The Contribution of Inherited Thrombophilia to Venous Thromboembolism in Cancer Patients

Abstract

Although the relationship between venous thromboembolism (VTE) and cancer has been a subject of study, knowledge of the contribution of thrombophilia to thrombosis in patients with cancer is still very limited. The aim of this article is to collect present knowledge on the contribution of inherited thrombophilia to VTE in cancer patients. We performed a search in Google Scholar and PubMed and selected 21 from 76 returned articles. Then we made a narrative review of the selected articles. We describe 11 studies on the contribution of inherited thrombophilia to VTE in cancer patients in general and 10 on that contribution in specific types of cancer: 1 in colorectal cancer, 4 in breast cancer, 1 in gynecologic cancer and 4 in hematopoietic malignancies. All studies investigate the relation of factor V Leiden (FVL) to VTE, 13 that of the prothrombin G20210A mutation (PTG20210A) and 7 studies also investigate other inherited thrombophilias, such methylenetetrahydrofolate reductase gene mutations, although only 2 investigate the contribution of deficiencies of the natural anticoagulants. Studies are very heterogeneous, in design and sample size and conclusions differ considerably. There is no consensus on the contribution of inherited thrombophilia to VTE in cancer patients except for acute lymphoblastic leukemia in children. Probably, that contribution is not the same for all types of cancer and more studies are needed to bring more knowledge on this subject.

Introduction

The relationship between cancer and venous thromboembolism (VTE) has been an important point of investigation for more than a century since the first report by Trousseau in 1865. ¹ However, research on the role of thrombophilia, and especially inherited thrombophilia, on the development of thrombosis in patients with cancer is relatively scarce with few clinical studies. The main reasons for this, in our opinion, are the low prevalence of thrombophilia and the complexity of the pathogenesis of cancer-related venous thrombosis, with multiple contributing factors, some independent and some interrelated. ² Presently, the decision to institute thromboprophylaxis in patients with cancer relies on the evaluation of thrombotic risk, which is based on risk assessment models (RAMs) that predict thrombotic risk by the presence or absence of specific known risk factors. ³ However, RAMs have a low positive predictive value and none of them includes thrombophilia as a risk factor.

There is no internationally accepted definition of thrombophilia. Individuals with a tendency for thrombosis are defined as having thrombophilia. The term inherited thrombophilia is applied to individuals with genetic defects that predispose them toward thromboembolism. ⁴

The inherited thrombophilias that have been clearly shown to be associated with an increased risk of VTE are (a) deficiencies of the natural inhibitors of coagulation, such as antithrombin, ⁵ protein C ⁶ and protein S, ⁷ due to mutations in the corresponding genes SERPINC1, PROC and PROS and (b) mutations in one of two genes encoding procoagulant factors, namely, F5G1691A /FVR560Q (factor V Leiden [FVL]) ⁸ and F2G20210A (the prothrombin gene mutation), ⁹ that result in a gain of function.

The prevalence of inherited thrombophilia, in the general population, varies from 0.02% for antithrombin deficiency to 5% for FVL but, in VTE cohorts, the prevalence rises to 0.5% for antithrombin deficiency and to 16% for FVL. ¹⁰

The aim of this review is to collect present knowledge on the relation of inherited thrombophilia to VTE in patients with cancer.

Material and Methods

We made a search of literature in Google Scholar and PubMed with the keywords “VTE,” “inherited thrombophilia” and “cancer” and selected only studies investigating the association between inherited thrombophilia and VTE in cancer patients. The search returned 76 articles and we selected 21. Our criteria were to select original studies that evaluated the presence of inherited thrombophilia in patients with cancer and VTE, including retrospective and prospective studies but excluding single case reports. Twenty of the excluded studies were review articles, 29 did not investigate the contribution of inherited thrombophilia to VTE in patients with cancer, 3 were case reports, 2 were letters to the editor and 1 was a study protocol. None of the review articles was a meta-analysis addressing our topic. The list of excluded studies can be found in Appendix.

As the selected studies were substantially different in design and sample size, we decided for a narrative review and divided it into studies including cancer patients in general and studies involving only patients with specific types of malignancies.

Results

Cancer Patients in General

Various studies have been performed to evaluate the role of inherited thrombophilia in patients with cancer in general, most of them being restricted to the contribution of FVL and the prothrombin gene mutation PT20210A (Table 1).

Table 1.

Overall Contribution of Inherited Thrombophilia to VTE in Cancer.

Study	N° patients	FVL	PT G20210A	MTHFR C677T	Deficiencies AT/PC/PS	PAI-1
Haim et al 11	223	No	-	-	-	-
Otterson et al 12	353	No	-	-	-	-
Ozkan et al 13	292	No	No	Yes	-	No
Ramacciotti et al 14	211	No	No	No	-	-
Blom et al 15	5351	Yes	Yes	-	.	.
Kennedy et al 16	202	No?	Yes	-	-	-
EDITH study 17	364	Yes	-	-	-	-
Mandalà et al 18	381	No	No	No	No	-
Pabinger et al 19	982	Yes	-	-	-	-
Gran et al 20	117	Yes	-	-	-	-
Eroglu et al 22	324	Yes	No

Abbreviations: FVL, factor V Leiden; PT G20210A, prothrombin mutation G20210A; MTHFR C677 T, methylenetetrahydrofolate reductase mutation C677 T; AT, antithrombin; PC, protein C; PS, protein S; PAI-1, plasminogen activator inhibitor 1.

A prospective study by Haim et al ¹¹ evaluated the prevalence of Activated Protein C Resistance (APC-R), either inherited or acquired, in 55 cancer patients with deep venous thrombosis (DVT), 58 cancer patients with no history of DVT, 54 patients with DVT and no cancer and 56 healthy controls. They found that the prevalence of FVL mutation in cancer patients with thromboembolism (1/55;2%) was not significantly different from that in cancer patients without thromboembolism (4/58;7%) or that of normal controls (2/56;4%), although it was significantly lower than that of patients with thromboembolism without cancer (18/54; 33%). However, they also reported a significantly higher prevalence of acquired activated protein C resistance in cancer patients with thromboembolism than in the other groups. The authors concluded that the FVL genotype does not play a major role in the hypercoagulable state of cancer despite it being a major risk factor for VTE in patients with no malignant conditions.

