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2.
Ned Tijdschr Geneeskd ; 157(39): A6237, 2013.
Artigo em Holandês | MEDLINE | ID: mdl-24063671

RESUMO

BACKGROUND: Type II heparin induced thrombocytopenia (HIT) is a procoagulant disorder that is caused by IgG-antibodies against platelet factor 4 (PF4)-heparin (H) complex. Clotting tendency is also increased. This is characterized by a ≥ 50% decrease in platelet count between 5-10 days after exposure to unfractionated or low-molecular weight heparin. CASE DESCRIPTION: A 49-year-old woman presented with neurological symptoms and pain in her right hand shortly after hospitalisation in Spain. She had an ischaemic CVA and arterial perfusion difficulties in her right arm due to a large thrombus in the aortic arch and some of its branches. She was treated with thrombolytic therapy and dalteparin. Based on initially mild thrombocytopenia that progressed rapidly after admission and her 7-day exposure to enoxaparin during the previous hospital admission, we diagnosed heparin induced thrombocytopenia (HIT) with arterial thrombosis. CONCLUSION: It can be difficult to diagnose HIT. A clinical probability score based on clinical parameters and laboratory results is useful in this. Quick diagnosis and treatment are of great importance because of the high risk of complications.


Assuntos
Anticoagulantes/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/complicações , Trombose/etiologia , Anticoagulantes/imunologia , Feminino , Heparina de Baixo Peso Molecular/imunologia , Humanos , Pessoa de Meia-Idade , Contagem de Plaquetas , Fator Plaquetário 4/imunologia , Espanha , Trombocitopenia/imunologia , Trombocitopenia/terapia
4.
Am J Respir Cell Mol Biol ; 47(2): 196-202, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22427536

RESUMO

Proteoglycans (PGs) and their associated glycosaminoglycan side chains are effectors of inflammation, but little is known about changes to the composition of PGs in response to lung infection or injury. The goals of this study were to identify changes to heparan sulfate PGs in a mouse model of gram-negative pneumonia, to identify the Toll-like receptor adaptor molecules responsible for these changes, and to determine the role of the heparan sulfate PG in the innate immune response in the lungs. We treated mice with intratracheal LPS, a component of the cell wall of gram-negative bacteria, to model gram-negative pneumonia. Mice treated with intratracheal LPS had a rapid and selective increase in syndecan-4 mRNA that was regulated through MyD88-dependent mechanisms, whereas expression of several other PGs was not affected. To determine the role of syndecan-4 in the inflammatory response, we exposed mice deficient in syndecan-4 to LPS and found a significant increase in neutrophil numbers and amounts of CXC-chemokines and total protein in bronchoalveolar lavage fluid. In studies performed in vitro, macrophages and epithelial cells treated with LPS had increased expression of syndecan-4. Studies performed using BEAS-2B cells showed that pretreatment with heparin and syndecan-4 decreased the expression of CXCL8 mRNA in response to LPS and TNF-α. These findings indicate that the early inflammatory response to LPS involves marked up-regulation of syndecan-4, which functions to limit the extent of pulmonary inflammation and lung injury.


Assuntos
Lipopolissacarídeos/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pneumonia/imunologia , Pneumonia/metabolismo , Sindecana-4/imunologia , Sindecana-4/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Proteoglicanas de Heparan Sulfato/genética , Proteoglicanas de Heparan Sulfato/imunologia , Proteoglicanas de Heparan Sulfato/metabolismo , Heparina de Baixo Peso Molecular/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Interleucina-8/metabolismo , Lipopolissacarídeos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Lesão Pulmonar/genética , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/metabolismo , Pneumonia/genética , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Sindecana-4/deficiência , Sindecana-4/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/genética , Regulação para Cima/imunologia
5.
Semin Thromb Hemost ; 37(3): 322-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21455866

RESUMO

Generic drugs are an important component for meaningful health-care reform currently being debated in the United States. Aside from defining the period of drug exclusivity, however, there is a critical need to ensure that generics of biologic medicines (biosimilars) are safe and effective. For low molecular weight heparins (LMWHs), the standard of care for management of venous thromboembolism, their complex structure and polypharmacological actions make producing a generic LMWH more challenging than a generic small molecule medicine. Because biosimilar LMWHs will be used interchangeably with their branded product, inherent variability between products could lead to important differences in potency, safety, or effectiveness, including unanticipated immune responses. Awareness of the specific problems associated with biosimilar LMWH development led to new recommendations from several expert bodies. This article discusses the implications of these differences for the production of biosimilar LMWHs and provides recommendations to address the limitations in the pending U.S. Congress legislation, a well-intentioned undertaking but one that must preserve the health and welfare of citizens who require these critical care medications.


