Thrombocytopenia, a low platelet count (<100 × 109/L), is a common side effect of cancer and its treatment. Its severity varies by cancer type, stage, and treatment approach, occurring in nearly 100% of acute leukemia patients but in less than 5% of some head and neck cancer cases.
Some cancers involve multiple factors leading to thrombocytopenia. Lymphoproliferative malignancies, for example, result in low platelet counts due to splenic platelet sequestration, reduced production in the bone marrow, and immune-related destruction [1].
Thrombocytopenia can also emerge due to the chemotherapy treatment used. The occurrence and prevalence of chemotherapy-induced thrombocytopenia vary significantly depending on the specific chemotherapy used, ranging from 8% in taxane-based regimens to 37% in gemcitabine-based regimens and even up to 82% in carboplatin monotherapy. [2].
Thrombocytopenia, bleeding risk and VTE
Thrombocytopenia is linked to a higher risk of bleeding but does not offer protection against venous thromboembolism (VTE). In a study involving 1514 patients who underwent hematopoietic stem cell transplantation, VTE incidence within six months was 4.6% (95% CI 3.6–5.8%), and 34% of these cases occurred when platelet counts were below 50 × 109/L. Meanwhile, clinically significant bleeding was prevalent, affecting 15.2% (95% CI 13.4–17.1%) of individuals, and the use of anticoagulation was associated with a 3.1-fold increased risk of bleeding [3].
Despite the common occurrence of VTE, the most effective anticoagulation management strategies for patients with cancer and thrombocytopenia remain uncertain. Clinical practice guidelines recommend low-molecular-weight heparin (LMWH) for initial treatment in patients with cancer-associated thrombosis (CAT) and thrombocytopenia (over direct oral anticoagulants) due to more evidence with LMWH in this setting[4].
However, the ideal dosing of LMWH for managing CAT in thrombocytopenic patients is not established. Some studies propose using reduced-dose LMWH for moderate thrombocytopenia (platelet counts <50 × 109/L) and temporarily stopping it for severe thrombocytopenia (platelet counts <25 × 109/L) as a safe and effective approach. Conversely, other studies suggest full-dose anticoagulation with transfusion support in the presence of thrombocytopenia [5].
Searching for the best anticoagulation strategy
An analysis of existing literature aimed to compare the efficacy of full-dose anticoagulation with platelet support against dose-modified LMWH strategies in managing anticoagulation in this context. However, the study revealed that the existing data were too poor to determine the superiority of either of these management strategies [5].
Trying to fill this gap, a systematic review and meta-analysis was conducted to assess the risks of recurrent VTE and bleeding events in patients with CAT and thrombocytopenia (platelet count <100 × 109/L) based on different anticoagulation management approaches [6].
After reviewing 4341 records, 62 studies underwent full-text evaluation for eligibility. Ultimately, 19 studies involving 1728 patients with platelet counts below 100 × 109/L were included in the systematic review. Among these, there were no randomized controlled trials (RCTs), two prospective cohort studies, and 17 retrospective cohort studies (with 15 being single-center studies). For the meta-analysis, six studies lacked sufficient data to calculate event rates per patient/month for different anticoagulation strategies and were therefore excluded. Additionally, studies with a median or overall follow-up significantly exceeding 100 days were excluded to assess event rates during thrombocytopenia accurately. This led to the inclusion of 10 studies involving 707 patients with platelet counts below 100 × 109/L in the meta-analysis [6].
The results confirmed the elevated risks of recurrent VTE and bleeding complications in patients with CAT and thrombocytopenia. The recurrence rate for VTE was 2-3% per month, while major bleeding occurred at a rate of 2-4% per month and total bleeding at 3-13% per month [6].
Interestingly, these risks were consistent across various anticoagulation management strategies; the meta-analysis indicated no statistically significant differences in the rates of recurrent VTE or major bleeding events when comparing various anticoagulation management strategies. LMWH seems to remain the preferred anticoagulant for CAT and thrombocytopenia, while data on the use of direct oral anticoagulants (DOACs) in this context are lacking [6].
Limitations in the existing data
It is essential to highlight the substantial limitations in the existing data. The included literature displayed substantial variability in patient characteristics, VTE acuity, bleeding criteria, and follow-up durations. Also, all the studies were observational and lacked random allocation of anticoagulation strategies, leading to baseline differences among patients receiving different strategies and potential confounding. Moreover, different modified anticoagulation approaches were employed, involving reduced dosages or shortened durations. Additionally, diverse bleeding event categorization criteria were utilized [6].
There are limited numbers of patients (16 in TROVE and 4 in CAVEaT studies) were initiated on DOACs [7, 8]. These individuals experienced high combined major bleeding and clinically relevant non-major bleeding rates: 20% over 60 days in TROVE and 50% over 90 days in CAVEaT [6]. More data are needed.
Conclusions
Based on these considerations, while the study could not determine a definitive “best treatment” option, it underscored the severe constraints of the current literature and emphasized the necessity for future research to offer guidance on optimal anticoagulation strategies for this specific population.
In particular, more prospective studies, preferably RCTs are needed to provide more substantial evidence and guide clinical practice. Also, more studies focusing on DOAC use within this population are necessary. Until more safety and efficacy data surface, cautious use of DOACs in patients with cancer-associated thrombosis and thrombocytopenia is advised [6].
References
- Liebman HA. Thrombocytopenia in cancer patients. Thromb Res. 2014;133 Suppl 2:S63-S69. doi:10.1016/S0049-3848(14)50011-4
- Shaw JL, Nielson CM, Park JK, Marongiu A, Soff GA. The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies. Eur J Haematol. 2021;106(5):662-672. doi:10.1111/ejh.13595
- Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB. The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention. Blood. 2008;112(3):504-510. doi:10.1182/blood-2007-10-117051
- Falanga A, Leader A, Ambaglio C, et al. EHA Guidelines on Management of Antithrombotic Treatments in Thrombocytopenic Patients With Cancer. Hemasphere. 2022;6(8):e750. Published 2022 Jul 13. doi:10.1097/HS9.0000000000000750
- Samuelson Bannow BR, Lee AYY, Khorana AA, et al. Management of anticoagulation for cancer-associated thrombosis in patients with thrombocytopenia: A systematic review. Res Pract Thromb Haemost. 2018;2(4):664-669. Published 2018 Jun 19. doi:10.1002/rth2.12111
- Wang TF, Carrier M, Carney BJ, Kimpton M, Delluc A. Anticoagulation management and related outcomes in patients with cancer-associated thrombosis and thrombocytopenia: A systematic review and meta-analysis. Thromb Res. 2023;227:8-16. doi:10.1016/j.thromres.2023.05.012
- Carney BJ, Wang TF, Ren S, et al. Anticoagulation in cancer-associated thromboembolism with thrombocytopenia: a prospective, multicenter cohort study. Blood Adv. 2021;5(24):5546-5553. doi:10.1182/bloodadvances.2021005966
- Booth S; HaemSTAR Network, Desborough M, Curry N, Stanworth S. Platelet transfusion and anticoagulation in hematological cancer-associated thrombosis and thrombocytopenia: The CAVEaT multicenter prospective cohort. J Thromb Haemost. 2022;20(8):1830-1838. doi:10.1111/jth.15748