human CRC patients [17][18][19][20]. Of these patients, 947 had biopsy-proven CRC and underwent curative (R0) resection [17,18,20]. The remaining 53 had advanced uncurable CRC malignancy [19].…”

“…Many new derivatives have been synthetically created, some of which have also been explored for their anti-neoplastic properties [7]. Examples of these include low molecular weight heparins (LMWH) such as tinzaparin and deltaparin, synthetic heparin mimetics such as G2.2 and Tet-29, heparin sulfate interacting factors, and others [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Cancer-Associated Thrombosis: Not All Low-Molecular-Weight Heparins Are the Same, Focus on Tinzaparin, A Narrative Review

“…In a prospective cohort study involving 76 patients with colon cancer, a prophylactic tinzaparin dose administrated after surgery normalized Vascular Endothelial Growth Factor (VEGF) values, whose postoperative increase is responsible for enhancing tumor growth and metastases formation due to surgical trauma-induced platelet activation. Despite the small sample size, these findings highlight the pleiotropic properties of tinzaparin, in addition to its antithrombotic ability [ 45 ]. Indeed, although it is still in infancy, its antimetastatic [ 46 ], antiangiogenetic, antidyslipidemic, and anti-inflammatory effects offer a new scenario for non traditional indications [ 47 ].…”

Prevention of Venous Thromboembolism in Colorectal Surgery With Enoxaparin

“…Recent studies recommend higher than usual doses of other LMWH for 30 days after colon cancer surgery. 4 In a study in bariatric surgery using high-dose bemiparin (5000 IU daily) for 30 days, target peak anti-factor Xa levels were achieved in 74% of patients, but there was not an association between anti-factor Xa levels and thrombosis or bleeding events. 5 Another relevant finding of the study by Pannucci and colleagues 3 was an inverse association between total body weight and anti-factor Xa levels.…”

“…However, the mean duration of prophylaxis was 9.1 days, with only 20% receiving prophylaxis after discharge. Recent studies recommend higher than usual doses of other LMWH for 30 days after colon cancer surgery . In a study in bariatric surgery using high-dose bemiparin (5000 IU daily) for 30 days, target peak anti–factor Xa levels were achieved in 74% of patients, but there was not an association between anti–factor Xa levels and thrombosis or bleeding events …”