Otterson et al ¹² in an earlier retrospective study involving 353 patients from a hematology/oncology clinic, had concluded that routine screening for the FVL mutation in cancer patients without a personal history of VTE would not be helpful in guiding management. The FVL mutation was present in 19 patients (5.4%) but only 2 of them had DVT and none had any other VTE. Indeed, in this study, only 2 of 25 patients with DVT had the FVL mutation and these 2 patients had also a personal or family history of recurrent thrombotic events. Thus, these results also suggest that the FVL mutation does not play a major role in the hypercoagulable state of cancer.

A prospective study, ¹³ by Ozkan et al, designed to investigate the relationship between VTE and FVL, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor-1 (PAI-1) gene mutation, involved 158 patients with cancer who had a thrombotic event and 134 patients with cancer and no thrombotic events. The two groups had similar features concerning age, gender, tumor site and performance status. The results only showed a statistically significant difference between the two groups for MTHFR mutation C677T (P = 0.040). However, in these patients, homocysteine levels were not measured and the authors concluded that they did not have enough evidence to recommend genetic analysis.

A prospective study, ¹⁴ conducted at two oncology clinics in S. Paulo, Brazil, evaluated the prevalence of four gene variations (FVL, prothrombin G20210A, factor XIII Val134Leu and MTHFR C677T) in cancer patients with and without VTE. This study enrolled 211 patients who were evaluated for symptoms of DVT or pulmonary embolism (PE) with all symptomatic patients being investigated to confirm or exclude the presence of VTE. The results showed that the prevalence of those four polymorphisms did not significantly differ between the two groups of patients. The authors concluded for a lack of association between these four polymorphisms and the risk of VTE in cancer patients.

A large population-based study ¹⁵ by Blom et al, the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis, involving 3220 patients with a first DVT or PE and 2131 controls, found that patients with cancer carrying the FVL mutation had a two-fold increased risk of VTE compared to noncarriers with cancer. Furthermore, the overall risk of VTE for carriers of the PT20210A was 2.5-fold higher compared to noncarriers.

Kennedy et al ¹⁶ genotyped 202 cancer patients for FVL and PTG20210A, 101 with VTE and 101 without VTE and found that 5 cases and 3 controls were heterozygous for FVL, while 5 cases and no controls were heterozygous for the PT20210A. Therefore, the PT20210A appears to be a risk factor for VTE in patients with cancer, but FVL is only weakly associated with VTE in these patients.

The EDITH study ¹⁷ was a hospital-based case-control study performed at the University Hospital of Brest between 2000 and 2011, involving 182 patients with cancer and VTE and 182 controls selected for each case, matched by age, gender and cancer site. All patients were genotyped for FVL which was detected in 21 (11.5%) cases and 4 (2.2%) controls, giving an independent sevenfold increased risk of VTE for cancer patients with this mutation.

A prospective observational study ¹⁸ involving patients with gastrointestinal or breast cancer found that FV Leiden and PT mutation were not associated with the risk of VTE. This study involved 381 patients, 199 with gastrointestinal cancer and 182 with breast cancer, who were followed up for symptomatic VTE during adjuvant chemotherapy. Patients were screened for protein C, protein S, antithrombin, homocysteine, FVL and prothrombin G20210A mutation. Acquired risk factors for VTE such as age, tumor type and body mass index were also evaluated. In multivariate analysis, the only variables that were independently associated with the risk of VTE during adjuvant chemotherapy were a platelet count ≥300 × 10⁹/L and a previous episode of VTE. Neither FVL nor the prothrombin G20210A mutation were associated with the risk of VTE.

Results from the Vienna Cancer and Thrombosis Study, a large observational cohort study that included 982 patients with various types of neoplasms, such as carcinomas (breast, lung, stomach, colorectal, pancreas, kidney and prostate), sarcomas, lymphomas and myelomas, led to a different conclusion regarding FVL. ¹⁹ Patients were followed up for a period of 2 years, until the occurrence of VTE, death or withdrawal of consent. Venous blood samples were drawn as they entered the study for, among other laboratory tests, FVL mutation identification by polymerase chain reaction (PCR). VTE occurred in 10 of 72 patients with FVL and 69 of the 910 patients without the mutation. Using a Kaplan–Meier estimate of the cumulative incidence of VTE, after 1 year, the probability of developing VTE was 15% for patients with the FVL mutation and 7.3% for those without. These data reveal that patients with cancer and FVL have twice the risk of developing VTE, compared with patients with cancer but no FVL.

Another large study, ²⁰ by Gran et al, led to a similar conclusion. This study recruited participants from two surveys of the Tromsø Study to assess the joint effect of active cancer and two variants of the factor 5 gene (rs6025 and rs4524) on the risk of VTE. The rs6025 encodes the FVL mutation while the rs4524 encodes the K858R variant. The Tromsø study ²¹ was a single-center population-based cohort study that began in 1974, in Norway, as an attempt to help combat the high mortality rate of cardiovascular disease. Throughout 37 years this study included a total of 29,128 patients aged 25–97 years and has also been directed toward other chronic conditions such as atrial fibrillation, VTE, diabetes mellitus, osteoporosis and fractures.

In the study of Gran et al, 609 patients had VTE, 117 of them related to cancer. They classified VTE events as related to active cancer when they occurred between 6 months prior to the diagnosis of cancer and 2 years following that diagnosis. Results revealed that both f5 gene variants were associated with a higher risk of VTE and there was a synergistic effect of active cancer and f5 rs4524 and FVL variants on the risk of VTE. In the case of FVL heterozygotes, the hazard ratio for VTE in patients with no cancer increases to 2.1, in patients with previous cancer to 3.4 and in patients with active cancer to 16.7.

