Thrombosis in Multiple Myeloma

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 437-444 ◽  
Author(s):  
Sigurdur Yngvi Kristinsson
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Protein C ◽  
Activated Protein C ◽  
Low Molecular Weight ◽  
Related Factors ◽  
Inherited Thrombophilia ◽  
Increased Risk ◽  
Multi Agent

Abstract Patients with multiple myeloma (MM) are at an increased risk of venous and arterial thrombosis. The pathogenesis remains unclear, but probably involves several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to general risk factors for venous thromboembolism, such as older age, immobility, surgery, and inherited thrombophilia, there are some MM-specific and treatment-related factors that contribute to the increased risk. The risk for venous thromboembolism is high when patients are treated with thalidomide or lenalidomide in combination with dexamethasone or multi-agent chemotherapy. Thromboprophylaxis should be given in these settings. Which agent is the most appropriate is a matter of debate, but aspirin, low-molecular-weight heparin, and warfarin all seem to be effective. This review discusses risk factors for thromboembolism in MM and general, disease-specific and treatment-related mechanisms for thrombosis. Recommendations for thromboprophylaxis are described and treatment choices for venous thrombosis in MM patients are reviewed.

Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk

2004 ◽  
Vol 91 (05) ◽  
pp. 905-911 ◽  
Author(s):  
Pilar Medina ◽  
Silvia Navarro ◽  
Amparo Estellés ◽  
Amparo Vayá ◽  
Barry Woodhams ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Receptor Gene ◽  
Activated Protein C ◽  
Soluble Form ◽  
Cell Protein ◽  
Endothelial Protein C Receptor ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
The Relationship

SummaryEndothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, we described two polymorphisms in exon 4 of the EPCR gene, 4600A/G that encodes the substitution of Ser219 by Gly in the transmembrane region of EPCR and 4678G/C in the 3’-UT region. The aim of this study was to investigate the relationship between these two polymorphisms and plasma sEPCR and APC levels and risk of venous thrombosis. We genotyped 401 healthy controls from the Spanish population and measured their plasma sEPCR and APC levels. Carriers of the 4600AG genotype had significantly higher sEPCR levels than those with the AA genotype, while the 4678CC genotype was associated, to a lesser extent, with elevated APC levels. To assess the effect of these polymorphisms on the risk of thrombosis, we genotyped 405 patients with venous thromboembolism. The frequency of the 4600AG genotype was very similar in patients and controls (p=0.975), whereas the 4678CC genotype was significantly more frequent in controls than in patients (p=0.008). In multivariate analysis, carriers of the 4678CC genotype had a decreased risk of thrombosis (OR=0.61, p=0.009). These data indicate that individuals carrying the 4600AG genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism.

Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S–C4b binding protein complex

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1192-1201 ◽  
Author(s):  
Suely Meireles Rezende ◽  
Rachel Elizabeth Simmonds ◽  
David Anthony Lane
Keyword(s):  
Venous Thromboembolism ◽  
Complement Activation ◽  
Protein C ◽  
Binding Protein ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Increased Risk ◽  
Established Role ◽  
Structure And Functions

AbstractProtein S (PS) has an established role as an important cofactor to activated protein C (APC) in the degradation of coagulation cofactors Va and VIIIa. This anticoagulant role is evident from the consequences of its deficiency, when there is an increased risk of venous thromboembolism. In human plasma, PS circulates approximately 40% as free PS (FPS) and 60% in complex with C4b-binding protein (C4BP). Formation of this complex results in loss of PS cofactor function, and C4BP can then modulate the anticoagulant activity of APC. It had long been predicted that the complex could act as a bridge between coagulation and inflammation due to the involvement of C4BP in regulating complement activation. This prediction was recently supported by the demonstration of binding of the PS-C4BP complex to apoptotic cells. This review aims to summarize recent findings on the structure and functions of PS, the basis and importance of its deficiency, its interaction with C4BP, and the possible physiologic and pathologic importance of the PS-C4BP interaction.

scholarly journals Evaluation of Direct Oral Anticoagulants in the Treatment of Venous Thromboembolism for Inherited Thrombophilia Disorders

