During the 10th ICTHIC, Dr. Avi Leader (hematologist at Rabin Medical Center in Petah Tikva, Israel) talked about managing patients with cancer and a platelet count below 50 × 109/L receiving antithrombotic therapy (antiplatelet or anticoagulant therapy).
Cancer patients with antithrombotic medication and thrombocytopenia are common, and thrombocytopenia does not reduce the risk of recurrent arterial/venous thrombosis [1].
Based on associated bleeding risks, the threshold for changes in anticoagulation therapy should generally be approximately 50 × 109/L. Still, the threshold for changes in patients receiving single antiplatelet therapy is generally lower, at 20 × 109/L to 50 × 109/L [2].
The balance between bleeding and thrombosis should drive management decisions. Since a high bleeding risk with anticoagulation exists in this setting, the thrombotic risk should be high enough to justify the bleeding risk [1].
The first management step is to decide whether to continue or hold anticoagulation/antiplatelet medication.
If anticoagulation is continued, the bleeding risk should be mitigated. To do so, the dose and/or class of antithrombotic medication may be changed, and modifications in platelet transfusion thresholds may be required. Although increasing the platelet transfusion threshold is suggested in some guidance documents, the efficacy of such a strategy is not proven [3].
Importantly increased platelet transfusion thresholds are associated with increased platelet utilization, which is not without risks [4, 5].
Another strategy is to reduce the dose of anticoagulation. Although, the efficacy of such a strategy is unclear, and evidence is sparse [6]. Some data suggest a relatively lower bleeding risk with a prophylactic dose of low-molecular-weight heparin (LMWH) in comparable populations [7].
What guidelines say
The Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) guidelines share information about anticoagulation in the cancer-associated thrombosis (CAT) setting [8].
In case of acute CAT, platelet count below 50 × 109/L, and high thrombotic risk (such as acute symptomatic pulmonary embolism), the guidelines suggest continuing full-dose LMWH with plenty of transfusion support to a target platelet count of about 40 × 109/L or 50 × 109/L [8].
In the case of acute CAT and low thrombotic risk or sub-acute or chronic CAT, the guidance suggests reducing the LMWH dose when the platelet count is between 25 × 109/L and 50 × 109/L and holding all anticoagulation treatments when the platelet count is below 25 × 109/L [8].
Inferior vena cava filters can be considered on a case-by-case basis in patients with acute venous thromboembolism (VTE) who are actively bleeding or have severe, prolonged thrombocytopenia when anticoagulation is contraindicated [8].
Direct oral anticoagulants (DOACs) when the platelet count is below 50 × 109/L might not be appropriate. The evidence on the use of DOACs in patients with thrombocytopenia is scarce. In most studies, only patients with platelet count from 50 × 109/L to 100 × 109/L were included [1].
In addition, in CAT treatment, more clinically relevant bleeding was seen for edoxaban and rivaroxaban compared with dalteparin [9, 10].
How do physicians manage anticoagulation in this setting?
A study analyzed 774 hypothetical case vignettes managed by 168 physicians. The results show that management varied greatly across physicians, but the management process generally is compatible with the ISTH guidelines explained above. Platelet count, anticoagulation indication, time since indication, type of hematological disease and treatment, prior major bleeding, and physician demographics and practice setting have influenced the management [11].
A variable incidence of bleeding and thrombosis across the small- to medium-sized prospective studies exists [1].
About antiplatelet therapy, no formal guidelines on thrombocytopenia exist. However, the society for cardiovascular angiography and interventions released a consensus statement for thrombocytopenia cancer patients with acute coronary syndrome [12].
Aspirin is recommended if the platelet count is above 10 × 109/L and dual antiplatelet therapy (aspirin and clopidogrel) is reserved for platelet count above 30 × 109/L [12].
A recent review, not focusing specifically on cancer, provided higher platelet thresholds for antiplatelet therapy. Therefore, it is suggested to use single antiplatelet therapy when platelets are about 50 × 109/L and dual antiplatelet therapy for above 100 × 109/L. Importantly, there is no convincing evidence to support or refute any of these recommendations [13].