A study by Eroglu et al, ²² aiming at evaluating the prevalence of FVL and PT G20210A in cancer patients with and without VTE, as well as in patients with no cancer, suggests that cancer patients with VTE should be evaluated for FVL, although PT G20210A is not a contributing factor to the development of VTE during cancer therapy. In this study, the FVL mutation was present in 30.2% of patients with cancer and VTE but only in 3.7% of patients with cancer but no VTE, a difference found to be statistically significant (P < 0.001). Concerning patients with no cancer, the mutation was present in 18% of patients with VTE and 8% of those without VTE, a difference also statistically significant (P < 0.001). However, no statistically significant difference was observed in the prevalence of PT G20210A between the above-mentioned groups of patients.

Colorectal Cancer

Falvella et al ²³ investigated the relation of single-nucleotide polymorphisms in factor V (FVL G1691A), prothrombin (PT G20210A), plasminogen activator inhibitor-1 (PAI-1 5G/4G) and methylenetetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C) to thromboembolic risk in metastatic colorectal cancer patients (Table 2). This was a prospective observational study involving 179 patients treated with bevacizumab-based first-line chemotherapy, 52 patients having had a thromboembolic event and 127 without thromboembolism. Of the 179 patients, 4 were carriers (heterozygous) of the FVL G1691A and all developed thromboembolism, yielding an OR (odds ratio) estimate too large to be reported as it tended to infinity. Five of the seven patients heterozygous for PT G20210A also developed thromboembolism. None of the 179 patients was homozygous for either the FVL G1691A or the PT G20210A mutation. Concerning the MTHFR C677T mutation, the incidence of thromboembolism was 23.6%, 24.2% and 55.2% for genotypes CC, CT and TT, respectively. In the case of the MTHFR A1298C, the incidence of thromboembolism was 33.3%, 24.4% and 30.8% for genotypes AA, AC and CC, respectively. Finally, for the genotypes of PAI-1 4G/5G, the incidence was 15%, 30.6% and 39% for genotypes 5G/5G, 5G/4G and 4G/4G, respectively. These results show that thromboembolism was significantly more frequent in patients carrying the FVL G1691A, PT G20210A, MTHFR C677T or PAI-1 5G/4G mutation. No significant association was found for MTHFR A1298C or double heterozygosity MTHFR A1298C/C677T with thromboembolism.

Table 2.

Contribution of Inherited Thrombophilia to VTE in Specific Cancers.

Study	N° patients	FVL	PT G20210A	MTHFR C677T	MTHFR A1298C	Deficiencies of AT, PC or PS	PAI-1 (5G/4G)
Colorectal cancer
Flavella et al 23	179	Yes	Yes	Yes	No	-	Yes
Breast cancer
Garber et al 24	412	Yes	-	-	-	-	-
Abramson et al 25	371	No	No	-	-	-	-
Kovac et al 27	150	Yes	No	-	-	-	-
Pruner et al 28	316	No	No	No	-	-	No
Gynecologic cancer
Ravin et al 29	75	No	-	-	-	-	-
Acute lymphoblastic leukaemia
Barzilai-Birenboim et al 31	584	Yes		-	-	-	-
Nowak-Gött 32	301	Yes					-
Sivasloglu et al 33	64	Yes	No	No		-	-
Acute promyelocytic leukaemia
Rees et al 35	48	No	-	No	-	-	-

Abbreviations: FVL, factor V Leiden; PT G20210A, prothrombin mutation G20210A; MTHFR C677 T, methylenetetrahydrofolate reductase mutation C677 T; MTHFR A1298C, methylenetetrahydrofolate reductase mutation A1298C; AT, antithrombin; PC, protein C; PS, protein S; PAI-1, plasminogen activator inhibitor 1.

Breast Cancer

A study ²⁴ including 412 women who took tamoxifen as adjuvant treatment for stage I, II or IIIA breast cancer, 141 cases and 271 controls, revealed 18.5% of cases had the FVL mutation while only 4.8% of controls had this mutation, a difference that was statistically significant (unadjusted OR = 4.66, 95% CI = 2.12–10.14; P < 0.001). This case–control study demonstrated that the likelihood of having had a VTE while taking adjuvant tamoxifen was significantly higher in women who carried the FVL mutation, and that women taking adjuvant tamoxifen for early-stage breast cancer who experienced a VTE were nearly five times more likely to carry a FVL mutation than those who took the same drug but did not develop VTE (Table 2).

A case-cohort study from the NSABP Breast Cancer Prevention Trial (P-1) ²⁵ that compared tamoxifen with a placebo in women with increased breast cancer risk revealed that the risk of VTE, in these women, was not associated with the FVL or the prothrombin G20210A mutation. In this study, FVL or PT G20210A was present in 9/76 cases and 20/295 controls. However, women in this study did not have cancer but a high risk of breast cancer. ²⁶

A prospective, single-center, case–control study, ²⁷ from Serbia, showed that FVL mutation and high levels of factor VIII are associated with an increased risk of VTE in women with breast cancer while on adjuvant tamoxifen. The study included 150 women with breast cancer on tamoxifen, 50 who developed VTE and 100 without VTE as a control group. FVL was present in 28% of those with VTE but only in 10% in the control group, a difference considered statistically significant, whereas PT G20210A was present in 8% and 3%, respectively, a difference not statistically significant (Table 2). Factor VIII activity greater than 1.5 UI/ml was also statistically significantly more frequent in the VTE group.