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5007-5007 ◽  
Author(s):  
Ali McBride ◽  
Reem Diri ◽  
Ravitharan Krishnadasan ◽  
Pavani Chalasani ◽  
Ivo Abraham ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Protein C ◽  
Factor V Leiden ◽  
Secondary Prophylaxis ◽  
Factor V ◽  
Inherited Thrombophilia ◽  
Dvt Prophylaxis ◽  
Prothrombin Gene ◽  
Baseline Characteristics

Abstract Background Venous thromboembolism can be classified according to the presence of either environmental or genetic risk factors. Risk factors for thrombosis can include activated protein C resistance, and heritable including deficiencies of antithrombin, protein C or protein S. Factor V Leiden deficiency and prothrombin gene mutations are some of the more common thrombophilias, with a slight increased risk for venous thromboembolism (VTE). Current guidelines suggest the use of low-molecular weight heparins for secondary prophylaxis in patients with VTE. However, there is a lack of data on the use of Direct Oral Anticoagulant (DOACs) in patients with inherited thrombophilia. We evaluated our use of rivaroxaban in patients with thrombophilia disorders treated for secondary DVT prophylaxis. Method We performed a retrospective evaluation of patients in our institution with inherited thrombophilia with an active VTE diagnosis who received DOACs for secondary prophylaxis from November 2013 until April 2016. Data collected included patient demographics, inherited thrombophilia mutation, previous history of VTE, prior treatments, and efficacy and safety of anticoagulation with DOACs. Results We had 13 patients with inherited thrombophilia mutation and 4 patients diagnosed with concomitant cancer (non-Hodgkin lymphoma, melanoma, and 2 with breast cancer) (Table 1). Out of 13 patients 3 failed warfarin, and one failed fondaparinux prior to switching to a DOAC. Mutation with heterozygous Factor V Leiden deficiency was reported in 7 patients, while mutations with Protein C and/or S deficiency were found in 4 patients. One patient had both Factor V Leiden and Protein C deficiency mutations. The prothrombin gene mutation was identified in one patient. The median of length of therapy was 2 years with 8/13 still on rivaroxaban in April 2016. The shortest treatment duration was 41 days for a patient who failed rivaroxaban with a second clot and was switched to apixaban without subsequent treatment failure. Two patients experienced 4 non-major episodes of gastrointestinal bleeding, nose bleeding and dark stool. One patient developed rash with noted bruising during their rivaroxaban therapy. Conclusion: This is the first report on outcomes for secondary DVT prophylaxis with DOACs in patients with underlying thrombophilia mutations. Safety and efficacy of DOACs for secondary VTE prophylaxis yielded favorable results; however, future prospective studies in the setting of thrombophilia are warranted. Table 1 Summary of baseline characteristics and outcomes. Table 1. Summary of baseline characteristics and outcomes. Disclosures McBride: Sanofi: Research Funding.

Risk Factors in Venous Thromboembolism

2001 ◽  
Vol 86 (07) ◽  
pp. 395-403 ◽  
Author(s):  
Ida Martinelli
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Nucleotide Substitutions ◽  
Inherited Thrombophilia ◽  
G20210a Mutation ◽  
Increased Risk

SummaryVenous thromboembolism is a serious disorder because of its potential complications, such as pulmonary embolism and the post-thrombotic syndrome. Inherited determinants of venous thromboembolism are only in part known, but in the past decades considerable progress has been made in the understanding of risk factors for the disease and their clinical impact. In particular, the development of molecular biology techniques and the increasing interest in their application, allowed an identification of two causes of inherited thrombophilia, i.e., factor V Leiden and the prothrombin G20210A mutation. Their recent discovery provided a new approach for improving the knowledge of inherited thrombophilia. In contrast to deficiencies of the naturally occurring anticoagulant proteins antithrombin, protein C and protein S, these two mutations cannot be considered true genetic defects, since they are nucleotide substitutions resulting in a more efficient coagulation process. Since they are rather common in the general populations of Caucasian descent and are associated with a moderate increased risk of venous thromboembolism, the effect of the interaction between inherited and environmental risk factors for venous thromboembolism has become an even greater field of interest. Prevention of first events and recurrences of venous thromboembolism can be optimized only through a knowledge of the main risk factors, their effect, and their interaction with environmental factors.