Data on the management of antiplatelet medications are restricted mainly to ischemic heart disease. However, these studies suggest that aspirin may be safe in acute coronary syndrome with acute thrombocytopenia with a platelet count between 30 × 109/L and 50 × 109/L [2] and in patients with chronic thrombocytopenia below 50 × 109/L receiving coronary angiography and interventions for acute coronary syndrome [14].
A case-vignette study (on 145 physicians who addressed 434 theoretical cases of antiplatelet therapy) showed that most physicians (80%) decided to continue antiplatelet therapy if the platelet count was above 50 × 109/L. It also showed that 34% of physicians used platelet transfusions to support antiplatelet therapy, although no published evidence supports this practice [15].
More data on the incidence of bleeding and thrombosis are needed and will help understand what the management should be.
Preliminary data from the MATTER study
In the last part of his talk, Dr. Leader shows some preliminary unpublished results from the MATTER study.
The MATTER study (NCT03288441) was designed to address some of the knowledge gaps by a collaborative group led by Doctor Leader and Dr. Galia Spectre from Israel, Professor Hugo ten Cate from The Netherland, and Professor Anna Falanga from Italy.
The study aims to evaluate how physicians manage anticoagulant and antiplatelet medication in patients with hematological malignancy and thrombocytopenia and assess the frequency of bleeding and thrombosis. Additional aims are to assess how management changes affect drug activity and blood clotting and evaluate the use of platelet transfusions.
This multinational prospective observational cohort study includes patients with hematological malignancy and thrombocytopenia preceding any antiplatelet and/or anticoagulant treatment of any duration. The follow-up time is 30 days after the baseline study visit. Patients were indexed at the time of the baseline visit. Patients with prior severe thrombocytopenia with the same antithrombotic and anticancer regimen were excluded.
Patients were divided into two cohorts. The antiplatelet-only cohort includes patients receiving antiplatelet medication but not anticoagulation. Antiplatelet drugs include any class, dose, or duration of any platelet aggregation inhibitor.
The anticoagulant-based cohort includes patients receiving only anticoagulants or both anticoagulant and antiplatelet medication combined. This includes any class, dose, or duration of any antiplatelet or anticoagulant drug.
The primary outcome was a composite of the ISTH-defined major bleeding, or VTE, or arterial thromboembolism (ATE), and the composite secondary outcome also included clinically relevant non-major bleeding.
Preliminary results (crude data, not curated and not adjudicated) indicate that the most common hematological malignancies for both the anticoagulation and the antiplatelet cohorts were acute leukemia, aggressive non-Hodgkin’s lymphoma, and multiple myeloma. In addition, autologous stem cell transplantation was the most prevalent anticancer regimen in both cohorts.
The main indication for anticoagulation was venous thromboembolism, followed by atrial fibrillation. Most patients in the anticoagulation cohort received full-dose LMWH, and 25% were treated with DOACs prior study index.
As antiplatelet therapy, aspirin was used in most cases.
The study outcomes at 30 days in the anticoagulation cohort indicate that the management was split almost evenly between holding anticoagulation (29%), continuing at full dose (34%), and continuing with reduced dose (31%).
Overall, the primary composite outcome of arterial-venous thrombosis or major bleeding occurred in 4.3% of patients. The secondary composed outcome, which also included clinically relevant non-major bleeding, occurred in 10% of all patients.
There was a low rate of clinically relevant non-major bleeding in patients with anticoagulation continued at a reduced dose at study index (6.9%) compared to other management strategies (11.4% and 13.4% for continued at full dose and holding, respectively).
However, the statistical significance of these differences remains to be analyzed.
In the anticoagulation cohorts, 23% of patients had changes in the platelet transfusion threshold, moving from 10 × 109/L to 30 × 109/L. The outcomes at 30 days in the antiplatelet cohort indicate that 41% of antiplatelet therapy was put on hold while 58% was continued.
The primary composite outcome occurred in 5% of all patients, while the secondary outcome occurred in 10.3% of all patients, compatible with the anticoagulation cohort.
Of note, the rate of ATE, which is a reason for using antiplatelet therapy, was 1.3% overall.