Another study ²⁸ from Serbia compared the frequencies of FVL, PT G20210A, MTHFR C677T and PAI-1 4G/5G, in 316 patients, 97 with breast cancer and VTE, 99 with breast cancer but no VTE and a healthy control group of 120 patients. Concerning patients with breast cancer, FVL was present in 14 patients with VTE (12 heterozygous, 2 homozygous) and 7 in the group with no VTE (6 heterozygous and 1 homozygous). Although the first group had twice the prevalence of FVL compared with the second, the difference was not considered statistically significant. Regarding the PT G20210A, three heterozygotes were found in each of the two groups while no homozygote carriers were detected. In what concerns the MTHFR C677T and PAI-1 4G/5G variants, the distribution of genotypes was similar in all groups. The study concludes for no association between the gene variants studied and VTE risk in Serbian breast cancer patients.

Gynecologic Cancer

Although there are several studies on VTE in gynecologic cancer patients, we found only one study addressing the relation of inherited thrombophilia to VTE in these patients (Table 2).

Ravin et al ²⁹ conducted a case–control study in gynecologic cancer patients to evaluate the odds ratio for having the FVL mutation for patients with and without VTE. The study enrolled 75 patients, 40 cases and 35 controls. The FVL mutation was found in 5% of cases and 15% of controls, yielding an odds ratio for FVL mutation in patients with a VTE of 0.3. Although the prevalence of FVL is higher in controls than in cases, the difference was not found to be statistically significant. Thus, this study does not support the hypothesis that FVL contributes to VTE in patients with gynecologic cancer.

Hematopoietic Malignancies

There are many studies on the incidence of VTE in hemopoietic malignancies but only a few evaluate the contribution of thrombophilia to VTE (Table 2).

In acute lymphoblastic leukemia (ALL) in children, thrombosis is a serious complication with prevalence ranging from 1% to 37%, ³⁰ most events occurring during the induction phase of therapy. As in other malignancies, thrombotic events are attributable to factors related either to patient, disease, or treatment. In ALL, the main treatment-related thrombotic factor is the use of asparaginase. A large study ³¹ involving 1191 children with ALL, aged 1–19 years, that compared the occurrence of VTE with two treatment protocols using different asparaginase formulas found that children with thrombophilia had significantly more VTEs than those without thrombophilia. However, only 584 children from this study were evaluated for thrombophilia, which included screening for FVL and PT20210A. An earlier prospective study ³² involving 301 children with ALL evaluated for the presence of MTHFR C677T, PT G20210A, FVL and deficiencies of protein C, protein S and antithrombin, had arrived at similar conclusions, as VTE occurred in 46.5% of leukemic children with a prothrombotic risk factor diagnosed and in 2.2% of those with no identified prothrombotic defect (P < 0.001). Children with at least one prothrombotic risk factor treated with a combination of asparaginase and steroids were at the highest risk. Another study ³³ involving 82 children diagnosed with ALL, of whom 64 were investigated for hereditary thrombotic risk factors, revealed that thrombosis occurred in 8/19 (42.1%) patients who had a thrombophilic risk factor and in 2/45 (4.4%) patients who had no thrombophilic risk factor. This study concludes that the thrombotic risk is significantly higher for FVL but not for PT20210A or the MTHFR mutations.

Acute promyelocytic leukemia (APL) is known to be associated with both hemorrhage and thrombosis, the latter occurring mainly in patients treated with all-trans-retinoic acid (ATRA). ³⁴ A study ³⁵ investigating 48 patients with APL treated with ATRA concluded that neither FVL nor MTHFR C677T were predictable of thrombosis. Indeed, 2 patients were heterozygotes for FVL, 17 were heterozygous for MTHFR C677T and 10 were homozygous for MTHFR C677T and only one, that was heterozygous for MTHFR C677T, had thrombosis. However, three patients that were wild type for both factor V and MTHFR had thromboses.

Discussion

The immediate conclusion is that the results from these studies are contradictory, and no consensual conclusions can be drawn. Studies are also very heterogeneous both in type, design and sample size. Some address specifically the contribution of thrombophilia to VTE in cancer patients, while others investigated not only thrombophilia but also other risk factors. Some studies are about FVL only, some address other forms of inherited thrombophilia, while the study of Mandala investigates the most important six inherited thrombophilias.

Otterson et al found a threefold increased risk of VTE in patients carrying the FVL mutation but, nevertheless, concluded that this genetic mutation does not play a major role in the hypercoagulable state of cancer, a conclusion based on the finding that only 8% of patients with VTE were carriers of the FVL mutation. This was, however, a retrospective cohort study of unselected patients.

The study of Haim et al, a prospective case-control study, leads to an identical conclusion but, although they state that FVL is not a major risk factor for thrombosis in cancer patients, they unexpectedly found acquired activated protein C resistance to be common in these patients. This later finding was not confirmed in other similar studies.

The studies of Ozkan et al and Ramacciotti et al were also prospective case-control studies but, besides FVL, they investigated other thrombophilias and both arrived at similar conclusions relative to FVL and PT20210A, which is that there is no relation to VTE. Ramacciotti addressed MTHFR C677T and FXIII Val34Leu, and concluded that their data do not point to an association between these mutations and the risk of VTE in cancer patients. Although Ozkan found an association between MTHFR C677T and VTE in cancer patients, no conclusion can be drawn from this finding as homocysteine levels were not measured.

The study of Mandalà et al is the only one that investigates all the six major thrombophilias and reveals that none of them was associated with the risk of VTE. However, this study included only patients with gastrointestinal or breast cancer on adjuvant chemotherapy so this conclusion cannot, in our opinion, be regarded as reflecting the case of cancer patients in general.

Pabinger et al, in a large study including patients from the Vienna CATS, not only concluded that there is an association of FVL with VTE in cancer patients but also considered that FVL could be used for individual risk assignment. Gran et al concluded that the combination of FVL and cancer synergistically increased the risk of VTE in a prospective study with patients recruited from the general population. The EDITH study, a larger case-control prospective involving in-hospital cancer patients, concluded that there is an independent significant risk of VTE associated with FVL. Eroglu et al also arrived at the same conclusion and suggested FVL testing in cancer patients. However, they found PT 20210A not to be a contributing factor to VTE in cancer patients.

