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Prevention of thromboembolism in Myeloma: expanding the tool-box of assays to predict the risk?
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Haemostasis is a complex process affected by many factors including both cellular and plasma components. It is a multistep process starting with platelet adhesion to damaged endothelium and ending in clot fibrinolysis. There are several methods available to study different aspects of haemostasis including adhesion, aggregation, coagulation and fibrinolysis. This review describes the different methods, what aspects of haemostasis they measure and their limitations. Methods discussed include methods to study adhesion (e.g. PFA-100, cone and platelet(let) analyzer and perfusion chambers) and aggregation (e.g. Multiplate, VerifyNow and Plateletworks). Furthermore the principles behind viscoelastic haemostatic assays are presented as well as methods that can analyse aspects of haemostasis in plasma or platelet-rich-plasma samples (thrombin generation, overall haemostasis potential and Thrombodynamics Analyzer).
To the Editor: The cohort study by Dr Mahmoodi and colleagues1 concluded that microalbuminuria is an independent risk factor for venous thromboembolism (VTE). Although the authors described several limitations to their work, they did not consider an important issue. Multivariable analysis controlled for the most common VTE risk factors that may confound the association between microalbuminuria and VTE. However, a diagnosis of antiphospholipid syndrome (APS) or high titers of antiphospholipid antibodies (aPLs) in the study population was not evaluated. We believe this is crucial.
The incidence of venous thromboembolism (VTE) is more than 1 per thousand annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with < or = 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.
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Thromboembolism (TE) is an important complication of cancer with substantial clinical implications. MM, treated with thalidomide (thal) and LEN, has TE rates up to 25%, particularly when used in combination with chemotherapy and corticosteroids. Given disease heterogeneity, bleeding and TE risks are different for all patients and individuals over time. With the emergence of novel antithrombotic agents, further understanding of the pathophysiology of both MM- and therapy-related hemostatic dysfunction and the identification of important biomarkers, may promote a risk-stratification process and allow a targeted therapeutic strategy. We prospectively and sequentially assessed novel thrombogenic biomarkers, with a plan to correlate with functional assays (thrombin generation and microparticles) in R-MM, before and after exposure to LEN/dex as part of a 150-patient phase-II clinical trial. Hemostatic assessments were performed at enrolment, 1-, 4-, 12-months and/or end of study. 27 patients at our institution, 15 males, median age 69 years (range 58–80) were included in the analysis: 16 had IgG monoclonal protein (13 kappa [k]), 9 IgA (6 k), 2 were k light chain only. The karyotype was diploid in 18, complex in 4 and 3 patients had t(4;14), t(11;14) or t(8;14) respectively. Median number of prior lines of therapy was 3 (range 1–7); 18 had prior thal and 15 had received a melphalan-based autologous stem cell transplant. Median (range) for Hb was 111g/L (80-137) and creatinine clearance 66.6mL/min (23-182). 6/27 had a prior TE: 1 arterial, 5 venous. All patients commenced antithrombotic therapy at enrolment: 20 received aspirin (100mg/day), 4 prophylactic and 2 therapeutic dose enoxaparin, 1 treatment dose warfarin. At enrolment (pre-LEN/dex) and after 4 weeks of therapy, the median (range) for the individual assays are outlined in table 1. Pre-LEN/dex: FVIIIc, vWFAg, Fib Mon, TAT, PF1+2 and TM were markedly elevated in the majority of patients. After 4 weeks of therapy, many biomarkers remained elevated, however, Fib Mon and PMN-E near normalised in all patients; FVIIIC and vWFAg was elevated in less patients; while Fib, PF1+2 and TAT increased. This early promising data demonstrate inflammatory, endothelial and hemostatic dysregulation in R-MM with an altered biomarker profile after exposure to LEN/dex. Further results of sequential analyses will be presented at the meeting.