Assuntos
Medicamentos Genéricos/normas , Heparina de Baixo Peso Molecular/química , Equivalência Terapêutica , Anticoagulantes/normas , Reações Antígeno-Anticorpo , Aprovação de Drogas , Desenho de Fármacos , Heparina de Baixo Peso Molecular/imunologia , Heparina de Baixo Peso Molecular/normas , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Preparações Farmacêuticas/normas , Tromboembolia/tratamento farmacológico , Estados Unidos
6.
Thromb Res ; 128(4): 361-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21458847

RESUMO

INTRODUCTION: Lower low-molecular-weight heparins are being developed to improve on the safety and efficacy of antithrombotic therapy. Semuloparin and bemiparin are two depolymerized heparins produced by distinct manufacturing processes. The objective of this investigation was to determine whether a common standard could be used to define their potency. MATERIALS AND METHODS: Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. RESULTS: The activity of semuloparin and bemiparin was comparable in FXa-based assays (anti-FXa, Heptest). However, bemiparin produced a stronger effect in the aPTT, ACT and anti-thrombin assays. Assessment of the parallelism of the concentration-response curves indicated that bemiparin and semuloparin are not equivalent in terms of anti-FIIa activity. Bemiparin had a stronger inhibitory effect on thrombin induced platelet aggregation, and a stronger interaction with HIT antibodies. CONCLUSIONS: These data demonstrate that depolymerized heparins can exhibit a range of biologic activities making them unique agents. Pharmacopoeial parameters such as anti-IIa and anti-Xa potency and molecular weight are insufficient to characterize such agents.


Assuntos
Testes de Coagulação Sanguínea/normas , Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Testes de Função Plaquetária/normas , Autoanticorpos/metabolismo , Relação Dose-Resposta a Droga , Inibidores do Fator Xa , Fibrinolíticos/química , Fibrinolíticos/imunologia , Heparina de Baixo Peso Molecular/química , Heparina de Baixo Peso Molecular/imunologia , Humanos , Estrutura Molecular , Peso Molecular , Tempo de Tromboplastina Parcial/normas , Agregação Plaquetária/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Protrombina/antagonistas & inibidores , Padrões de Referência , Relação Estrutura-Atividade , Trombina/metabolismo , Tempo de Coagulação do Sangue Total/normas
7.
Blood Coagul Fibrinolysis ; 22(1): 76-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21076279

RESUMO

Heparin-induced thrombocytopenia (HIT) related to fondaparinux has been rarely reported, although the ability of fondaparinux to cross-react with heparin antibodies has been often a subject of debate. A patient previously exposed to unfractionated heparin and low-molecular-weight heparin (LMWH) was diagnosed with HIT. During treatment with fondaparinux for 5 consecutive days, his thrombocytopenia significantly deteriorated. A functional platelet activation test in vitro showed clear platelet activation after serum exposure with fondaparinux. After discontinuation of fondaparinux, the platelet count was rapidly reestablished. Fondaparinux cross-reacted with heparin antibodies in this case of HIT, resulting in a deterioration of thrombocytopenia. The implication of this drug in HIT was observed clinically and demonstrated in vitro using a platelet activation test.


Assuntos
Anticorpos/imunologia , Anticoagulantes/imunologia , Heparina/imunologia , Polissacarídeos/imunologia , Trombocitopenia/induzido quimicamente , Anticoagulantes/efeitos adversos , Reações Cruzadas , Fondaparinux , Heparina/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polissacarídeos/efeitos adversos , Trombocitopenia/imunologia
8.
Acta Haematol ; 123(3): 140-5, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20134155

