Detection of a Platelet-Agglutinating Factor in Thrombotic Thrombocytopenic Purpura

Kelton, John G.; Moore, Jane C.; Santos, Aurelio; Sheridan, David P.

doi:10.7326/0003-4819-101-5-589

Cited by 100 publications

(34 citation statements)

References 12 publications

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“…O retorno da função endotelial às condições de normalidade, é acompanhado de redução dos níveis circulantes aos limites fisiológicos. A atividade antigênica plasmática do fvW (vWF:Ag) é portanto, considerada universalmente como um marcador de disfunção endotelial e assim utilizada em várias doenças [11][12][13][14][15][16] . Em pacientes com hipertensão arterial pulmonar, os sintomas aparecem em etapas onde já existe considerável dano à microcirculação naquele território.…”

Section: Resultados -Em 40 Pacientes Observamos Aumento Significativunclassified

Fator von Willebrand e disfunção endotelial pulmonar. Implicações prognósticas

Lopes

Maeda

Bydlowski

1998

Arq. Bras. Cardiol.

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Section: Resultados -Em 40 Pacientes Observamos Aumento Significativunclassified

Fator von Willebrand e disfunção endotelial pulmonar. Implicações prognósticas

Lopes

Maeda

Bydlowski

1998

Arq. Bras. Cardiol.

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“…9,10,13 The purpose of the current study was to investigate whether BMT patients with TTP had functional calpain present in their serum. The rationale for these studies was that calpain has been observed in patients with classical TTP [3][4][5][6] but not in other seriously ill hospitalized patients including patients with leukemia. Calpain is a calciumdependent protease that is present ubiquitously in human tissues and cells and in high concentrations within platelets.…”

Section: Discussionmentioning

confidence: 99%

“…8 Clinical and laboratory observations have led us to postulate that calpain is important in the pathogenesis of TTP. [4][5][6] An unusual and particularly severe form of TTP can complicate bone marrow transplantation. [9][10][11][12][13][14] This variant of TTP can be mild and self-limited but is often rapidly fulminant.…”

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confidence: 99%

Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura

Zeigler

Kelton

Moore

et al. 1999

Bone Marrow Transplant

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Summary:The pathophysiology of thrombotic thrombocytopenic purpura (TTP) is not well understood. Recent studies have described a platelet aggregating factor which has been characterized as a calcium-dependent cysteine protease (calpain) in patients with TTP. A type of TTP, sometimes called secondary TTP, has been associated with bone marrow transplantation (BMT). However, unlike primary adult TTP, BMT-TTP has important differences and often does not respond well to plasma exchange. We describe the measurement of calpain activity in a group of BMT patients (with and without the clinical syndrome of transplant-associated TTP). Calpain was measured using a functional assay ( 14 Cserotonin platelet release with inhibition by the cysteine protease inhibitor, leupeptin) in the sera of patients following autologous (auto) or allogeneic (allo) BMT. We also independently diagnosed and graded the BMT-TTP on the day of blood sampling using a scale that related to the percentage schistocytes and lactic dehydrogenase level. Calpain activity was detected in 1/8 (13%) grade 0-1 (6 auto, 2 allo); 6/16 (38%) grade 2 (3 auto, 13 allo) 9/16 (56%) grade 3 (2 auto, 14 allo) and 8/8 (100%) grade 4 BMT-TTP. Pre-BMT samples were tested in 10 allo-BMT patients who had positive calpain results post-BMT. One patient gave positive results before the transplant. This patient developed grade 4 BMT-TTP (day 24 post-BMT) and died despite apheresis. Positive calpain results were highly associated with neurologic symptoms, P Ͻ 0.001. Nineteen of 24 (79%) patients with positive results had neurologic symptoms compared to three of 21 (14%) patients with negative results. In conclusion, calpain was detected in half of the BMT patients with mild to moderate BMT-TTP (grades 2-3) and was uniformly found in those with severe (grade 4) BMT-TTP. Typically the calpain activity develops as TTP complicates the transplant process. It is unknown whether calpain contributes to the pathogenesis of this disorder, or is a secondary event.

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“…The pathogenesis of the platelet thrombi is not fully understood, but evidence suggests that activation and aggregation of platelets within the microcirculation is an important event (Lian et al, 1979;Kelton et al, 1984Kelton et al, , 1987. The disseminated platelet thrombi led early investigators to wonder if TTP could be mediated by excessive thrombin, disseminated intravascular coagulation.…”

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Proteolytic Degradation of High Molecular Weight Kininogen in Acute Thrombotic Thrombocytopenic Purpura

et al. 1997

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Summary. Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by thrombocytopenia and schistocytic haemolytic anaemia. The majority of patients have normal coagulation parameters including the activated partial thromboplastin time (APTT). An intracellular cysteine protease, calpain, has been found in the plasma of many patients with acute TTP, and we hypothesize that it participates in the pathogenesis of the disorder. However, certain aspects of the disorder remain unresolved. For example, high molecular weight kininogen (HK) is one of the primary plasma inhibitors of calpain, and it also can act as a substrate for calpain. Consequently, one might anticipate that the HK could be defective or altered in TTP. In this report we describe the analysis of HK in plasma from five patients with acute TTP and following recovery. The HK was studied immunogenically and functionally. We observed that the HK in plasma samples from patients with acute TTP was proteolysed. This degradation was not observed in remission samples from the same patients. However, both acute and remission TTP samples had normal HK coagulant activity (acute samples,x ¼ 0 . 84 Ϯ 0 . 26 U/ml; remission samples,x ¼ 0 . 89 Ϯ 0 . 21 U/ml; control samples, x ¼ 0 . 87 Ϯ 0 . 05 U/ml). Although the TTP plasmas were able to inhibit calpain activity, less inhibition activity was found in the acute samples (acute: mean inhibition 71 Ϯ 2 . 4%; remission: mean 92 Ϯ 2 . 1%; control samples: mean 93 Ϯ 5 . 4%: P < 0 . 001). Normal HK treated with calpain also had reduced calpain inhibition capacity (mean 58%). This study suggests that although HK is proteolysed during acute TTP, the proteolysis occurs without a major loss in the coagulation function or depletion of the protease inhibitory activity of HK.

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Detection of a Platelet-Agglutinating Factor in Thrombotic Thrombocytopenic Purpura

Cited by 100 publications

References 12 publications

Fator von Willebrand e disfunção endotelial pulmonar. Implicações prognósticas

Fator von Willebrand e disfunção endotelial pulmonar. Implicações prognósticas

Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura

Proteolytic Degradation of High Molecular Weight Kininogen in Acute Thrombotic Thrombocytopenic Purpura

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