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1.
Arthritis Rheumatol ; 72(12): 2130-2135, 2020 12.
Article in English | MEDLINE | ID: mdl-32729667

ABSTRACT

OBJECTIVE: The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils has recently been recognized to play an important role in antiphospholipid syndrome (APS). This study was undertaken to evaluate autoantibodies targeting NETs in patients with primary APS, and to determine their potential functions and clinical associations. METHODS: We measured global anti-NET activity in 76 patients with primary APS, 23 patients with systemic lupus erythematosus without antiphospholipid antibodies (aPL), 11 patients with a history of unprovoked venous thrombosis without aPL, and 44 healthy controls. The ability of APS sera to degrade NETs was also assessed. RESULTS: We found markedly elevated levels of anti-NET IgG and IgM in patients with primary APS compared with healthy controls (for IgG, mean ± SD optical density 0.55 ± 0.34 versus 0.33 ± 0.17; for IgM, mean ± SD optical density 0.76 ± 0.51 versus 0.26 ± 0.23). This anti-NET activity did not correlate with levels of traditional aPL and was relatively stable over time. Mechanistically, anti-NET antibodies (especially of the IgG isotype) impaired the ability of patient sera to degrade NETs (r = 0.4, P = 0.003). Levels of anti-NET IgM inversely correlated with complement C4 (r = 0.4, P = 0.019). Clinically, anti-NET antibodies associated with certain APS clinical manifestations, and in particular recurrent venous thrombosis (odds ratio 4.3; P = 0.002). Interestingly, anti-NET antibody levels also appeared to be associated with unprovoked venous thrombosis in the general population (for IgM, mean ± SD optical density 0.67 ± 0.34 versus 0.26 ± 0.23). CONCLUSION: Our data indicate high levels of anti-NET antibodies in patients with primary APS, which may impair NET clearance and activate the complement cascade. These findings may ultimately enable more effective risk stratification.


Subject(s)
Antibodies, Antiphospholipid/blood , Antiphospholipid Syndrome/immunology , Autoantibodies/blood , Extracellular Traps/immunology , Adult , Aged , Antiphospholipid Syndrome/metabolism , Extracellular Traps/metabolism , Female , Humans , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Male , Middle Aged , Prospective Studies , Retrospective Studies , Young Adult
2.
Arthritis Rheumatol ; 72(1): 114-124, 2020 01.
Article in English | MEDLINE | ID: mdl-31353826

ABSTRACT

OBJECTIVE: While the role of antiphospholipid antibodies in activating endothelial cells has been extensively studied, the impact of these antibodies on the adhesive potential of leukocytes has received less attention. This study was undertaken to investigate the extent to which antiphospholipid syndrome (APS) neutrophils adhere to resting endothelial cells under physiologic flow conditions and the surface molecules required for that adhesion. METHODS: Patients with primary APS (n = 43), patients with a history of venous thrombosis but negative test results for antiphospholipid antibodies (n = 11), and healthy controls (n = 38) were studied. Cells were introduced into a flow chamber and perfused across resting human umbilical vein endothelial cells (HUVECs). Surface adhesion molecules were quantified by flow cytometry. Neutrophil extracellular trap release (NETosis) was assessed in neutrophil-HUVEC cocultures. RESULTS: Upon perfusion of anticoagulated blood through the flow chamber, APS neutrophils demonstrated increased adhesion as compared to control neutrophils under conditions representative of either venous (n = 8; P < 0.05) or arterial (n = 15; P < 0.0001) flow. At the same time, APS neutrophils were characterized by up-regulation of CD64, CEACAM1, ß2 -glycoprotein I, and activated Mac-1 on their surface (n = 12-18; P < 0.05 for all markers). Exposing control neutrophils to APS plasma or APS IgG resulted in increased neutrophil adhesion (n = 10-11; P < 0.0001) and surface marker up-regulation as compared to controls. A monoclonal antibody specific for activated Mac-1 reduced the adhesion of APS neutrophils in the flow-chamber assay (P < 0.01). The same monoclonal antibody reduced NETosis in neutrophil-HUVEC cocultures (P < 0.01). CONCLUSION: APS neutrophils demonstrate increased adhesive potential, which is dependent upon the activated form of Mac-1. In patients, this could lower the threshold for neutrophil-endothelium interactions, NETosis, and possibly thrombotic events.


