Effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients

The management of venous thromboembolic (VTE) risk is challenging in patients with multiple myeloma (MM)who are considered to be at high-VTE risk. A recently published article addressed this question, especially the potential need of a high-dose oral anticoagulant with a target International Normalized Ratio (INR) of 2–3 as an alternative to prophylactic heparin in the highest risk patients (Swan et al, 2018). The level of this guideline is not high because of the lack of large trials, but it is important to develop recommendations. Indeed, in the two randomized studies of patients with de novoMMtreatedwith immunomodulatory drugs with a high-VTE risk, thromboprophylaxis using prophylactic low molecular weight heparin (LMWH) did not demonstrate a significant effect on VTE occurrence compared to aspirin (Palumbo et al, 2011; Larocca et al, 2012). So, there is a gap between the high incidence of VTE events observed in MM and the apparent inefficiency of thromboprophylaxis with LMWH. One potential explanation is that MM patients present a “resistance” to prophylactic doses of LMWH. To test this hypothesis, we studied prophylaxis heparinmodified thrombin generation tests (TGT), a global coagulation test, in 3 groups of patients. The first group comprised 6 inpatients with MM considered at high VTE risk; the second group, with intermediate VTE risk, comprised 6 inpatients with aggressive lymphoma; and the third group, with low VTE risk, comprised 6 patients hospitalized with a diagnosis of acute respiratory failure. The objective was to compare the anticoagulant potential of a prophylactic dose of LMWH (4 500 anti-Xa international units of tinzaparin) using a TGT on platelet-poor plasma (PPP) and platelet-rich plasma (PRP). For each patient, PPP and PRP were obtained from blood drawn at 0, 3, 8, 18 and 24 h after tinzaparin injection. TGT was monitored using the calibrated thrombogram method in which the initial derivative curves of fluorescence accumulation are converted into thrombin generation curves using a human thrombin calibrator and Thrombinoscope software (version 3.0.25; Biodis, Signes, France). TGT was performed in the presence of exogenous tissue factor (TF) at low (1 pmol/l) or high (5 pmol/l) concentrations. We choose to test tinzaparin because no accumulation of the anti-Xa activity has been observed with tinzaparin in patients older than 75 years and with a creatinine clearance between 0 33 and 0 83 ml/s. No patients presented a previous history of VTE. Of 6 MM patients 5 were treated with immunomodulatory drugs and one received erythropoietin, also known to increase the risk of VTE (Anaissie et al, 2012). In 2 patients already receiving thromboprophylaxis with LMWH, the drug was stopped 48 h before inclusion in the study. None of the patients presented a platelet count less than 100 9 10/l and only one patient per group presented with a moderate renal insufficiency. All patients with MM or lymphoma were in first line therapy and were included before their fourth cycle of chemotherapy, with a median Korana score of 1 (range 0–3, high-risk: 1 patient; intermediate-risk: 9 patients; low-risk: 2 patients). In all groups the endogenous thrombin potential (ETP) levels followed the same curve aspect, with an abrupt decrease at 3 h and an increase at 8 h, returning to initial values at 18 h, and no statistically significant difference between the 3 groups (Fig 1A). A similar effect on the thrombin peak, time to peak and lag time was observed regardless of the TF level used (1 or 5 pmol/l) (Fig 1B–D). Therefore, our study found no evidence for an in vitro LMWH specific resistance in MM patients depending on their intrinsic VTE risk compared with other haematological malignancies or medical patients, even though our MM patients were known to have a high-VTE risk because of their treatments. Indeed, it was demonstrated that MM patients treated with immunomodulatory drugs have a higher VTE risk and higher TGT level than other patients with MM (Chalayer et al, 2019). Our patients with lymphoma present similar results although they do not seem to be at high VTE risk: the median Korana score, recently validated by Parker et al (2018) in in-hospital VTE development in cancer, was 1. Parker et al (2018) also reported some surprising results about thromboprophylaxis. For example, there was no difference in VTE incidence between patients who received thromboprophylaxis and those who did not. Moreover, there was no statistically significant difference in major bleeding between those who received thromboprophylaxis and those who did not, questioning the efficacy of thromboprophylaxis. Currently, the bleeding risk, known to be increased in acutely ill, hospitalized medical patients, always causes physicians to be careful regarding the use of thromboprophylaxis and limited anticoagulant dose (Decousus et al, 2011). Thus, in the light of this study and our data, the preference between treatment with full-dose oral anticoagulant or curative LMWH and prophylactic LMWH seems to be debatable. In addition to the dose, the number of treatment injections can also be discussed. In our study, it seems that one prophylactic dose is not enough efficient to protect against VTE for 24 h. This was already demonstrated in surgical patients, comparing the use of 1 vs. 2 prophylactic LMWH injections (Laporte et al, 2014). However two injections could decrease the patient’s quality of life (Chalayer et al, 2016). We acknowledge that our series is small and does not addresse the importance of the roles regarding the reasons Correspondence