Study (cycle, day) C1D1 (pre–LEN/dex) n* C2D1 (4–weeks LEN/dex) n* Biomarker (units, NR) Median Range >ULN, ULN <LLN APTT (s, 24–34) 34 24–48 13 0 33 26–52 8 0 PT (s, 11.8–14.6) 13.5 12–25.6 10 0 13.2 11.2–45.2 2 3 Fib (g/L, 2.0–4.0) 4 2.4–6.8 12 0 5.5 0.7–8.4 21 2 D-dimer (mg/L, 0.0–0.5) 0.5 0.1-1.5 9 NA 0.6 0.1–6.4 15 NA Plt (×109/L, 150–450) 214 43–372 0 7 225 30–385 0 6 FVIIIc (%, 50–150) 298 96–600 22 0 236.5 159–600 10 0 vWFAg (%, 50–160) 206 98–325 18 0 298 148–364 12 0 APC-R ratio (2–3.5) 2.3 1.7–3.4 0 3 3.2 1.7–3.6 1 1 AT (%, 80–120) 98 69–135 3 3 108 77–126 4 1 Fib Mon (μg/ml, 0.1– 6) 4.3 2.0–61.2 8 0 3.1 0–95 2 1 TAT (μg/L, <2.0–4.2) 1.1 0.4–37.6 9 14 8.1 2.7–54.7 19 0 PF1+2 (pmol/L, 69–229) 192.3 0.7–705.5 11 2 197.3 35.8–1266.5 8 5 anti-CG (U/ml, <15) 0.2 0-5.2 0 NA 0.1 0–0.6 0 NA TM (pg/mL, 2353–4541) 4739.1 2628–11656.3 15 0 4050.3 244–10613.2 8 2 PMN-E (ng/mL, 0–90) 44 22–276 6 NA 34.8 14–92 1 NA NR: Normal range; APTT: Activated partial thromboplastin time; PT: Prothrombin time; Fib: Fibrinogen; Plt: Platelet count; FVIIIc: Factor VIII-coagulant; vWFAg: von Willebrand factor Antigen; APC-R: Activated protein C resistance ratio; AT: Antithrombin; Fib Mon: Fibrin Monomers; TAT: Thrombin-antithrombin complex; PF1+2: Prothrombin fragments1+2; CG: Cathepsin G; TM: Thrombomodulin; PMN-E: PMN Elastase; NA: values ULN not clinically applicable. * Number of patients (n) within the cohort (n=27), in whom measured level was >upper limit of normal (>ULN) or <lower limit of normal (<LLN).
Disclosures
Curnow: Celgene: Research Funding; Novartis: Consultancy. Lynch:Celgene Pty Ltd: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Prince:Celegene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westerman:Celgene: Research Funding.
Patients with multiple myeloma (MM) are at increased risk of venous thromboembolism. Therefore, adequate laboratory control of hemostasis and subsequent adjustments of anticoagulant therapy are necessary. We studied hemostasis changes using thromboelastography (TEG), thrombin generation test (TGT) and thrombodynamics (TD) in primary MM patients (PMMpt, n=25) and patients in remission (RMMpt, n=34) during blood stem cell (BSC) mobilization. TD and TEG reveal hypercoagulability in PMMpt (*P<0.05) in relation to healthy volunteers. There was no difference in any of the tests between PMMpt and RMMpt. We detected no heparin effect in 22% of patients one day after the onset of the prophylactic heparin treatment (500 IU/h) during BSC mobilization; tests shifted toward the hypercoagulability in 75% of patients one day after cyclophosphamide (4 g/m(2)) chemotherapy. Global hemostasis tests were in good agreement with each other, revealed hypercoagulability and heparin "resistance" in patients with MM and may be useful for therapy individualization.
Rates of venous thromboembolism (VTE) vary substantially between cancer patients. Multiple clinical risk factors including primary site of cancer and systemic therapy, and biomarkers including leukocyte and platelet counts and tissue factor are associated with increased risk of VTE. However, risk cannot be reliably predicted based on single risk factors or biomarkers. New American Society of Clinical Guidelines recommend that patients with cancer be assessed for VTE risk at the time of chemotherapy initiation and periodically thereafter. This narrative review provides an update on risk stratification approaches including a validated Risk Score. Potential applications of risk assessment including targeted thromboprophylaxis are outlined. © 2014 Elsevier Ltd. All rights reserved.
Preclinical evidence suggests that anticoagulants, in particular the low-molecular-weight heparins (LMWH), exert an antitumor effect, whereas clinical trials have reported conflicting results. The authors conducted a comprehensive, systematic review and meta-analysis of the evidence from randomized controlled trials (RCTs), to evaluate the impact of anticoagulants on survival and safety in cancer patients without venous thromboembolism.
A comprehensive systematic literature review of RCTs was performed without language restrictions through May 2006 with subsequent updates to the end of 2006, including an exhaustive search of electronic databases, major conference proceedings, article references, and content experts. Two reviewers extracted data independently. Primary study outcomes were 1-year overall mortality and all bleeding complications. Major and fatal bleeding complications were secondary outcomes.
Across all 11 studies that were identified, anticoagulation significantly decreased 1-year overall mortality with a relative risk (RR) of 0.905 (95% confidence interval [95% CI], 0.847-0.967; P = .003). The RR for mortality was 0.877 (95% CI, 0.789-0.975; P = .015) for LMWH, compared with an RR of 0.942 (95% CI, 0.854-1.040; P = .239) for warfarin, resulting in an absolute risk difference (ARD) of 8% for LMWH and an ARD of 3% for warfarin. Improved survival with anticoagulation may be dependent on tumor type. Major bleeding episodes occurred less frequently in patients who received LMWH (ARD, 1%) compared with patients who received warfarin (ARD, 11.5%; P < .0001). Overall, fatal bleeding occurred rarely (ARD, 0.32%; P = .542).
Anticoagulants, particularly LMWH, significantly improved overall survival in cancer patients without venous thrombosis while increasing the risk for bleeding complications. However, given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results.