The only study involving specifically patients with colorectal cancer found a significant association of VTE with FVL, PT20210A, MTHFR C677T and PAI-1 4G, but no significant association with MTHFR A1298C. Concerning breast cancer, two studies concluded that FVL was associated with an increased risk of VTE, although two found no association; all four studies found no significant association between PT20210A and VTE. The only study addressing patients with gynecologic cancer suggests that FVL does not increase the risk of VTE.

The case of hematopoietic malignancies is a little different, however, at least in the case of ALL in children. All three studies concluded with an association between FVL and VTE, and two of them arrived at the same conclusion for PT20210A. The association is so strong that some authors even advocate screening those children for FVL. Nowak-Gött also concluded there was a significant association of various thrombophilias with VTE in children with ALL.

One study addressing APL found no significant contribution of FVL or PT 20210A to VTE.

Conclusion

Apart from ALL in children, there is no consensus on the contribution of inherited thrombophilia to VTE in patients with malignant conditions. Studies arrive at different conclusions but, as they are few and very heterogeneous, comparing them is no easy task. This result is not unexpected, considering the low prevalence of inherited thrombophilias, the differences in prevalence among different populations and ethnic groups, and the complexity of the pathogenesis of VTE in cancer. However, there is, in our opinion, an important group of studies pointing to the contribution of FVL to VTE in cancer patients.

In summary, we are left with two hypotheses, either the cancer on its own is a strong risk factor for VTE making inherited thrombophilia a negligible risk factor, or inherited thrombophilia, especially FVL, has an important role in the development of VTE in cancer patients. In the latter scenario, thrombophilia should be considered an important item in the evaluation of the thrombotic risk of patients with cancer, and probably, better RAMs could be developed. A third and alternative hypothesis is that the relative contribution of inherited thrombophilia to VTE is not equal in all neoplasms nor in different stages of each type of malignancy.

Until more studies bring more knowledge on this subject, screening for thrombophilia in cancer patients cannot be recommended on a routine basis. However, in our opinion, children diagnosed with ALL should be screened for thrombophilia and results should be considered in evaluating the risk of VTE. Further studies, particularly on the role of FVL in the development of VTE in cancer patients, will probably give us better knowledge and contribute to better prevention.

Appendix. Excluded studies (articles returned in search but excluded from our study; some may be cited in our manuscript but were not considered to withdraw the conclusions).