Subject(s)
Antiphospholipid Syndrome/metabolism , Cell Adhesion , Endothelial Cells/metabolism , Macrophage-1 Antigen/metabolism , Neutrophils/metabolism , Adult , Aged , Case-Control Studies , Extracellular Traps , Female , Human Umbilical Vein Endothelial Cells , Humans , Male , Middle Aged , Young Adult
3.
Nat Commun ; 10(1): 1916, 2019 04 23.
Article in English | MEDLINE | ID: mdl-31015489

ABSTRACT

Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A2A receptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.


Subject(s)
Adenosine A2 Receptor Agonists/pharmacology , Adenosine/analogs & derivatives , Antiphospholipid Syndrome/drug therapy , Extracellular Traps/drug effects , Neutrophils/drug effects , Phenethylamines/pharmacology , Venous Thrombosis/drug therapy , Adenosine/immunology , Adenosine/metabolism , Adenosine/pharmacology , Animals , Antibodies, Antiphospholipid/blood , Antiphospholipid Syndrome/genetics , Antiphospholipid Syndrome/immunology , Antiphospholipid Syndrome/pathology , Cyclic AMP/immunology , Cyclic AMP/metabolism , Dipyridamole/pharmacology , Disease Models, Animal , Extracellular Traps/immunology , Extracellular Traps/metabolism , Fibrinolytic Agents/pharmacology , Gene Expression Regulation , Humans , Immunoglobulin G/blood , Male , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/immunology , Signal Transduction , Vena Cava, Inferior/drug effects , Vena Cava, Inferior/immunology , Vena Cava, Inferior/metabolism , Venous Thrombosis/genetics , Venous Thrombosis/immunology , Venous Thrombosis/pathology
4.
Curr Opin Rheumatol ; 31(3): 231-240, 2019 05.
Article in English | MEDLINE | ID: mdl-30747734

ABSTRACT

PURPOSE OF REVIEW: Although antiphospholipid syndrome (APS) is best known for conveying increased risk of thrombotic events and pregnancy morbidity, thrombocytopenia is also recognized as a common association. In this review, we will explore the relationship between thrombocytopenia and APS, highlighting our evolving understanding - and persistent knowledge gaps - through clinically oriented questions and answers. RECENT FINDINGS: A history of thrombocytopenia likely portends a more severe APS phenotype (including increased risk of thrombosis). Although the pathophysiology underlying thrombocytopenia in APS has yet to be definitively revealed, mechanisms that play a role (at least in subsets of patients) include: immune thrombocytopenic purpura/ITP-like autoantibodies against platelet glycoproteins; antiphospholipid antibody (aPL)-mediated platelet activation and consumption; and potentially life threatening thrombotic microangiopathy. Although thrombocytopenia is often 'mild' in APS (and therefore, may not require specific therapy), there are causes of acute-onset thrombocytopenia that mandate emergent work-up and treatment. When APS-related thrombocytopenia does require therapy, the approach must be individualized (requiring an understanding of pathophysiology in the particular APS patient). For patients with ITP-like disease, rituximab is emerging as a popular approach to treatment; in contrast, there are hints that thrombopoietin mimetics may be associated with elevated thrombotic risk. SUMMARY: Thrombocytopenia is common in APS, and is likely associated with more severe disease. Improved understanding of thrombocytopenia in APS has the potential to improve risk stratification, reveal novel aspects of APS pathophysiology, and lead to treatments that are more individualized and holistic.


Subject(s)
Antibodies, Antiphospholipid , Antiphospholipid Syndrome/complications , Thrombocytopenia/complications , Antiphospholipid Syndrome/immunology , Female , Humans , Male , Pregnancy , Thrombocytopenia/immunology
5.
J Natl Compr Canc Netw ; 16(11): 1289-1303, 2018 11.
Article in English | MEDLINE | ID: mdl-30442731

ABSTRACT

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.


Subject(s)
Anticoagulants/administration & dosage , Hemorrhage/prevention & control , Medical Oncology/standards , Neoplasms/complications , Venous Thromboembolism/drug therapy , Anticoagulants/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination/methods , Drug Therapy, Combination/standards , Hemorrhage/chemically induced , Hemorrhage/mortality , Humans , Medical Oncology/methods , Medication Adherence , Neoplasms/mortality , Patient Selection , Randomized Controlled Trials as Topic , Societies, Medical/standards , Survival Analysis , Time Factors , Treatment Outcome , United States , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/mortality
6.
JCI Insight ; 2(18)2017 09 21.
Article in English | MEDLINE | ID: mdl-28931754

