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1.
Swiss Med Wkly ; 138(9-10): 142-9, 2008 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-18330734

RESUMO

AIM: This pilot study seeks to determine whether contact system activation (CSA) occurs in human sepsis patients and to characterise blood levels of the 47kD light chain of high-molecular weight kininogen (47kD HK). METHODS: Six consecutive patients with clinical suspicion of sepsis were evaluated on days 1, 2, 3 and 6-8 for 47kD HK blood levels expressed in U/ml of whole blood and as percent of total HK. 47kD HK was measured in whole blood by quantitative immunoblot analysis. RESULTS: On study day 1 or 2, analysis of 47kD HK in U/ml of whole blood identified CSA in 3/6 patients. When 47kD HK levels were expressed as percent of total HK, 4/6 patients were identified with CSA before day 3. The degree of CSA as assayed by the presence of 47kD HK correlated with the severity of the systemic inflammatory syndrome (SIRS), i.e. mean CSA increased progressively from basal levels in healthy controls (0.08 U/ml or 10.4%) to patients without SIRS (0.10 U/ml or 15.1%), to patients with sepsis (0.12 U/ml or 15.0%), and finally to patients in a combined category of severe sepsis and septic shock (0.13 U/ml or 17.4%). CONCLUSION: CSA, defined by increased 47kD HK, occurred early on in the course of sepsis in a subset of sepsis patients. 47kD HK levels, an indicator of bradykinin release, correlated with sepsis severity. Future larger studies will need to evaluate the role of 47kD HK as a biomarker for both prognosis and treatment response in human sepsis..


Assuntos
Immunoblotting/métodos , Cininogênio de Alto Peso Molecular/sangue , Sepse/sangue , Biomarcadores , Testes de Coagulação Sanguínea , Humanos , Sepse/fisiopatologia , Índice de Gravidade de Doença
3.
Blood ; 103(11): 4195-7, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-14982879

RESUMO

Thrombotic thrombocytopenic purpura (TTP) either occurs in a congenital form caused by ADAMTS13 gene mutations or it is acquired and most often due to ADAMTS13 inhibitory autoantibodies. In congenital TTP siblings are often affected, while acquired TTP occurs sporadically and familial clustering has not been described so far. We report identical twin sisters suffering from acquired TTP due to immunoglobulin G (IgG) autoantibodies inactivating ADAMTS13, suggesting an important role of hitherto unidentified genetic determinants of ADAMTS13 inhibitor formation. These cases also demonstrate that familial clustering is not sufficient for unambiguously diagnosing hereditary ADAMTS13 deficiency and congenital TTP.


Assuntos
Metaloendopeptidases/genética , Metaloendopeptidases/imunologia , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/imunologia , Proteínas ADAM , Proteína ADAMTS13 , Adulto , Autoanticorpos/sangue , Feminino , Teste de Histocompatibilidade , Humanos , Metaloendopeptidases/deficiência , Gêmeos Monozigóticos/genética
5.
Expert Rev Cardiovasc Ther ; 1(2): 243-55, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15030284

RESUMO

Thrombotic thrombocytopenic purpura (TTP) is a dramatic intravascular platelet-clumping disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, renal insufficiency and fever. TTP is a rare disease but is almost always fatal if untreated. More than 80% of patients survive with plasma therapy. In healthy individuals, the proteolytic cleavage of ultralarge von Willebrand factor (vWF) multimers prevents spontaneous clumping of platelets in the microcirculation. Patients with TIP have either severe congenital deficiency of von Willebrand factor-cleaving protease (vWF-cp), or have autoantibodies that inhibit the protease. Determination of vWF-cp levels in patient plasma helps to distinguish between TTP and other thrombotic microangiopathies with similar clinical signs and symptoms. vWF-cp is a member of the ADAMTS family of metalloproteases and has been designated ADAMTS13.