Authors	Number of patients	Type of study	Comments	Reference
Gupta et al	-	Review	Review article addresses only acquired thrombophilia and hypercoagulability of cancer	Gupta PK, Charan VD, Kumar H. Cancer related thrombophilia: clinical importance and management strategies. J Assoc Physicians India. 2005;53:877–882. PMID: 16459532.
Paulsen et al	684	Cohort study	Addressed exclusively fibrinogen gamma gene rs2066865	Paulsen B, Skille H, Smith EN, Hveem K, Gabrielsen ME, Brækkan SK, Rosendaal FR, Frazer KA, Gran OV, Hansen JB. Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism. Haematologica. 2020;105(7):1963–1968. doi: 10.3324/haematol.2019.224279. Epub 2019 Oct 3. PMID: 31582554; PMCID: PMC7327659.
Jacobsen		Cohort profile	Description of Tromsø study	Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Njølstad I. Cohort profile: the Tromso Study. Int J Epidemiol. 2012;41(4):961–967. doi: 10.1093/ije/dyr049. Epub 2011 Mar 21. PMID: 21422063; PMCID: PMC3429870.
Horowitz et al	-	Review		Horowitz N, Brenner B. Thrombophilia and cancer. Pathophysiol Haemost Thromb. 2008;36(3–4):131–136. doi: 10.1159/000175151. Epub 2009 Jan 27. PMID: 19176986.
Amanat et al	91	Cross-sectional	Estimation of plasma levels of anticoagulant proteins in patients with solid tumors; relation to VTE was not investigated	Samina T.Amanat, Masooma Raza, Huma Abdul Shakoor, Waqar Mehmood (2014) “Levels of Natural Anticoagulants Protein C, Protein S and Antithrombin III in Patients with Solid Malignancies.” Journal of Rawalpindi Medical College, 18(1). Available at: https://www.journalrmc.com/index.php/JRMC/article/view/369.
Dalen	-	Review		Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med. 2008;121(6):458–463. doi: 10.1016/j.amjmed.2007.10.042. PMID: 18501222.
Galioto et al	-	Review		Galioto NJ, Danley DL, Van Maanen RJ. Recurrent venous thromboembolism. Am Fam Physician. 2011 Feb 1;83(3):293–300. PMID: 21302870.
Micco et al	-	Case report	Thrombophilia and malignancy	Di Micco, Pierpaolo and Viggiano, Giuseppe and Diadema, Maria and Niglio, Alferio. (2009). Venous Thromboembolism Involving Internal Jugular, Subclavian, Axillar and Brachial Veins in a Patient with Multiple Thrombophilic Defects and Malignancy. The Open Atherosclerosis & Thrombosis Journal. 2. 10.2174/1876506800902010001. Cancer and its related therapies are acquired thrombophilic risk factors. Patients with a malignancy can suffer a thrombotic complication such as deep venous thrombosis (DVT) in the lower extremities with a possible following pulmonary embolism. Recently, an increased association between upper extremity DVT and malignancy has been observed and several risk factors were identified. However, few data are available for the association between upper extremity DVT and inherited thrombophilia in oncological patients. Here we report a case of upper extremity DVT complicated by fatal pulmonary embolism in an oncological patient receiving chemotherapy and carrying 2 heterozygous genetic thrombo-philic risk factors.
Oger et al	1808	Case-control	Investigates inherited thrombophilia in patients with VTE; relation to VTE in cancer was not investigated	Oger, E., Lacut, K., Le Gal, G., Couturaud, F., Abalain, J. H., Mercier, B., … and EDITH (Etude des Déterminants/Interaction de la THrombose veineuse) Collaborative Study Group. (2007). Interrelation of hyperhomocysteinemia and inherited risk factors for venous thromboembolism. Results from the EDI TH. study: A hospital-based case–control study. Thrombosis research, 120(2), 207–214.
Andrea	237	Cross-sectional	Investigates inherited thrombophilia and cancer susceptibility; relation to VTE was not investigated	D’Andrea E, Lagerberg T, De Vito C, Pitini E, Marzuillo C, Massimi A, Vacchio MR, Grammatico P, Villari P. Patient experience and utility of genetic information: a cross-sectional study among patients tested for cancer susceptibility and thrombophilia. Eur J Hum Genet. 2018;26(4):518–526. doi: 10.1038/s41431–017-0083-1. Epub 2018 Jan 26. Erratum in: Eur J Hum Genet. 2018;26(9):1398. PMID: 29374276; PMCID: PMC5891505.
Matej	-	Case report	Inherited thrombophilia in a patient with colorectal carcinoma	Hrnčár M, Breznický J, Chudej J, Sokol J, Staško J. Inherited thrombophilia in a patient with colorectal carcinoma. Prz Gastroenterol. 2020;15(2):175–177. doi: 10.5114/pg.2019.86746. Epub 2019 Jul 17. PMID: 32550952; PMCID: PMC7294978.
Kozak	3590	Retrospective case-control	relation to VTE was not investigated	Kozak PM, Xu M, Farber-Eger E, Gailani D, Wells QS, Beckman JA. Discretionary Thrombophilia Test Acquisition and Outcomes in Patients With Venous Thromboembolism in a Real-World Clinical Setting. J Am Heart Assoc. 2019;8(22):e013395. doi: 10.1161/JAHA.119.013395. Epub 2019 Nov 7. PMID: 31696751; PMCID: PMC6915257.
Fijnheer	277	Prospective	Investigates FVL in CVC thrombosis; not all patients had cancer	Fijnheer R, Paijmans B, Verdonck LF, Nieuwenhuis HK, Roest M, Dekker AW. Factor V Leiden in central venous catheter-associated thrombosis. Br J Haematol. 2002;118(1):267–270. doi: 10.1046/j.1365-2141.2002.03591.x. PMID: 12100159.
Pihusch	175	Case-control	Determined the prevalence of FVL, PTG20210A and MTHFR C677 T in patients with GI carcinoma; relation to VTE was not investigated as both groups, case and control had thrombosis	Pihusch R, Danzl G, Scholz M, Harich D, Pihusch M, Lohse P, Hiller E. Impact of thrombophilic gene mutations on thrombosis risk in patients with gastrointestinal carcinoma. Cancer. 2002;94(12):3120–3126. doi: 10.1002/cncr.10590. PMID: 12115343.
Decousus		Review	Thrombophilia in cancer	Decousus H, Moulin N, Quenet S, Bost V, Rivron-Guillot K, Laporte S, Mismetti P. Thrombophilia and risk of venous thrombosis in patients with cancer. Thromb Res. 2007;120 Suppl 2:S51–S61. doi: 10.1016/S0049-3848(07)70130-5. Erratum in: Thromb Res. 2008;123(1):187–190. PMID: 18023713.
Abitia-Castro et al		Review		Abitia-Castro, J. C., Agredano-Pérez, S., Mariscal-Ramírez, I., Ronquillo-Carreón, C., Villa-Grajeda, G., Nava-Zavala, A. H., and Rubio-Jurado, B. (2015). Estado protrombótico en pacientes con cáncer. El Residente, 10(3), 166–172.