RESUMO

BACKGROUND: Philadelphia-negative myeloproliferative disorders (Ph-MPD) are common causes of unusual splanchnic or cerebral vein thrombosis, which is treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Heparin-induced thrombocytopenia (HIT) is a dangerous potential complication of this therapy, but it has rarely been reported in Ph-MPD. PATIENTS AND METHODS: We retrospectively reviewed clinical records of 29 patients with Ph-MPD who have been treated with UFH or LMWH for unusual splanchnic or cerebral vein thrombosis (3 cerebral sinus, 6 portal and 20 hepatic vein). The goal of the study was to determine the occurrence of new thrombotic events during heparin therapy secondary to HIT (HITT). RESULTS: During heparin therapy, 5 out of the 29 patients (17%) developed a new thrombotic episode (pulmonary embolism) with a high clinical probability of HIT based on the 4 T's score even though not all the patients developed 'true' thrombocytopenia. A diagnosis of HIT was established in 2 patients (6.8%) through the presence of heparin-related antibodies. CONCLUSIONS: Ph-MPD patients on heparin warrant careful monitoring and HIT has to be suspected whenever platelet counts drop or a new thrombosis is detectable.


Assuntos
Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Transtornos Mieloproliferativos/complicações , Embolia Pulmonar/epidemiologia , Trombocitopenia/induzido quimicamente , Trombose/tratamento farmacológico , Adulto , Anticoagulantes/imunologia , Anticoagulantes/uso terapêutico , Síndrome de Budd-Chiari/complicações , Síndrome de Budd-Chiari/tratamento farmacológico , Monitoramento de Medicamentos , Feminino , Heparina/imunologia , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/imunologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Trombose Intracraniana/complicações , Trombose Intracraniana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Policitemia Vera/complicações , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Estudos Retrospectivos , Trombocitemia Essencial/complicações , Trombocitopenia/etiologia , Trombocitopenia/imunologia , Trombose/complicações , Fatores de Tempo , Adulto Jovem
9.
Blood ; 115(9): 1797-803, 2010 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-19965682

RESUMO

Heparin can induce heparin-induced thrombocytopenia (HIT). The combined effect of type of surgery (major vs minor) and heparin on this prothrombotic immune reaction to platelet factor 4 (PF4)/heparin was analyzed. In a randomized, double-blind study, trauma patients receiving low-molecular-weight (LMWH) or unfractionated heparin (UFH) for thrombosis prophylaxis were assessed for PF4/heparin-antibody seroconversion, HIT, and thrombosis according to type of surgery. The risk for seroconversion was higher than major versus minor surgery odds ratio, 7.98 [95% confidence interval, 2.06-31.00], P = .003, controlled for potential confounders, as was the risk for HIT (2.2% [95% confidence interval, 0.3%-4.1%] vs 0.0%, P = .010). During LMWH compared with UFH thromboprophylaxis, HIT (1 of 298 vs 4 of 316; P = .370) and PF4/heparin seroconversion (1.7% vs 6.6%; P = .002) were less frequent, driven by differences in patients undergoing major surgery (incidence of HIT: LMWH 0.8% vs UFH 4.0%; P = .180; seroconversion rates: 4.0% vs 17.0%; P = .001). After minor surgery, no case of HIT occurred. The severity of trauma and the need for major surgery strongly influence the risk of an anti-PF4/heparin immune response, which is then increased by UFH. In major trauma certoparin may be safer than UFH because it induces HIT-antibody seroconversion, and the corresponding risk of HIT, less frequently.


Assuntos
Heparina/efeitos adversos , Heparina/imunologia , Fator Plaquetário 4/imunologia , Trombocitopenia/induzido quimicamente , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/imunologia , Método Duplo-Cego , Feminino , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Fatores de Risco , Trombocitopenia/imunologia , Trombose/prevenção & controle , Ferimentos e Lesões/complicações , Adulto Jovem
10.
Thromb Res ; 125(4): e138-42, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19962723