ABSTRACT

Antiphospholipid antibodies, present in one-third of lupus patients, increase the risk of thrombosis. We recently reported a key role for neutrophils - neutrophil extracellular traps (NETs), in particular - in the thrombotic events that define antiphospholipid syndrome (APS). To further elucidate the role of neutrophils in APS, we performed a comprehensive transcriptome analysis of neutrophils isolated from patients with primary APS. Moreover, APS-associated venous thrombosis was modeled by treating mice with IgG prepared from APS patients, followed by partial restriction of blood flow through the inferior vena cava. In patients, APS neutrophils demonstrated a proinflammatory signature with overexpression of genes relevant to IFN signaling, cellular defense, and intercellular adhesion. For in vivo studies, we focused on P-selectin glycoprotein ligand-1 (PSGL-1), a key adhesion molecule overexpressed in APS neutrophils. The introduction of APS IgG (as compared with control IgG) markedly potentiated thrombosis in WT mice, but not PSGL-1-KOs. PSGL-1 deficiency was also associated with reduced leukocyte vessel wall adhesion and NET formation. The thrombosis phenotype was restored in PSGL-1-deficient mice by infusion of WT neutrophils, while an anti-PSGL-1 monoclonal antibody inhibited APS IgG-mediated thrombosis in WT mice. PSGL-1 represents a potential therapeutic target in APS.


Subject(s)
Antiphospholipid Syndrome/immunology , Extracellular Traps/immunology , Neutrophils/immunology , Animals , Antibodies, Antiphospholipid/immunology , Antiphospholipid Syndrome/genetics , Humans , Immunoglobulin G/administration & dosage , Immunoglobulin G/immunology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Mice , Mice, Knockout , Transcriptome , Up-Regulation
7.
Curr Opin Rheumatol ; 29(5): 458-466, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28538012

ABSTRACT

PURPOSE OF REVIEW: Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and pregnancy loss. Upon diagnosis (which is unlikely to be made until at least one morbid event has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future events. This approach is not uniformly effective and does not prevent associated autoimmune and inflammatory complications. The goal of this review is to update clinicians and scientists on mechanistic and clinically relevant studies from the past 18 months, which have especially focused on inflammatory aspects of APS pathophysiology. RECENT FINDINGS: How antiphospholipid antibodies leverage receptors and signaling pathways to activate cells is being increasingly defined. Although established mediators of disease pathogenesis (like endothelial cells and the complement system) continue to receive intensive study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention. In-vivo animal studies and small clinical trials are demonstrating how repurposed medications (hydroxychloroquine, statins, and rivaroxaban) may have clinical benefit in APS, with these concepts importantly supported by mechanistic data. SUMMARY: As anticoagulant medications are not uniformly effective and do not comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.


Subject(s)
Antibodies, Antiphospholipid/immunology , Anticoagulants/therapeutic use , Antiphospholipid Syndrome , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Thrombosis , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/drug therapy , Antiphospholipid Syndrome/immunology , Global Health , Humans , Incidence , Thrombosis/epidemiology , Thrombosis/etiology , Thrombosis/prevention & control
8.
Ann Rheum Dis ; 76(2): 450-457, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27432357

ABSTRACT

OBJECTIVES: Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. METHODS: We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes. RESULTS: Endothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody. CONCLUSIONS: We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.


Subject(s)
Antiphospholipid Syndrome/immunology , Cell Differentiation/physiology , Endothelial Progenitor Cells/physiology , Interferon-alpha/immunology , Leukocytes, Mononuclear/immunology , Adult , Aged , Antibodies, Neutralizing/pharmacology , Antiphospholipid Syndrome/physiopathology , Case-Control Studies , Cell Differentiation/drug effects , Endothelial Progenitor Cells/drug effects , Female , Flow Cytometry , Humans , Interferon Type I/immunology , Male , Middle Aged , Receptor, Interferon alpha-beta/antagonists & inhibitors , Young Adult
9.
J Natl Compr Canc Netw ; 13(9): 1079-95, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26358792

ABSTRACT

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.


Subject(s)
Anticoagulants/administration & dosage , Neoplasms/complications , Obesity/complications , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & control , Adult , Body Mass Index , Body Weight , Dalteparin/administration & dosage , Enoxaparin/administration & dosage , Fondaparinux , Heparin/administration & dosage , Humans , Polysaccharides/administration & dosage , Practice Guidelines as Topic , Renal Insufficiency, Chronic/complications , Venous Thromboembolism/etiology
10.
Arthritis Rheumatol ; 67(11): 2990-3003, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26097119

