Effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients

Chalayer, Emilie; Tardy‐Poncet, Brigitte; Montmartin, Aurélie; Boussoualim, Karima; Genthon, Alexis; Tardy, Bernard

doi:10.1111/bjh.15815

Cited by 4 publications

(5 citation statements)

References 9 publications

(9 reference statements)

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“…Several studies have tried to study coagulation in MM-patients with standard plasma thrombin generation profiles. The results of those studies were inconclusive: some studies observed an increased TG (ETP) in PPP (29)(30)(31)(32), other studies, including ours, found no difference between MM patients and controls (33,34) while there are also studies that reported a reduced TG (ETP) in MM patients (35,36). One study observed no effect on the ETP and Peak, however, the TTP was reduced and the velocity index increased in MM patients compared to controls (37).…”

Section: Discussionmentioning

confidence: 83%

Patients With Multiple Myeloma Have a Disbalanced Whole Blood Thrombin Generation Profile

Roest

Sang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundMultiple myeloma (MM) is associated with a high prevalence of bleeding and an increased risk of thrombo-embolism. MM patients have reduced platelet- and red blood cell (RBC) numbers in blood, which may indicate that the paradoxical hemostasis profile is a consequence of a disturbed platelet and RBC homeostasis.ObjectivesTo get better insight in the disbalanced hemostasis of MM patients.MethodsWe conducted a case-control study on the whole blood (WB) coagulation profiles of 21 MM patients and 21 controls. We measured thrombin generation (TG) in WB and platelet poor plasma (PPP) of MM patients and controls.ResultsIn WB-TG, we observed that the median time to the thrombin Peak was 52% longer in MM patients than in controls, while the median endogenous thrombin potential until the Peak (ETPp) was 39% higher in MM-patients than in controls. In line with these findings, the levels of platelets, RBCs, white blood cells and agonist induced platelet activation were decreased in MM patients compared to controls. The plasma TG experiments showed no differences between MM-patients and controls.ConclusionPatients with MM have a disturbed blood cell metabolism and a disbalanced WB-TG profile. This disbalance may explain the paradoxically high prevalence of bleeding symptoms in MM patients vs. an increased thrombosis risk. There was no disturbance observed in plasma TG, indicating that blood cells are the major determinants for the disbalanced hemostasis in MM patients.

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Section: Discussionmentioning

confidence: 83%

Patients With Multiple Myeloma Have a Disbalanced Whole Blood Thrombin Generation Profile

Roest

Sang

et al. 2022

Front. Cardiovasc. Med.

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“…The reasons behind this failure are not fully understood but are likely multifactorial 27 . Some studies have proposed the possibility of “heparin resistance” in MM and have sought to evaluate the role of thrombin generation testing, a test of global hemostasis, to evaluate heparin efficacy in MM disease but results have been conflicting thus far 28,29 …”

Section: Thrombosis In Multiple Myelomamentioning

confidence: 99%

“…27 Some studies have proposed the possibility of "heparin resistance" in MM and have sought to evaluate the role of thrombin generation testing, a test of global hemostasis, to evaluate heparin efficacy in MM disease but results have been conflicting thus far. 28,29 A number of internationally validated and clinically utilized risk scores have been developed to stratify VTE risk in patients with solid tumors who may benefit from thromboprophylaxis with anticoagulant agents. 30 These prediction tools are based upon a number of laboratory/clinical parameters.…”

Section: Thrombos Is In Multiple Myelomamentioning

confidence: 99%

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

Comerford

Glavey

Quinn

et al. 2022

Journal of Thrombosis and Haemostasis

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Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti‐myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS‐13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS‐13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.

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“…Chalayer et al . [ 38 ] describe their observations where they sought to characterise the effect of heparin thromboprophylaxis on thrombin generation in a cohort of patient with MM with a view to exploring potential mechanisms of heparin resistance. They compared a group of patients with MM with intermediate/high VTE risk factors with a group of patients hospitalised with respiratory illness who were deemed to have a low thrombotic risk.…”

Section: Possible Mechanisms Of Resistance: Thrombin-mediatedmentioning

confidence: 99%

“…They compared a group of patients with MM with intermediate/high VTE risk factors with a group of patients hospitalised with respiratory illness who were deemed to have a low thrombotic risk. They observed similar ETP levels in both of the groups and concluded that there was no in vitro evidence of specific resistance to LMWH in this particular cohort of MM patients [ 38 ] . Gracheva et al [ 39 ] also assessed a variety of global haemostasis assays (including TGAs, thromboelastography and thrombodynamics) in a cohort of 59 patients, 25 with NDMM and 34 patients undergoing stem cell mobilisation.…”

Section: Possible Mechanisms Of Resistance: Thrombin-mediatedmentioning

confidence: 99%

Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma

Comerford¹,

Glavey²,

O’Sullivan³

et al. 2022

CDR

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Multiple Myeloma (MM) is a common haematological malignancy that is associated with a high rate of venous thromboembolism (VTE) with almost 10% of patients suffering thrombosis during their disease course. Recent studies have shown that, despite current thromboprophylaxis strategies, VTE rates in MM remain disappointingly high. The pathophysiology behind this consistently high rate of VTE is likely multifactorial. A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients, however, the optimal method of clinically evaluating this is unclear at present, though some groups have attempted its characterisation with thrombin generation testing (TGT). In addition to testing for heparin resistance, TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels. Apart from these thrombin-mediated processes, other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance, endothelial toxicity secondary to chemotherapy agents, tissue factor abnormalities and the effect of immunoglobulins/“M-proteins” on both the endothelium and on fibrin fibre polymerisation. It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.

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Effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients

Cited by 4 publications

References 9 publications

Patients With Multiple Myeloma Have a Disbalanced Whole Blood Thrombin Generation Profile

Patients With Multiple Myeloma Have a Disbalanced Whole Blood Thrombin Generation Profile

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma

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