RESUMO

BACKGROUND: P-selectin antagonism has been shown to decrease thrombogenesis and inflammation in animal models of deep venous thrombosis (DVT). OBJECTIVE: To determine the effectiveness of P-selectin inhibitors versus saline and enoxaparin in venous thrombus resolution in nonhuman primate models of venous thrombosis. METHODS: Studies reporting vein re-opening, inflammation expressed as Gadolinium enhancement and coagulation parameters were searched in the literature and pooled into a meta-analysis using an inverse variance with random effects. RESULTS: Five studies were identified comparing P-selectin/ PSGL-1 inhibitors versus saline or enoxaparin regarding venous thrombosis resolution. Vein re-opening was significantly higher on P-selectin/ PSGL-1 compounds, when compared to saline (Inverse Variance [IV] 95% CI; 44.37 [17.77-70.96], p=0.001, I(2)=97%) and similar to enoxaparin (IV 95% CI; 5.03 [-8.88-18.95], p=0.48, I(2)=41%). Inflammation, reflected as Gadolinium enhancement at magnetic resonance venography (MRV), was significantly decreased in the P-selectin treated group when compared to saline (IV 95% CI; -17.84 [-14.98-(-8.30)], p<0.00001, I(2)=80%). No significant differences on vein wall inflammation were observed between P-selectin/ PSGL-1 inhibitors and enoxaparin treated animals (IV95% CI; -3.59 [-10.67-3.48], p=0.32, I(2)=66%). In addition, there was no differences in the coagulation parameters (aPTT, TCT, BT, D-Dimer, fibrinogen, platelets) between P-selectin/ PSGL-1 inhibitors and enoxaparin (IV 95% CI; -1.12[-2.36-0.11], p=0.07, I(2)=92%), although there was a trend showing less of a prolongation in TCT with P-selectin/PSGL-1 inhibitors compared to enoxaparin (p<0.0001). CONCLUSION: P-selectin antagonism successfully paralleled the low-molecular-weight-heparin enoxaparin, for the treatment of DVT in nonhuman primate models, by decreasing both thrombus burden and inflammation without causing any bleeding complications and without increasing coagulation times.


Assuntos
Enoxaparina/farmacologia , Selectina-P/efeitos dos fármacos , Selectina-P/imunologia , Trombose/tratamento farmacológico , Trombose Venosa/patologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/imunologia , Testes de Coagulação Sanguínea , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Plaquetas/patologia , Enoxaparina/imunologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Gadolínio/farmacologia , Hemorragia/complicações , Hemorragia/tratamento farmacológico , Hemorragia/imunologia , Heparina de Baixo Peso Molecular/imunologia , Heparina de Baixo Peso Molecular/farmacologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/imunologia , Angiografia por Ressonância Magnética/efeitos adversos , Selectina-P/farmacologia , Tempo de Tromboplastina Parcial , Flebografia/efeitos adversos , Ratos , Selectinas/imunologia , Selectinas/farmacologia , Tempo de Trombina , Trombose/complicações , Trombose/imunologia , Veias/efeitos dos fármacos , Veias/imunologia , Veias/patologia , Trombose Venosa/sangue , Trombose Venosa/etiologia
12.
Interact Cardiovasc Thorac Surg ; 9(6): 1023-5, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19783545

RESUMO

We report a patient who died as a result of heparin induced thrombocytopenia (HIT) and arterial thromboses following cardiac surgery. The onset was three days after exposure to low molecular weight heparin on the eighth postoperative day. The patient was heterozygous for the factor V Leiden mutation. We have reviewed 15 patients previously diagnosed as HIT on clinical and laboratory criteria and found an incidence of 6.7% (1/15) activated protein C resistance. This second patient had a pulmonary embolus and HIT after only three days exposure to low molecular weight heparin. We postulate that factor V Leiden hastens the onset and magnifies the severity of HIT.


Assuntos
Resistência à Proteína C Ativada/genética , Anticoagulantes/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Fator V/genética , Implante de Prótese de Valva Cardíaca/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Trombocitopenia/induzido quimicamente , Idoso , Anticorpos/sangue , Anticoagulantes/imunologia , Evolução Fatal , Heparina de Baixo Peso Molecular/imunologia , Heterozigoto , Humanos , Masculino , Fator Plaquetário 4/imunologia , Índice de Gravidade de Doença , Trombocitopenia/genética , Trombocitopenia/imunologia , Trombose/induzido quimicamente , Trombose/genética
13.
Tuberk Toraks ; 57(1): 68-72, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19533440

RESUMO

A successful desensitization protocol in a patient with low molecular weight heparin induced anaphylactic reaction is being presented. A 72-years-old patient who was known to have multiple drug allergies and asthma was admitted with acute renal insufficiency. She had an anaphylactic reaction with a low molecular weight heparin during a hemodialysis session. Peritoneal dialysis was not feasible. Anticoagulation with warfarin was not considered appropriate; alternative anticoagulants were not available. Therefore a desensitization protocol was planned and applied, comprising of IV administration of diluted heparin by gradually increasing doses (0.1 to 5000 units), at 15 minute intervals, completing 8 hours before the procedure. By this way, IV heparin could be administered during the subsequent hemodialysis sessions with no reactions. The Naranjo probability scale revealed a probable adverse reaction associated with nadroparin for this patient. Anaphylactic reaction to low molecular weight heparins is reported rarely in the literature. To the best of our knowledge, this is the third case of successful heparin desensitization. When other anticoagulants are not available and anticoagulation is indispensible, heparin desensitization can be an option.


