Platelet Cut-Off For Anticoagulant Therapy In Cancer Patients With Venous Thromboembolism and Thrombocytopenia: An Expert Opinion Based On RAND/UCLA Appropriateness Method (RAM)
Authors: Saccullo Giorgia , Marietta Marco , Carpenedo Monica , De Stefano Valerio , Falanga Anna , Federici Augusto B. , Rodeghiero Francesco , Tosetto Alberto , Siragusa Sergio 
Published: October 2019

Abstract

Introduction
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.

Objective
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).

Materials and methods
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.).

Consensus Development
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.

Results
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.

Conclusions
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.

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