ABSTRACT

OBJECTIVE: Antiphospholipid antibodies (aPL), especially those targeting ß2 -glycoprotein I (ß2 GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. This study was undertaken to determine whether aPL activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent in the antiphospholipid syndrome (APS). METHODS: Neutrophils, sera, and plasma were prepared from patients with primary APS (n = 52) or from healthy volunteers and characterized. No patient had concomitant systemic lupus erythematosus. RESULTS: Sera and plasma from patients with primary APS had elevated levels of both cell-free DNA and NETs, as compared to healthy volunteers. Freshly isolated neutrophils from patients with APS were predisposed to high levels of spontaneous NET release. Further, APS patient sera, as well as IgG purified from APS patients, stimulated NET release from control neutrophils. Human aPL monoclonal antibodies, especially those targeting ß2 GPI, also enhanced NET release. The induction of APS NETs was abrogated with inhibitors of reactive oxygen species formation and Toll-like receptor 4 signaling. Highlighting the potential clinical relevance of these findings, APS NETs promoted thrombin generation. CONCLUSION: Our findings indicate that NET release warrants further investigation as a novel therapeutic target in APS.


Subject(s)
Antibodies, Antiphospholipid/immunology , Antiphospholipid Syndrome/immunology , Extracellular Traps , Neutrophils/immunology , Thrombosis/immunology , Antiphospholipid Syndrome/metabolism , Humans , Immunoglobulin G/immunology , Neutrophils/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/physiology , Thrombosis/metabolism , Toll-Like Receptor 4/metabolism
11.
Thromb Res ; 133(1): 108-11, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24246297

ABSTRACT

INTRODUCTION: Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes. METHODS: Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC). RESULTS: Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population. CONCLUSIONS: Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes.


Subject(s)
Black or African American/statistics & numerical data , Pregnancy Complications, Hematologic/blood , Pregnancy Complications, Hematologic/ethnology , Thrombosis/blood , Thrombosis/ethnology , White People/statistics & numerical data , Adult , Female , Health Status Disparities , Humans , Pregnancy , Pregnancy Complications, Hematologic/epidemiology , Risk Factors , Thrombosis/epidemiology , United States/epidemiology
12.
J Natl Compr Canc Netw ; 11(11): 1402-29, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24225973

ABSTRACT

Venous thromboembolism (VTE) remains a common and life-threatening complication among patients with cancer. Thromboprophylaxis can be used to prevent the occurrence of VTE in patients with cancer who are considered at high risk for developing this complication. Therefore, it is critical to recognize the various risk factors for VTE in patients with cancer. Risk assessment tools are available to help identify patients for whom discussions regarding the potential benefits and risks of thromboprophylaxis would be appropriate. The NCCN Clinical Practice Guidelines in Oncology for VTE provide recommendations on risk evaluation, diagnosis, prevention, and treatment of VTE in patients with cancer.


Subject(s)
Neoplasms/complications , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Anticoagulants/therapeutic use , Humans , Premedication , Risk Assessment , Venous Thromboembolism/prevention & control
14.
Hematol Oncol Clin North Am ; 25(2): 293-310, vii-viii, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21444031

ABSTRACT

Thrombocytopenia in pregnancy is most frequently a benign process that does not require intervention. However, 35% of cases of thrombocytopenia in pregnancy are related to disease processes that may have serious bleeding consequences at delivery or for which thrombocytopenia may be an indicator of a more severe systemic disorder requiring emergent maternal and fetal care. Thus, all pregnant women with platelet counts less than 100,000/µL require careful hematological and obstetric consultation to exclude more serious disorders.


Subject(s)
Pregnancy Complications, Hematologic , Thrombocytopenia , Blood Flow Velocity , Delivery, Obstetric , Female , HELLP Syndrome/blood , HELLP Syndrome/diagnosis , HELLP Syndrome/therapy , Hemostasis , Humans , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/therapy , Placenta/blood supply , Platelet Count , Pregnancy , Pregnancy Complications, Hematologic/blood , Pregnancy Complications, Hematologic/diagnosis , Pregnancy Complications, Hematologic/therapy , Thrombocytopenia/blood , Thrombocytopenia/diagnosis , Thrombocytopenia/etiology , Thrombocytopenia/therapy , Uterine Hemorrhage/blood , Uterine Hemorrhage/diagnosis , Uterine Hemorrhage/prevention & control
15.
Am J Hematol ; 85(7): 467-71, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20575037