Assuntos
Metaloendopeptidases/metabolismo , Púrpura Trombocitopênica Trombótica/enzimologia , Proteínas ADAM , Proteína ADAMTS13 , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/enzimologia , Síndrome Hemolítico-Urêmica/imunologia , Síndrome Hemolítico-Urêmica/terapia , Humanos , Metaloendopeptidases/deficiência , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/imunologia , Púrpura Trombocitopênica Trombótica/terapia , Estados Unidos/epidemiologia
6.
Blood ; 100(10): 3626-32, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12393399

RESUMO

Deficient von Willebrand factor (VWF) degradation has been associated with thrombotic thrombocytopenic purpura (TTP). In hereditary TTP, the specific VWF-cleaving protease (VWF-cp) is absent or functionally defective, whereas in the nonfamilial, acquired form of TTP, an autoantibody inhibiting VWF-cp activity is found transiently in most patients. The gene encoding for VWF-cp has recently been identified as a member of the metalloprotease family and designated ADAMTS13, but the functional activity of the ADAMTS13 gene product has not been verified. To establish the functional activity of recombinant VWF-cp, we cloned the complete cDNA sequence in a eukaryotic expression vector and transiently expressed the encoded recombinant ADAMTS13 in HEK 293 cells. The expressed protein degraded VWF multimers and proteolytically cleaved VWF to the same fragments as those generated by plasma VWF-cp. Furthermore, recombinant ADAMTS13-mediated degradation of VWF multimers was entirely inhibited in the presence of plasma from a patient with acquired TTP. These data show that ADAMTS13 is responsible for the physiologic proteolytic degradation of VWF multimers.


Assuntos
Clonagem Molecular , Metaloendopeptidases/genética , Proteínas ADAM , Proteína ADAMTS13 , DNA Complementar , Dimerização , Humanos , Metaloendopeptidases/biossíntese , Metaloendopeptidases/metabolismo , Fragmentos de Peptídeos/análise , Púrpura Trombocitopênica Trombótica/enzimologia , RNA Mensageiro/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Distribuição Tecidual , Fator de von Willebrand/metabolismo
7.
Thromb Res ; 105(6): 463-70, 2002 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12091043

RESUMO

Hereditary plasma prekallikrein (PK) deficiency was diagnosed in a 71-year-old man with an 8-year history of osteomyelofibrosis. PK deficiency was suspected in view of a severely prolonged activated partial thromboplastin time (aPTT) that nearly normalized following prolonged preincubation (10 min) of patient plasma with kaolin-inosithin reagent. Hereditary PK deficiency was demonstrated by very low PK values in the propositus (PK clotting activity 5%, PK amidolytic activity 5%, PK antigen 2% of normal plasma, respectively) and half normal PK values in his children. Normalization of a severely increased aPTT (>120 s) after prolonged preincubation with aPTT reagent occurred in plasma deficient in PK but not in plasma deficient in factor XII (FXII), high-molecular-weight kininogen (HK), factor XI (FXI), factor IX, factor VIII, Passovoy trait plasma or plasma containing lupus anticoagulant. Autoactivation of FXII in PK-deficient plasma in the presence of kaolin paralleled the normalization of aPTT. Addition of OT-2, a monoclonal antibody inhibiting activated FXII, prevented the normalization of aPTT. We conclude that the normalization of a severely prolonged aPTT upon increased preincubation time (PIT), characteristic of PK deficiency, is due to FXII autoactivation.


Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Pré-Calicreína/deficiência , Idoso , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/congênito , Fatores de Coagulação Sanguínea/metabolismo , Fator XII/metabolismo , Saúde da Família , Humanos , Immunoblotting , Masculino , Tempo de Tromboplastina Parcial
8.
Blood ; 100(2): 710-3, 2002 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12091372

RESUMO

A severe deficiency in von Willebrand factor-cleaving protease (ADAMTS13) activity (< 5% that in normal plasma) has been observed in most patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) but not in those with a diagnosis of hemolytic uremic syndrome. However, ADAMTS13 deficiency has been claimed not to be specific for TTP, since it was observed in various thrombocytopenic and other conditions. We studied 68 patients with thrombocytopenia due to severe sepsis or septic shock (n = 17), heparin-induced thrombocytopenia (n = 16), idiopathic thrombocytopenic purpura (n = 10), or other hematologic (n = 15) or miscellaneous conditions (n = 10). Twelve of the 68 patients had subnormal levels of ADAMTS13 activity (

Assuntos
Metaloendopeptidases/deficiência , Trombocitopenia/enzimologia , Proteínas ADAM , Proteína ADAMTS13 , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Metaloendopeptidases/sangue , Pessoa de Meia-Idade , Púrpura Trombocitopênica Trombótica/enzimologia , Estudos Retrospectivos
9.
Swiss Med Wkly ; 132(15-16): 181-9, 2002 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-12070783

RESUMO

A vascular fissure requires a patch that must be provided by constituents of the cellular and fluid phases of flowing blood. The principal components involved in primary haemostasis are platelets, collagen and von Willebrand factor (vWF). Platelets, the cellular elements of the patch, are inert until they encounter conditions that trigger their activation. Platelet adhesion and aggregation at the site of vascular injury lead to the formation of a platelet plug and to a local activation of the coagulation cascade. The resulting final product of blood coagulation is a fibrin network that stabilises the primary platelet plug. Most coagulation factors are zymogens of serine proteases. They are converted from an inactive form to an active enzyme by limited proteolytic cleavage of one or a few peptide bonds. The coagulation reactions must become extinguished as soon as the patch in the injured blood vessel has been established. Several inhibitors, present in excess in plasma, neutralise the surplus of remaining proteases, and the fibrinolytic system dissolves the plug after the surrounding tissue has been repaired. In fulfilling their function to control the fluidity and integrity of the vascular system, the plasmatic and cellular haemostatic players undergo multiple interactions of two kinds: they recognize and bind, often irreversibly, to several partners which are present in their immediate environment. On the other hand, some haemostatic factors, such as fibrinogen and von Willebrand factor, enhance their stickiness by polymerisation of identical subunits carrying multiple adhesive sites. Several haemostatic plasma proteins and their cellular surface receptors are involved in or may be affected by other homeostatic systems, such as immune response, complement activation, cytokine release, cell proliferation, growth and differentiation. These diverse functions are only possible because of the modular structure of participating proteins. In the process of evolution a series of structural modules have been incorporated into protein molecules as their integral domains by exon duplication and shuffling. Owing to variable conformations of the resulting multi-domain proteins, the same modules may perform different tasks and be recognized only by specific ligands, thus controlling the delicately balanced system of haemostasis.


Assuntos
Fatores de Coagulação Sanguínea/fisiologia , Coagulação Sanguínea/fisiologia , Hemostasia/fisiologia , Trombose/fisiopatologia , Fator VIII/fisiologia , Fator XIII/fisiologia , Fibrinogênio/fisiologia , Fibrinólise/fisiologia , Humanos , Polímeros , Trombina/fisiologia , Trombospondinas/fisiologia , Aderências Teciduais , Vitronectina/fisiologia , Fator de von Willebrand/fisiologia
10.
Semin Thromb Hemost ; 28(2): 167-72, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11992240

RESUMO

Endothelial cells secrete von Willebrand factor (vWF) multimers that are larger than those found in the circulating plasma. These very large multimeric forms of vWF, capable of spontaneously binding to and agglutinating the blood platelets under conditions of high fluid shear rate, are degraded by a specific metalloprotease cleaving the peptide bond 842Tyr-843Met of the vWF subunit. The vWF-cleaving protease was found to be deficient in patients with familial thrombotic thrombocytopenic purpura (TTP). The acute events in these patients can be successfully treated and prophylactically prevented by repletion of the missing protease using fresh frozen plasma (FFP). In another, apparently more common, form of TTP, the protease deficiency is due to inhibiting circulating antibodies directed against the vWF-cleaving protease. Therapy of these patients should include immunosuppressive treatment in addition to plasma exchange and replacement with FFP. Normal activity of vWF-cleaving protease was established in patients with a clinically similar disorder: hemolytic-uremic syndrome (HUS). The level of vWF-cleaving protease activity is thus a laboratory parameter that provides important information for the differential diagnosis and treatment of patients with TTP/HUS. Several assays of vWF-cleaving protease have been described and are summarized here.