Vairaktaris et al	204	Case-control	Investigates relation of thrombophilia to risk of oral cancer; relation to VTE was not investigated	Vairaktaris E, Yapijakis C, Wiltfang J, Ries J, Vylliotis A, Derka S, Vasiliou S, Neukam FW. Are factor V and prothrombin mutations associated with increased risk of oral cancer? Anticancer Res. 2005;25(3c):2561–2565. PMID: 16080493.
Pfrepper		Review		Pfrepper C. Paraneoplastic Thromboembolism and Thrombophilia: Significance in Visceral Medicine. Visc Med. 2020;36(4):280–287. doi: 10.1159/000509150. Epub 2020 Jul 15. PMID: 33005653; PMCID: PMC7506244.
Boersma		Review		Boersma RS, Hamulyak K, Cate HT, Schouten HC. Congenital thrombophilia and central venous catheter-related thrombosis in patients with cancer. Clin Appl Thromb Hemost. 2010;16(6):643–649. doi: 10.1177/1076029610371471. Epub 2010 Jun 7. PMID: 20530049.
Tormene et al	52	Case-control	Evaluates relation of thrombophilia to risk of gynecologic cancer and prognosis; relation to VTE was not investigated	Tormene D, Beltramello P, Perlati M, Brandolin B, Barbar S, De Toffoli G, Simioni P. The risk of cancer progression in women with gynecological malignancies and thrombophilic polymorphisms: a pilot case-control study. Clin Appl Thromb Hemost. 2009;15(5):535–539. doi: 10.1177/1076029608317941. Epub 2008 Jun 29. PMID: 18591179.
Simkovic	346	Retrospective cross-sectional	Relation to VTE was not investigated	Šimkovič M, Vodárek P, Motyčková M, Belada D, Vrbacký F, Žák P, Smolej L. Venous thromboembolism in patients with chronic lymphocytic leukemia. Thromb Res. 2015;136(6):1082–1086. doi: 10.1016/j.thromres.2015.05.010. Epub 2015 May 20. PMID: 26467608.
Franchini		Review		Franchini M. Thromboembolic risk in hematological malignancies. Clin Chem Lab Med. 2015;53(8):1139–47. doi: 10.1515/cclm-2014–1010. PMID: 25503466.
Torun	82	prospective	relation to VTE was not investigated	Torun YA, Patiroglu T, Ozdemir MA, Ozkul Y, Ekici A, Karakukcu M. Inherited prothrombotic risk factors in Turkish children with acute lymphoblastic leukemia: significance of concomitant genetic mutation. Clin Appl Thromb Hemost. 2012;18(2):218–221. doi: 10.1177/1076029611412366. Epub 2011 Aug 25. PMID: 21873357.
Sifontes			Only children	Sifontes MT, Nuss R, Hunger SP, Wilimas J, Jacobson LJ, Manco-Johnson MJ. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol. 1997;96(3):484–489. doi: 10.1046/j.1365-2141.1997.d01-2046.x. PMID: 9054652.
Athale		Not a study	Study protocol	Athale, U. H., Laverdiere, C., Nayiager, T., Delva, Y. L., Foster, G., Thabane, L., and Chan, A. K. (2017). Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study. BMC Cancer, 17, 1–14.
Sciacca	250	Case-control	Relation to VTE was not investigated.	Sciacca FL, Ciusani E, Silvani A, Corsini E, Frigerio S, Pogliani S, Parati E, Croci D, Boiardi A, Salmaggi A. Genetic and plasma markers of venous thromboembolism in patients with high grade glioma. Clin Cancer Res. 2004;10(4):1312–1317. doi: 10.1158/1078-0432.ccr-03-0198. PMID: 14977830.
Makoto et al	33	Cross-sectional	Investigates frequency of thrombophilia in patients with visceral VTE. Does not distinguish cancer patients.	Makoto I, Usui M, Wada H, Matsumoto T, Ohishi K, Shindo A, Yamashita Y, Nakatani K, Tamaki S, Tomimoto H, Isaji S. Congenital Thrombophilia in Patients With Superior Mesenteric Venous Thrombosis or Portal Vein Thrombosis. Clin Appl Thromb Hemost. 2018;24(7):1117–1121. doi: 10.1177/1076029618774146. Epub 2018 May 10. PMID: 29747524; PMCID: PMC6714751.
O’Malley et al		Case report		O’Malley TJ, Sooppan R, Yeo CJ. Perioperative Management of Factor V Leiden and Pancreatic Adenocarcinoma. J Pancreat Cancer. 2017;3(1):53–57. doi: 10.1089/pancan.2017.0010. PMID: 30631843; PMCID: PMC5933490.
Campello et al		Review		Campello E, Ilich A, Simioni P, Key NS. The relationship between pancreatic cancer and hypercoagulability: a comprehensive review on epidemiological and biological issues. Br J Cancer. 2019;121(5):359–371. doi: 10.1038/s41416-019-0510-x. Epub 2019 Jul 22. PMID: 31327867; PMCID: PMC6738049.
Cumbo et al	93	Prospective descriptive	Prothrombin gene analyzed in patients with colorectal cancer. Relation to VTE was not investigated.	Cumbo M, Tomic B, Dunjic S, Jovanovic T, Gvozdenov M, Pruner I, Aralica G, Kapitanovic S, Cacev T, Djordjevic V. Prothrombin 3′ end Gene Variants in Patients With Sporadic Colon Adenocarcinoma. Anticancer Res. 2019;39(11):6067–6071. doi: 10.21873/anticanres.13814. PMID: 31704834.
Emoto et al		Review		Emoto S, Nozawa H, Kawai K, Hata K, Tanaka T, Shuno Y, Nishikawa T, Sasaki K, Kaneko M, Hiyoshi M, Murono K, Ishihara S. Venous thromboembolism in colorectal surgery: Incidence, risk factors, and prophylaxis. Asian J Surg. 2019;42(9):863–873. doi: 10.1016/j.asjsur.2018.12.013. Epub 2019 Jan 23. PMID: 30683604.
Flemming et al		Guideline		Fleming F, Gaertner W, Ternent CA, Finlayson E, Herzig D, Paquette IM, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guideline for the Prevention of Venous Thromboembolic Disease in Colorectal Surgery. Dis Colon Rectum. 2018;61(1):14–20. doi: 10.1097/DCR.0000000000000982. PMID: 29219916.
Battistelli et al	193	Case-control	Investigates frequency of homocysteine levels and MTHFR gene mutations in patients with colorectal cancer and healthy controls. Relation to VTE was not investigated.	Battistelli S, Vittoria A, Stefanoni M, Bing C, Roviello F. Total plasma homocysteine and methylenetetrahydrofolate reductase C677T polymorphism in patients with colorectal carcinoma. World J Gastroenterol. 2006;12(38):6128–6132. doi: 10.3748/wjg.v12.i38.6128. PMID: 17036383; PMCID: PMC4088105.
Ely		Letter to the editor		Ely SF. Potential risk of a common hereditary thrombophilia and adjuvant chemotherapy for low-stage breast cancer. J Clin Oncol. 2005;23(18):4242–4243. doi: 10.1200/JCO.2004.00.4226. PMID: 15961781.
Ferrigno et al	343	Descriptive	Investigated abnormalities of coagulation in patients with lung cancer. Relation to VTE was not investigated.	Ferrigno D, Buccheri G, Ricca I. Prognostic significance of blood coagulation tests in lung cancer. Eur Respir J. 2001;17(4):667–673. doi: 10.1183/09031936.01.17406670. PMID: 11401062.