A prospective study of venous thromboembolism in relation to factor V Leiden and related factors

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2720-2725 ◽  
Author(s):  
Aaron R. Folsom ◽  
Mary Cushman ◽  
Michael Y. Tsai ◽  
Nena Aleksic ◽  
Susan R. Heckbert ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Population Based ◽  
Factor V ◽  
Related Factors ◽  
Apc Resistance ◽  
Increased Risk ◽  
Plasma Factor ◽  
V Antigen

Abstract The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V–related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V–deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.

Risk of Venous Thromboembolism in Multiple Myeloma: Identification of Risk Factor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4726-4726 ◽  
Author(s):  
Kristen M. Sanfilippo ◽  
Natasha Catherine Edwin ◽  
Brian F. Gage ◽  
Suhong Luo ◽  
David Calverley ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Venous Thromboembolism ◽  
Research Funding ◽  
Laboratory Data ◽  
Cell Transplant ◽  
Filter Placement ◽  
Blood Institute ◽  
Increased Risk

Abstract Background Compared to the general population, patients with multiple myeloma (MM) have a 9-fold increased risk of developing venous thromboembolism (VTE). VTE is a preventable disease that causes death and morbidity. Thromboprophylaxis is a safe and effective way to decrease VTE in other high-risk populations (i.e. atrial fibrillation). Current guidelines recommend pharmacologic thromboprophylaxis in patients with MM receiving an immunomodulatory agent in the presence of additional VTE risk factors. However, putative risk factors vary across guidelines and lack validation. Recently, an attempt to validate the International Myeloma Working Group 2014 guidelines for thromboprophylaxis found current risk factors to be inadequate. Identification of risk factors for VTE in MM can allow for effective risk-stratification to clarify thromboprophylaxis in the MM population. We sought to identify risk factors for VTE in patients with MM. Methods We identified patients diagnosed with MM within the Veterans Administration Central Cancer Registry from September 1, 1999 and December 31, 2013 and followed them through October 2014. We excluded patients who did not receive MM-directed therapy within 6 months of diagnosis. Using a previously validated algorithm, (Thromb Res, 2015), we identified patients diagnosed with VTE after MM diagnosis by a combination of ICD-9 code for VTE plus pharmacologic treatment for VTE or IVC filter placement. We obtained information on baseline patient demographics, medical comorbidities, laboratory data, MM-directed therapy, and use of aspirin and/or warfarin. Univariate analyses identified the association between individual variables and VTE in the cohort. Clinically meaningful and significant associations were included in the multivariate model. Multivariate analysis was done using competing risks regression modeling. The study was approved by the Saint Louis VHA Medical Center and Washington University institutional review boards. Results A total of 3,384 patients comprised the final cohort of whom 414 developed a VTE. Patients who developed VTE were more likely to be younger (66.2 vs 68.5, p < .001), have a body mass index (BMI) ≥ 25 (p < .001), be diagnosed with MM prior to 2007 (p < .001), have a VTE before MM diagnosis (p < .001), have a lower comorbidities (p < .001), have received autologous stem cell transplant (ASCT) (p < .001), have received lenalidomide, thalidomide, or bortezomib (p < .001), and less likely to have received warfarin (p < .001). Among predefined risk factors, age (Hazard Ratio (HR) 0.99, 95% Confidence Interval (CI) 0.98-1.00, p = 0.02), VTE before MM diagnosis (HR 4.13, 95% CI 2.81-6.05, p < .001), heart failure (HR 0.70, 95% CI 0.51-0.96, p = 0.03), treatment with thalidomide (HR 2.02, 95% CI 1.63-2.50, p < 0.001), BMI ≥ 30 (HR 1.34, 95% CI 1.03-1.74, p = 0.03), and diabetes mellitus (HR 0.79, 95% CI 0.63-0.99, p = 0.04) were associated with VTE. After inclusion into multivariate analysis and adjusting for warfarin/aspirin use; age, BMI, year of MM diagnosis, VTE before MM, thalidomide, warfarin, and aspirin were all associated with VTE in MM (Table 1). Conclusion We identified several risk factors associated with VTE in MM. Incorporation of these risk factors into a MM-specific risk model has the potential to reduce risk of VTE in MM. Disclosures Sanfilippo: National Heart, Lung, and Blood Institute: Research Funding. Gage:National Heart, Lung, and Blood Institute: Research Funding. Carson:American Cancer Society: Research Funding.