Assuntos
Metaloendopeptidases/análise , Técnicas de Sonda Molecular , Púrpura Trombocitopênica Trombótica/diagnóstico , Proteínas ADAM , Proteína ADAMTS13 , Autoanticorpos/sangue , Saúde da Família , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/enzimologia , Humanos , Metaloendopeptidases/deficiência , Metaloendopeptidases/imunologia , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/etiologia
11.
Br J Haematol ; 116(4): 909-11, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11886400

RESUMO

Antibodies that inhibit von Willebrand Factor (VWF)-cleaving protease activity occur in patients with acute thrombotic thrombocytopenic purpura (TTP) and often persist in the chronic phase. A deficiency of this protease is likely to be responsible for the generation of ultrahigh VWF multimers and influence the formation of intra-arterial platelet aggregates that result in microangiopathic haemolytic anaemia, thrombocytopenia and end in organ failure. This report demonstrates complete deficiency of VWF-cleaving protease and the presence of a concentration-dependent IgG1 inhibitor in the plasma of a patient with acquired immunodeficiency syndrome (AIDS). These data may contribute to understanding the pathophysiology of human immunodeficiency syndrome (HIV)-related TTP.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Autoanticorpos/sangue , Imunoglobulina G/sangue , Metaloendopeptidases/imunologia , Púrpura Trombocitopênica Trombótica/imunologia , Proteínas ADAM , Proteína ADAMTS13 , Síndrome de Imunodeficiência Adquirida/complicações , Ensaios Enzimáticos Clínicos , Humanos , Masculino , Metaloendopeptidases/análise , Pessoa de Meia-Idade , Púrpura Trombocitopênica Trombótica/complicações
12.
Atherosclerosis ; 161(2): 261-7, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11888508

RESUMO

Increased levels of hemostatic factors may play a role in the pathogenesis of myocardial infarction by triggering thrombin formation. We measured factor XII (FXII), factor XI (FXI), plasma prekallikrein (PK) and high-molecular-weight kininogen (HK) in 200 patients having survived myocardial infarction for at least 2 months, and in 100 healthy controls. We found significantly elevated levels of FXI clotting activity (FXI:C), HK:C and of the amidolytic activity of PK (PK:Am) among the patients as compared to the controls. Plasma levels of FXI:C, HK:C and PK:Am in the highest quartile were associated with an odds ratio of 1.9 (95% CI: 1.0-3.8), 2.0 (95% CI: 1.0-4.0) and 5.4 (95% CI: 2.6-11.2), respectively, compared to the respective plasma levels in the lowest quartile. After correction for established clinical and laboratory risk factors, the association between PK:Am plasma levels and myocardial infarction remained significant (P=0.0007). Combination of high PK:Am plasma levels and smoking or arterial hypertension, respectively, resulted in a more than additive relative risk for myocardial infarction.


Assuntos
Fator XI/metabolismo , Cininogênio de Alto Peso Molecular/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Pré-Calicreína/metabolismo , Adulto , Idoso , Biomarcadores/análise , Estudos de Casos e Controles , Estudos de Coortes , Intervalos de Confiança , Fator XI/análise , Humanos , Cininogênio de Alto Peso Molecular/análise , Pessoa de Meia-Idade , Razão de Chances , Pré-Calicreína/análise , Probabilidade , Prognóstico , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade
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