Assuntos
Injúria Renal Aguda/terapia , Anafilaxia/induzido quimicamente , Anticoagulantes/imunologia , Dessensibilização Imunológica/métodos , Heparina de Baixo Peso Molecular/imunologia , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Infusões Intravenosas
15.
Br J Dermatol ; 157(3): 514-7, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17573880

RESUMO

BACKGROUND: Cross-reactivity is a widespread phenomenon in patients who develop cutaneous delayed-type hypersensitivity (DTH) reactions to low molecular weight heparins (LMWHs). As molecular weight is believed to be a key determinant of sensitization to heparins, the recently developed LMWH bemiparin, with the lowest molecular weight of all LMWHs, appeared to be a significant improvement. OBJECTIVES: To evaluate cross-reactivity between bemiparin and several other LMWHs and heparinoids by means of subcutaneous testing. Methods Test doses of bemiparin and several other LMWHs/heparinoids were given to eight patients with a history of local eczematous reactions after subcutaneous injection of enoxaparin. RESULTS: Seven of eight patients showed cross-reactivity following subcutaneous injection of bemiparin. In addition, nearly all tested substances caused local eczematous reactions in at least some patients, with the exception of fondaparinux, which was well tolerated by all patients. Of all substances tested, bemiparin had the highest cross-reactivity with enoxaparin. Substances with a lower molecular weight did not cross-react less frequently than the others. CONCLUSIONS: No significant correlation was found between the molecular weight of the tested substances and the frequency of DTH reactions. In patients with DTH to enoxaparin, the LMWH bemiparin is not a suitable alternative.


Assuntos
Anticoagulantes/efeitos adversos , Toxidermias/etiologia , Heparina de Baixo Peso Molecular/efeitos adversos , Heparinoides/efeitos adversos , Hipersensibilidade Tardia/induzido quimicamente , Idoso , Anticoagulantes/química , Anticoagulantes/imunologia , Reações Cruzadas/imunologia , Toxidermias/imunologia , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/imunologia , Heparinoides/química , Heparinoides/imunologia , Humanos , Hipersensibilidade Tardia/imunologia , Masculino , Pessoa de Meia-Idade , Peso Molecular , Testes Cutâneos
16.
Blood Coagul Fibrinolysis ; 17(8): 605-13, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17102645

RESUMO

Heparins are widely used as anticoagulants. Immunologically-mediated side effects raise the question as to whether other substances with heparin-like pharmacological effects can be safely applied. Hypersensitivity reactions to heparin consist of heparin-induced immune thrombocytopenia, allergic vasculitis, hypereosinophilia, immediate hypersensitivity as well as delayed-type skin reactions. Hypersensitivity to unfractionated and low-molecular-weight heparins and semisynthetic heparinoids is increasingly common, and the pathogenesis, however, is still not fully understood. Clinically, this phenomenon is of relevance because of its increasing incidence and the resulting therapeutic difficulties that arise because several cross-reactions between unfractionated and low-molecular-weight heparins as well as between various heparins and heparinoids have been observed. In some patients with cross-reactivity between various heparins and semisynthetic heparinoids, recombinant hirudins, may be safe and effective. Combined allergy to recombinant hirudins and heparins, however, has been reported. Therefore, there is an urgent need for therapeutic alternatives.


Assuntos
Anticoagulantes/imunologia , Hipersensibilidade a Drogas/diagnóstico , Heparina de Baixo Peso Molecular/imunologia , Heparinoides/imunologia , Anticoagulantes/efeitos adversos , Hipersensibilidade a Drogas/tratamento farmacológico , Heparina de Baixo Peso Molecular/efeitos adversos , Heparinoides/efeitos adversos , Hirudinas/efeitos adversos , Hirudinas/imunologia , Humanos
17.
Arterioscler Thromb Vasc Biol ; 26(10): 2386-93, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16873726