Kadlec et al	950	Descriptive	Investigated abnormalities of coagulation in patients with lung cancer. Relation of inherited thrombophilia to VTE was not investigated.	Kadlec B, Skrickova J, Merta Z, Dusek L, Jarkovsky J. The incidence and predictors of thromboembolic events in patients with lung cancer. ScientificWorldJournal. 2014;2014:125706. doi: 10.1155/2014/125706. PMID: 24574864; PMCID: PMC3918375.
Walker et al	10598	Descriptive retrospective	Investigated risk of VTE in patients with lung cancer. Relation of inherited thrombophilia to VTE was not investigated.	Walker AJ, Baldwin DR, Card TR, Powell HA, Hubbard RB, Grainge MJ. Risk of venous thromboembolism in people with lung cancer: a cohort study using linked UK healthcare data. Br J Cancer. 2016;115(1):115–121. doi: 10.1038/bjc.2016.143. Epub 2016 Jun 2. Erratum in: Br J Cancer. 2017 Mar 14;116(6):e1. PMID: 27253177; PMCID: PMC4931366.
Vitale et al		Review		Vitale C, D’Amato M, Calabrò P, Stanziola AA, Mormile M, Molino A. Venous thromboembolism and lung cancer: a review. Multidiscip Respir Med. 2015;10(1):28. doi: 10.1186/s40248–015-0021-4. PMID: 26380084; PMCID: PMC4570636.
Marinho et al		Review		Marinho FC, Takagaki TY. Hypercoagulability and lung cancer. J Bras Pneumol. 2008;34(5):312–322. English, Portuguese. doi: 10.1590/s1806-37132008000500011. PMID: 18545828.
Blanco, Lazzari		Letter to the editor
Caruso et al*	1752	Meta-analysis	Investigates thrombotic complications in children with ALL and includes studies already included in our analysis. Investigates not only thrombophilia but other contributing factors. Relation to VTE not investigated	Caruso V, Iacoviello L, Di Castelnuovo A, Storti S, Mariani G, de Gaetano G, Donati MB. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. 2006;108(7):2216–2222. doi: 10.1182/blood-2006-04-015511. Epub 2006 Jun 27. PMID: 16804111.
Chang et al*	127	Retrospective, descriptive	Investigates incidence of thrombosis in patients with acute promyelocytic leukemia. Relation of inherited thrombophilia to VTE was not investigated.	Chang H, Kuo MC, Shih LY, Wu JH, Lin TL, Dunn P, Tang TC, Hung YS, Wang PN. Acute promyelocytic leukemia-associated thrombosis. Acta Haematol. 2013;130(1):1–6. doi: 10.1159/000345833. Epub 2013 Jan 23. PMID: 23343825.
Akin et al		Review		Akın, D. F., and Akar, N. (2013). Effect of Factor V Leiden on thrombosis in childhood leukemia. Open Journal of Blood Diseases, 3(3), 100–103.
Battistelli et al	251	Case-control	Compares the prevalence of FVL and PT G20210A in patients with gastric cancer and controls. Relation of inherited thrombophilia to VTE was not investigated.	Battistelli S, Stefanoni M, Genovese A, Vittoria A, Cappelli R, Roviello F. Prevalence of factor V Leiden and prothrombin G20210A in patients with gastric cancer. World J Gastroenterol. 2006;12(26):4179–4180. doi: 10.3748/wjg.v12.i26.4179. PMID: 16830369; PMCID: PMC4087368.
Clouston	-	Thesis	Relation of inherited thrombophilia to VTE was not investigated.	Clouston, H. W. (2016). Thrombosis in Colorectal Cancer. The University of Manchester (United Kingdom).
Fisher et al	13175	Retrospective	Relation of inherited thrombophilia to VTE was not investigated.	Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, Bevers TB, Kavanah MT, Atkins JN, Margolese RG, Runowicz CD, James JM, Ford LG, Wolmark N. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97(22):1652–1662. doi: 10.1093/jnci/dji372. PMID: 16288118.
El Simpson et al		Review and meta-analysis	Relation of inherited thrombophilia to VTE was not investigated.	Simpson EL, Stevenson MD, Rawdin A, Papaioannou D. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis. Health Technol Assess. 2009;13(2):iii, ix-x, 1–91. doi: 10.3310/hta13020. PMID: 19080721.
Harlivasari et al		Review	Hypercoagulability in lung cancer. Relation of inherited thrombophilia to VTE was not investigated. Article in Indonesian	Harlivasari, Annisa Dian, and Elisna Syahruddin. “Hypercoagulation in Lung Cancer.” Jurnal Respirologi Indonesia 39.2 (2019): 130–139.
Falanga		Review		Falanga, A. (2005, February). Thrombophilia in cancer. In Seminars in thrombosis and hemostasis(Vol. 31, No. 01, pp. 104–110). Copyright© 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.
Kolomansy et al	147	Prospective study	Patients with VTE were characterized but relation between inherited thrombophilia and VTE was not investigated	Kolomansky, Albert, et al “Prospective evaluation of patients hospitalized with venous thromboembolism: comparison between cancer and non-cancer patients.” IMAJ-RAMAT GAN-8.12 (2006): 848.
Streiff		Review		Streiff MB. Association between cancer types, cancer treatments, and venous thromboembolism in medical oncology patients. Clin Adv Hematol Oncol. 2013;11(6):349–357. PMID: 24472803.
Mulder et al		Review and metanalysis	Addresses treatment of cancer associated venous thromboembolism with DOACs Relation between inherited thrombophilia and VTE was not investigated	Mulder FI, Bosch FTM, Young AM, Marshall A, McBane RD, Zemla TJ, Carrier M, Kamphuisen PW, Bossuyt PMM, Büller HR, Weitz JI, Middeldorp S, van Es N. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Blood. 2020;136(12):1433–1441. doi: 10.1182/blood.2020005819. PMID: 32396939.
Martinelli et al	723	Retrospective	Relation between inherited thrombophilia and VTE was not investigated	Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F, Paciaroni K, Leone G, Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. 1998;92(7):2353–2358. PMID: 9746774.
Simioni et al	844	Retrospective	Relation between inherited thrombophilia and VTE was not investigated	Simioni P, Sanson BJ, Prandoni P, Tormene D, Friederich PW, Girolami B, Gavasso S, Huisman MV, Büller HR, Wouter ten Cate J, Girolami A, Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999;81(2):198–202. PMID: 10063991.
De Stefano et al		Review		De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 1996;87(9):3531–3544. PMID: 8611675.