Thrombophilia refers to a group of conditions where the blood has an elevated tendency to form clots. It can stem from inherited or acquired factors.
Secondary causes include heparin-induced thrombocytopenia, antiphospholipid antibody syndrome, neoplasia, obesity, smoking, and surgery. Primary causes, or genetic factors, encompass issues, such as the factor V Leiden mutation, deficiencies of antithrombin III, protein C or S, histidine-rich glycoprotein, and prothrombin-related thrombophilia .
Thrombophilia increases the risk of deep venous thrombosis and venous thromboembolism (VTE). At times, clot formation might occur in unusual locations like splanchnic, cerebral, and retinal veins. The clinical presentation of hereditary thrombophilia varies widely. Some individuals may never experience clotting issues, while others could remain symptom-free until adulthood. Some might face recurrent thromboembolism before the age of 30 years .
Specific genetic mutations affect coagulation proteins in people with inherited thrombophilia, with a prevalence in patients with VTE from 21% to 35%. Notable mutations include factor V Leiden (FVL) and prothrombin G20210A, linked to elevated thrombin and prothrombin levels .
Inherited thrombophilia and cancer-associated thrombosis
As known, cancer is also a recognized VTE risk factor, whereas the impact of inherited thrombophilia on cancer-associated thrombosis (CAT) risk is disputed, with studies showing varying results [3-5]. Testing for thrombophilia isn’t standard due to the controversy, necessitating more evidence.
A new study tried to assess common thrombophilia gene mutation prevalence and their link to VTE risk in intermediate- to high-risk (defined as patients with a Khorana score ≥2) patients with cancer undergoing chemotherapy .
The post-hoc analysis utilized blood samples from patients in the AVERT trial to investigate whether known thrombophilia gene mutations (Prothrombin FII G20210A, Factor XI, Fibrinogen Gamma, Serpin Family A Member 10, Factor V K858R, Factor XIII, FVL, and AB0 blood types) were linked to occurrences of VTE or bleeding within seven months of beginning chemotherapy .
Results indicate that FVL mutation and having a non-0 blood group were more prevalent among patients who developed VTE. The risk of VTE was notably higher, with a 5.2-fold increase for cancer patients with a heterozygous or homozygous FVL mutation and a 2.7-fold increase for those with a non-0 blood type. Patients with FVL mutation had a 30.0% VTE rate compared to 7.8% without, while non-0 blood type patients had an 11.5% VTE rate versus 4.6% with 0 blood type .
This elevated VTE risk coincided with a lower risk of bleeding, though this difference wasn’t statistically significant. Interestingly, among FVL patients receiving prophylactic anticoagulation (using apixaban), complete protection against VTE was observed, in contrast to those without prophylactic anticoagulation, who had a VTE rate of 119 per 100 patient-years .
Other thrombophilia gene mutations, including F2, F11, FGG, SERPINA10, and F5, did not significantly correlate with VTE or bleeding events. Furthermore, it was found that prophylactic anticoagulation in patients with FVL mutation or non-0 blood type effectively lowered the VTE risk without substantially increasing bleeding risk .
Mechanisms linking FVL mutation and non-0 blood types to thrombosis are known. FVL mutation results in resistance to activated protein C, hampering the cleavage of factor VIII by activated protein C and inducing a hypercoagulable state . Conversely, non-0 blood type patients exhibit elevated Von Willebrand Factor and Factor VIII levels, potentially heightening the risk of thrombosis .
This study is the first to comprehensively evaluate various thrombophilia genes’ connection to VTE and bleeding events while assessing the efficacy and safety of prophylactic anticoagulation in cancer patients carrying thrombophilia gene mutations.
Presently, established clinical guidelines do not advocate thrombophilia screening for cancer patients. However, they recommend considering primary thromboprophylaxis for those with notable VTE risk factors, as they are more likely to gain from preventive treatment. FVL mutation and non-0 blood types could be additional risk factors to be evaluated in determining primary prophylaxis use in cancer patients with a Khorana score ≥2 .
Limitations and conclusions
It is important to mention that this study’s results are confined to patients fulfilling the inclusion and exclusion criteria of the AVERT trial, including a Khorana Score of ≥ 2 and not being on anticoagulation for other reasons. For this reason, these findings might not extend to all cancer patients. Moreover, potential residual confounding is plausible since the authors couldn’t account for the impact of genetic ancestry and family history of VTE, as this data was unavailable .
Also, grouping non-Caucasians for ethnicity adjustment could have led to some loss of precision. The sample size and the number of VTE and bleeding events were relatively small, limiting statistical power .
Despite this, the study is useful to include FVL mutation and non-O blood types when evaluating the risk of VTE in intermediate to high-risk ambulatory cancer patients undergoing chemotherapy, who might benefit from prophylactic anticoagulation with minimal bleeding risk.
- Dautaj A, Krasi G, Bushati V, et al. Hereditary thrombophilia. Acta Biomed. 2019;90(10-S):44-46. doi:10.23750/abm.v90i10-S.8758
- Roy DC, Wang TF, Carrier M, et al. Thrombophilia Gene Mutations Predict Venous Thromboembolism in Ambulatory Cancer Patients Receiving Chemotherapy. J Thromb Haemost. 2023. doi:10.1016/j.jtha.2023.07.017. Epub ahead press.
- Heraudeau A, Delluc A, Le Henaff M, et al. Risk of venous thromboembolism in association with factor V Leiden in cancer patients – The EDITH case-control study. PLoS ONE 2018; 13: e0194973.
- Pabinger I, Ay C, Dunkler D, Thaler J, et al. Factor V Leiden mutation increases the risk for venous thromboembolism in cancer patients – results from the Vienna Cancer And Thrombosis Study (CATS). J Thromb Haemost 2015;13:17–22.
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- Englisch C, Moik F, Nopp S, Raderer M, Pabinger I, Ay C. ABO blood group type and risk of venous thromboembolism in patients with cancer. Blood Adv 2022;6:6274–81.