RESUMO

OBJECTIVE: Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by antibodies that recognize positively charged platelet factor 4 (PF4), bound to the polyanion, heparin. The resulting immune complexes activate platelets. Unfractionated heparin (UFH) causes HIT more frequently than low-molecular-weight heparin (LMWH), whereas the smallest heparin-like molecule (the pentasaccharide, fondaparinux), induces anti-PF4/heparin antibodies as frequently as LMWH, but without exhibiting cross-reactivity with these antibodies. To better understand these findings, we analyzed the molecular structure of the complexes formed between PF4 and UFH, LMWH, or fondaparinux. METHODS AND RESULTS: By atomic force microscopy and photon correlation spectroscopy, we show that with any of the 3 polyanions, but in the order, UFH>LMWH>>fondaparinux--PF4 forms clusters in which PF4 tetramers become closely apposed, and to which anti-PF4/heparin antibodies bind. By immunoassay, HIT antibodies bind strongly to PF4/H/PF4 complexes, but only weakly to single PF4/heparin molecules. CONCLUSIONS: HIT antigens are formed when charge neutralization by polyanion allows positively charged PF4 tetramers to undergo close approximation. Whereas such a model could explain why all 3 polyanions form antibodies with similar specificities, the striking differences in the relative size and amount of complexes formed likely correspond to the observed differences in immunogenicity (UFH>LMWH approximately fondaparinux) and clinically relevant cross-reactivity (UFH>LMWH>>fondaparinux).


Assuntos
Anticorpos/imunologia , Heparina/efeitos adversos , Fator Plaquetário 4/química , Fator Plaquetário 4/imunologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Adsorção , Formação de Anticorpos , Ensaio de Imunoadsorção Enzimática , Fondaparinux , Heparina/imunologia , Heparina de Baixo Peso Molecular/imunologia , Humanos , Microscopia de Força Atômica , Fótons , Polissacarídeos/imunologia , Análise Espectral/métodos
19.
Pathophysiol Haemost Thromb ; 35(6): 445-50, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17565238

RESUMO

The aim of this study was to determine the frequency of heparin/platelet factor (PF) 4 complex antibodies in 305 uremic patients treated with chronic intermittent hemodialysis using unfractionated heparin or low-molecular-weight heparin for 3 months. Heparin-induced thrombocytopenia (HIT) antibodies were detected by ELISA in 7 patients (2.3%) who had no history of HIT. Two patients abruptly developed HIT associated with the formation of clots in the extracorporeal circuit after they were found to be carrying HIT antibodies. These patients were suspected to have a similar trigger: an increased dose of recombinant human erythropoietin (rHuEPO). The drug might induce parallel changes in hematocrit (Ht) levels and platelet counts until the onset of HIT. After the onset of HIT, a parallel phenomenon between Ht and platelet counts was not found because of the thrombocytopenia due to HIT. Although HIT onset has been reported during the initial phase of dialysis sessions, there have been few reports on the onset of HIT in uremic patients on dialysis with long-term heparin anticoagulation. In this study, HIT was observed in 2 uremic patients on chronic dialysis with intermittent use of heparin. In some patients on chronic intermittent dialysis carrying HIT antibodies, HIT may occur following rHuEPO treatment. The presence of HIT should be borne in mind in chronic dialysis patients carrying HIT antibodies for 3 months or more.


Assuntos
Autoanticorpos/sangue , Heparina de Baixo Peso Molecular/efeitos adversos , Fator Plaquetário 4/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Diálise Renal , Uremia/sangue , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Diálise Renal/efeitos adversos , Trombose/sangue , Trombose/induzido quimicamente , Trombose/tratamento farmacológico , Trombose/imunologia , Uremia/complicações , Uremia/imunologia , Uremia/terapia
20.
Neurology ; 64(7): 1285-7, 2005 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-15824368

RESUMO

The authors prospectively studied the risk for immune-mediated heparin-induced thrombocytopenia (HIT) in neurologic patients during administration of low-molecular-weight heparin (LMWH) vs unfractionated heparin (UFH). None of 111 neurologic patients receiving LMWH developed HIT, whereas HIT occurred in 2.5% of 200 patients treated with UFH (p = 0.17). The rate of heparin-induced antibodies in patients treated with LMWH was lower than in patients treated with UFH (1.8 vs 20.5%; p < 0.001).


Assuntos
Anticoagulantes/efeitos adversos , Transtornos Cerebrovasculares/tratamento farmacológico , Heparina de Baixo Peso Molecular/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Esquema de Medicação , Feminino , Heparina/administração & dosagem , Heparina/efeitos adversos , Heparina/imunologia , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/imunologia , Humanos , Doença Iatrogênica/prevenção & controle , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombocitopenia/epidemiologia
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