Thrombotic Variables and Risk of Idiopathic Venous Thromboembolism in Women Aged 45-64 Years

2000 ◽  
Vol 83 (04) ◽  
pp. 530-535 ◽  
Author(s):  
Mark Woodward ◽  
Martin Vessey ◽  
Ann Rumley ◽  
Parimala Gough ◽  
Edel Daly ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Relative Risk ◽  
Protein C ◽  
Controlled Trial ◽  
Hormone Replacement ◽  
Activated Protein C ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Apc Resistance ◽  
Increased Risk

SummaryHormone replacement therapy (HRT) has been shown to increase the relative risk of idiopathic venous thromboembolism (VTE) about threefold in several observational studies and one randomised controlled trial. Whether or not this relative risk is higher in women with underlying thrombophilia phenotypes, such as activated protein C (APC) resistance, is unknown. We therefore restudied the participants in a case-control study of the relationship between the use of HRT and the occurrence of idiopathic VTE in women aged 45-64 years. After protocol exclusions, 66 of the cases in the original study and 163 of the controls were studied. Twenty haematological variables relevant to risk of VTE were analysed, including thrombotic states defined from the literature. The relative risk of VTE showed significant associations with APC resistance (OR 4.06; 95% CI 1.62, 10.21); low antithrombin (3.33; 1.15, 9.65) or protein C (2.93; 1.06, 8.14); and high coagulation factor IX (2.34; 1.26, 4.35), or fibrin D-dimer (3.84; 1.99, 7.42). HRT use increased the risk of VTE in women without any of these thrombotic states (OR 4.09; 95% CI 1.26, 13.30). A similar effect of HRT use on the relative risk of VTE was also found in women with prothrombotic states. Thus for example, the combination of HRT use and APC resistance increased the risk of VTE about 13-fold compared with women of similar age without either APC resistance or HRT use (OR 13.27; 95% CI 4.30, 40.97).We conclude that the combination of HRT use and thrombophilias (especially if multiple) increases the relative risk of VTE substantially; hence women known to have thrombophilias (especially if multiple) should be counselled about this increased risk prior to prescription of HRT. However, HRT increases the risk of VTE about fourfold even in women without any thrombotic abnormalities: possible causes are discussed.

State-of-the-Art Review: Activated Protein C Resistance: Clinical Implications

1997 ◽  
Vol 3 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Bengt Zöller ◽  
Andreas Hillarp ◽  
Björn Dahlbäck
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Factor V ◽  
Thrombotic Risk ◽  
Western Countries ◽  
Apc Resistance ◽  
Increased Risk

The discovery of inherited resistance to activated protein C (APC) as a major risk factor for venous thrombosis has dramatically improved our understanding of the pathogenesis of venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene (FV) that results in substitution of arginine, R, at position 506 by glutamine, Q. (FV:Q506). The mutation renders factor Va partially resistant to degradation by APC. A functional APC resistance test, which includes predilution of the patient plasma with factor V-deficient plasma, is found to be 100% sensitive and specific for the presence of FV:Q506 and is useful as a screening assay. Carriers of the FV:Q506 allele have increased thrombin generation, resulting in hypercoagulability and a lifelong increased risk of venous thrombosis. In Western countries, APC resistance due to the FV mutation is present in 20-60% of thrombosis patients and in 1-15% of healthy controls, whereas the mutation is virtually absent from ethnic groups other than Caucasians. This may explain the high incidence of venous thrombosis in Western countries. The thrombotic risk in APC-resistant individuals may be further increased by other genetic defects, e.g., protein C or protein S deficiency, and by exposure to circumstantial risk factors, e.g., oral contraceptives, pregnancy, immobilization, and surgery. The question is thus raised as to whether general screening for APC resistance before circumstantial risk factors occur is warranted in Western countries. Key Words: Factor V—APC resistance-Protein C-Protein S—Thrombosis—Mutation.

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