Chemotherapy is well known to be an independent risk factor for development of TEs in cancer patients [23–26].
In the PROTECHT study , nadroparin was shown to reduce the absolute rate of clinically overt TEs by about 50% in cancer outpatients receiving chemotherapy for metastatic or locally advanced solid tumors in comparison to placebo. Despite the results of the PROTECHT study thromboembolic prophylaxis could not be reasonable for the whole ambulatory cancer patients receiving chemotherapy. To improve the risk-benefit ratio of thromboprophylaxis, clinicians should identify patients at higher risk of TEs, who could have more benefit from anticoagulant administration. The aim of our retrospective analysis has been to identify in the PROTECHT population which subgroups of patients were at higher risk of TEs, stratified according to the type of chemotherapy, who could have an enhanced benefit from TEs prophylaxis.
Our results suggest that cancer outpatients receiving chemotherapy in the absence of thromboprophylaxis (placebo group) had a high incidence of TEs during treatment with gemcitabine, cisplatin or carboplatin. Etoposide and epirubicin showed also a high rate of TEs, but in a small subgroup of patients. Among platinum agents, cisplatin and carboplatin showed a higher risk of TE complications in comparison to oxaliplatin. Combination therapy of gemcitabine with platinum-compounds (cisplatin or carboplatin) further increased the risk of TEs. Additionally, the combination docetaxel with platinum compounds appeared to increase the risk of TEs, although the sample size was too small to make any definitive conclusions.
The thromboembolic risk of cisplatin and gemcitabine has been previously described [14, 15]. In vitro studies have demonstrated that cisplatin activates platelets, mononuclear cells and endothelial cells, which together may result in a prothrombotic state ; however, the exact role of gemcitabine in the activation of the coagulation cascade and haemostasis remains unknown . Published case series, isolated reports and observational studies have suggested that gemcitabine, particularly if combined with cisplatin, increases the risk of TEs [28–30]. Cisplatin is already known as a chemotherapy drug with a higher thromboembolic risk in comparison to oxaliplatin [13, 31]. Recently, Moore and colleagues published a large retrospective analysis which confirmed an unacceptable incidence of TEs in cancer patients receiving cisplatin-based chemotherapy .
At the time of the enrolment in the PROTECHT study, targeted therapies were not commonly used in cancer patients. In fact, only 4.2% (48/1150) of patients were treated with trastuzumab, cetuximab or bevacizumab. Nonetheless, it is worthwhile noting that the CALGB 80303 trial  recently compared bevacizumab plus gemcitabine versus gemcitabine alone in patients with advanced pancreatic cancer. In that trial, the rates of grade 3/4 venous thrombosis was similar in both arms (14% and 15%, respectively) suggesting that the role of gemcitabine in cancer-induced thrombosis could be prevalent. Of note that currently, the efficacy of thromboprophylaxis in patients receiving antiangiogenic agents remains an open questions to be evaluated in well-designed randomized trials.
According to published data , the rate of TEs is more than two-fold higher in chemotherapy naïve patients (5.2%, 11/213) compared to non-naïve patients (2.4%, 4/168). Nadroparin prophylaxis shown a trend in reduction for thromboembolic risk by 52% and 42% in naïve and non-naïve patients, respectively.
The results in the global PROTECHT population have shown that thromboprophylaxis reduced the risk of developing TEs by 48.8% compared to placebo (. Considering the subgroup of patients receiving cisplatin or carboplatin, thromboprophylaxis reduced the risk of thrombotic complications by 68% and 85%, respectively. Thromboprophylaxis reduced risk of thromboembolic complications in patients receiving gemcitabine by 68%, further decreasing to 78% when gemcitabine was combined with platinum-compounds.
Our retrospective analysis has an exploratory purpose. Subgroup samples have not the adequate statistical power to detect clinically meaningful differences as statistically significant and to adjust p-values for the multiplicity across subgroups . For the same reason, a multivariable analysis testing the interaction between subgroups and study treatment cannot be performed because such a statistical model would be clearly over-parameterized. Nevertheless and despite the aforementioned limitations  these data could be useful for stratifying the TE risk in ambulatory cancer population, when planning controlled clinical studies.
In conclusion, our results suggest that patients receiving gemcitabine, cisplatin or carboplatin or their combination are at increased risk of TEs. The clinical benefit of thromboprophylaxis with nadroparin, in outpatients receiving chemotherapy, could be even more evident when gemcitabine was combined with platinum-compounds containing regimens.