ABSTRACT

When compared with Whites, Black-Americans may have a 40% higher incidence venous thromboembolism (VTE) incidence. However, whether other VTE characteristics and risk factors vary by race is uncertain. To compare demographic and baseline characteristics among White- and Black-Americans with VTE, we used data prospectively collected from consecutive consenting adults enrolled in seven Centers for Disease Control (CDC) Thrombosis and Hemostasis Centers from August 2003 to March 2009. These characteristics were compared among Whites (n = 2002) and Blacks (n = 395) with objectively diagnosed VTE, both overall, and by age and gender. When compared with Whites, Blacks had a significantly higher proportion with pulmonary embolism (PE), including idiopathic PE among Black women, and a significantly higher proportion of Blacks were women. Blacks had a significantly higher mean BMI and a significantly lower proportion with recent surgery, trauma or infection, family history of VTE, and documented thrombophilia (solely from reduced factor V Leiden and prothrombin G20210A prevalence). Conversely, Blacks had a significantly higher proportion with hypertension, diabetes mellitus, chronic renal disease and dialysis, HIV, and sickle cell disease. When compared with White women, Black women had a significantly lower proportion with recent oral contraceptive use or hormone therapy. We conclude that Whites and Blacks differ significantly regarding demographic and baseline characteristics that may be risk factors for VTE. The prevalence of transient VTE risk factors and idiopathic VTE among Blacks appears to be lower and higher, respectively, suggesting that heritability may be important in the etiology of VTE among Black-Americans.


Subject(s)
Black or African American/statistics & numerical data , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology , Cross-Sectional Studies , Humans , Incidence , Prospective Studies , Pulmonary Embolism/etiology , Risk Factors , Venous Thromboembolism/ethnology , White People/statistics & numerical data
17.
Article in English | MEDLINE | ID: mdl-17124097

ABSTRACT

The clinical management of individuals with hereditary hypercoaguable disorders has evolved from initial broad recommendations of lifelong anticoagulation after first event of venous thromboembolism to a more intricate individualized risk-benefit analysis as studies have begun to delineate the complexity of interactions of acquired and hereditary factors which determine the predilection to thrombosis. The contribution of thrombophilic disorders to risk of thrombotic complications of pregnancy, organ transplantation, central venous catheter and dialysis access placement have been increasingly recognized. The risk of thrombosis must be weighed against risk of long-term anticoagulation in patients with venous thromboembolism. Thrombophilia screening in select populations may enhance outcome.


Subject(s)
Thrombophilia/drug therapy , Anticoagulants/therapeutic use , Blood Coagulation Disorders, Inherited/complications , Blood Coagulation Disorders, Inherited/drug therapy , Disease Management , Humans , Thrombophilia/complications , Thrombophilia/genetics , Thrombosis/etiology , Thrombosis/prevention & control
19.
Arch Neurol ; 60(9): 1303-6, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12975299

ABSTRACT

OBJECTIVE: To describe a patient with idiopathic zinc overload without an identifiable source and secondary copper deficiency causing myelopolyneuropathy and pancytopenia. DESIGN: Case report. PATIENT AND RESULTS: A 46-year-old man presented with severe bone marrow suppression and subsequently developed progressive myelopathy with sensory ataxia. No identifiable cause of myelopathy was detected, and his neuroimaging findings were unremarkable. Plasma analysis demonstrated a low copper level and an increased zinc level (<10 micro g/dL [<12.6-18.9 micro mol/L] and 184 micro g/dL [28.2 micro mol/L], respectively; normal range for both, 80-120 micro g/dL [12.6-18.9 micro mol/L and 12.3-18.4 micro mol/L, respectively) and a low level of ceruloplasmin. There was no evidence for an external source of zinc. Daily oral supplementation with 2 mg resulted in the prompt reversal of hematologic abnormalities, improved but still subnormal plasma copper levels, and normalization of ceruloplasmin values. The patient's neurologic condition deteriorated further, with worsening of myelopathy and development of polyneuropathy. Analyses of plasma copper and zinc levels demonstrated persisting hyperzincemia and subnormal copper levels during 4 years of follow-up. Increased copper supplementation to 8 mg/d partially reversed his neurologic signs. A clinical investigation of 6 siblings and 1 surviving parent did not identify family members with similar abnormalities. CONCLUSIONS: Persistent hyperzincemia without an identifiable external source appears to be a primary metabolic defect, while copper deficiency is a secondary phenomenon, causing hematologic and neurologic abnormalities. Two unrelated patients with similar idiopathic hyperzincemia and hypocupremia have been recently described. This suggests the existence of a new metabolic disorder with idiopathic zinc overload.


Subject(s)
Copper/deficiency , Pancytopenia/complications , Polyneuropathies/complications , Polyneuropathies/metabolism , Spinal Cord Diseases/complications , Spinal Cord Diseases/metabolism , Zinc/blood , Copper/blood , Copper/therapeutic use , Humans , Male , Middle Aged , Polyneuropathies/drug therapy
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