Platelet Cut-Off For Anticoagulant Therapy In Cancer Patients With Venous Thromboembolism and Thrombocytopenia: An Expert Opinion Based On RAND/UCLA Appropriateness Method (RAM)

Cancer-related Venous Thromboembolism (VTE) requires treatment with Low Molecular Weight Heparin (LMWH), which is more effective and safer than warfarin; however, the risk of major hemorrhage still remains clinically relevant (up to 5%). This rate is even higher in case of impaired hemostasis, such as during thrombocytopenia (due to myelosuppression or chemo-therapy) where the bleeding risk is directly related to the platelet count level. At the present, the best management of adult patients with acute or non-acute cancer-related VTE during thrombocytopenia is uncertain.

To develop a consensus about the platelet cut-off for a safe LMWH administration in cancer patients with acute (lasting < 1 month) or non-acute VTE and thrombocytopenia, based on RAND/UCLA Appropriateness Method (RAM).

A systematic review of the literature was performed via electronic databases (MEDLINE, EMBASE, and Cochrane Library Central Registry). Topics and research terms were: cancer, venous thromboembolism, platelets, risk of bleeding, anticoagulant drugs, low-molecular-weight heparin, and treatments. The main study outcomes were rates of VTE (first event, recurrence, and catheter-related DVT), major and minor bleeding, thrombocytopenia, and death. A panel of experts was identified; the literature review and the list of indications were sent to all members of this panel. For each indication, the panel members rated the benefit-to-harm ratio of the procedure on a scale of 1 to 9, where 1 means that the expected harms greatly outweigh the expected benefits, and 9 means that the expected benefits greatly outweigh the expected harms. A middle rating of 5 means either that the harms and benefits are about equal or that the rater cannot make the judge for the patient described in the indication. The working group comprised 9 hematologists expert in thrombosis and haemostasis (G.S., M.M., M.C., V.D.S., A.F., A.F., F.R., A.T., S.S.) including two methodologists (G.S. and M.M.) and one coordinator (S.S.).

the RAND was construed identifying 3 platelet count cut-offs (i.e., PLT >50.000 <100.000 µL; PLT >30.000 <50.000 µL; PLT <30.000 µL) and 3 doses of LMWH (weight adjusted fixed-dose, prophylactic dose, and half of the weight adjusted fixed-dose) by administering 13 questions to the experts.

The panel of expert reached the following consensus: 1. Cancer patients with acute VTE and a platelet count <100.000 µL - >50.000 should receive full therapeutic dose LMWH ; 2. In cases of non-acute VTE with platelet count <100.000 µL - >50.000, the dose of LMWH should be reduced to 75% of the full dose; 3. In cancer patients with acute VTE and platelet count <50.000 - >30.000 µL, the LMWH dose should be reduced to 50% of the full therapeutic dose; 4. In case of non-acute VTE and a platelet count <50.000 µL - >30.000, the expert panel considers uncertain a treatment with a reduced dose to 50% or a low dose (i.e. 4.000 IU anti-FXa/d); 5. In case of platelet count below 30.000 µL, the expert panel agreed to suspend LMWH both in acute and non-acute VTE.

This is the first expert opinion based on RAM to establish the safe platelet cut-off to administer LMWH therapy in cancer patients affected by acute and non-acute VTE. The present panel of experts suggests as appropriate the use of dose-adjusted LMWH according to platelets count. Further investigations by means of well designed prospective clinical trials are needed to establish the best management of cancer-related VTE in patients with thrombocytopenia.

Rodeghiero:Amgen, GSK: Honoraria; Amgen, Eisai, GSK, LFB, Suppremol: Membership on an entity’s Board of Directors or advisory committees.