The main numerical difference in outcomes between the management groups was a lower rate of the composite outcome, specifically VTE, in patients who continued antiplatelet therapy compared to those who hold it (0% compared to 9.4%, respectively).
Similarly, in the antiplatelet cohort, 22% of patients had changes in the platelet transfusion threshold, and the median platelet threshold changed from 10 × 109/L without antiplatelet therapy to 20 × 109/L with antiplatelet therapy.
Preliminary conclusions from the MATTER study
Very preliminary conclusions of these interim results are:
- Around 60% of patients continued anticoagulation and antiplatelet therapy when platelets dropped below 50 × 109/L; half of the patients continued with a full dose and half with a reduced-dose therapy.
- The platelet transfusion threshold increased from 10 × 109/L to 20 × 109/L with antiplatelet therapy and 30 × 109/L with anticoagulation.
- 5% of patients had major bleeding or ATE at 30 days in both anticoagulant and antiplatelet cohorts. However, there was an overall low rate of ATE in the antiplatelet cohort. This suggests that current management may achieve a reasonable risk/benefit ratio.
References
1. Leader A, Gurevich-Shapiro A, Spectre G. Anticoagulant and antiplatelet treatment in cancer patients with thrombocytopenia. Thromb Res. 2020;191 Suppl 1:S68-S73.
2. Feher A, Kampaktsis PN, Parameswaran R, Stein EM, Steingart R, Gupta D. Aspirin Is Associated with Improved Survival in Severely Thrombocytopenic Cancer Patients with Acute Myocardial Infarction. Oncologist. 2017;22(2):213-221.
3. Li A, Davis C, Wu Q, et al. management of venous thromboembolism during thrombocytopenia after autologous hematopoietic cell transplantation. Blood Adv. 2017;1(12):707-714. Published 2017 Apr 27.
4. Houghton DE, Key NS, Zakai NA, Laux JP, Shea TC, Moll S. Analysis of anticoagulation strategies for venous thromboembolism during severe thrombocytopenia in patients with hematologic malignancies: a retrospective cohort. Leuk Lymphoma. 2017;58(11):2573-2581.
5. Samuelson Bannow BT, Walter RB, Gernsheimer TB, Garcia DA. Patients treated for acute VTE during periods of treatment-related thrombocytopenia have high rates of recurrent thrombosis and transfusion-related adverse outcomes. J Thromb Thrombolysis. 2017;44(4):442-447.
6. 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.
7. Simon M, Hahn T, Ford LA, et al. Retrospective multivariate analysis of hepatic veno-occlusive disease after blood or marrow transplantation: possible beneficial use of low molecular weight heparin. Bone Marrow Transplant. 2001;27(6):627-633.
8. Samuelson Bannow BT, Lee A, Khorana AA, et al. management of cancer-associated thrombosis in patients with thrombocytopenia: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16(6):1246-1249.
9. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378(7):615-624.
10. Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018;36(20):2017-2023.
11. Leader A, Ten Cate V, Ten Cate-Hoek AJ, et al. anticoagulation in thrombocytopenic patients with hematological malignancy: A multinational clinical vignette-based experiment. Eur J Intern Med. 2020;77:86-96.
12. Iliescu CA, Grines CL, Herrmann J, et al. SCAI Expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologıa intervencionista). Catheter Cardiovasc Interv. 2016;87(5):E202-E223.
13. McCarthy CP, Steg G, Bhatt DL. The management of antiplatelet therapy in acute coronary syndrome patients with thrombocytopenia: a clinical conundrum. Eur Heart J. 2017;38(47):3488-3492.
14. Iliescu C, Balanescu DV, Donisan T, et al. Safety of Diagnostic and Therapeutic Cardiac Catheterization in Cancer Patients With Acute Coronary Syndrome and Chronic Thrombocytopenia. Am J Cardiol. 2018;122(9):1465-1470.
15. Leader A, Ten Cate V, Ten Cate-Hoek AJ, et al. Managing Anti-Platelet Therapy in Thrombocytopaenic Patients with Haematological Malignancy: A Multinational Clinical Vignette-Based Experiment. Thromb Haemost. 2019;119(1):163-174.