Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura

Furlan, Miha

doi:10.1586/14779072.1.2.243

Cited by 85 publications

(115 citation statements)

References 81 publications

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“…[17][18][19] Recent studies have demonstrated that vWF cleaving metalloprotease activity is generally preserved in the transplantation-associated form of this disease. [20][21][22] However, as with classical TTP, abnormalities of the vascular endothelium have been described on ultrastructural examination which are felt to be central to the pathogenesis of this disorder.…”

Section: Pathophysiology Of Ta-tmamentioning

confidence: 99%

Transplantation-associated thrombotic microangiopathy: twenty-two years later

Daly

Xenocostas

Lipton

2002

Bone Marrow Transplant

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Summary:A syndrome of microangiopathic hemolytic anemia, renal dysfunction and neurological abnormalities was first noted in bone marrow transplant recipients 22 years ago. Now known as transplantation-associated thrombotic microangiopathy (TA-TMA) to distinguish it from other thrombotic microangiopathies, this disorder responds poorly to conventional treatments for thrombotic thrombocytopenic purpura. In this review, we discuss the incidence and risk factors for TA-TMA and describe a pathophysiologic model of the disorder based on results obtained from laboratory models of the thrombotic microangiopathies. We conclude by suggesting possible approaches to the early diagnosis and treatment of TA-TMA based on this model that may warrant testing in future clinical trials.

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Section: Pathophysiology Of Ta-tmamentioning

confidence: 99%

Transplantation-associated thrombotic microangiopathy: twenty-two years later

Daly

Xenocostas

Lipton

2002

Bone Marrow Transplant

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“…Plasma VWF-CPase activity was assayed by the modified method of Furlan et al 25 based on VWFM analysis, as described in recent publications. [26][27][28] One hundred percent of VWF-CPase activity was defined as the amount contained in 1 ml of pooled normal plasma (NP).…”

Section: Vwf-cpase Activity and Its Inhibitormentioning

confidence: 99%

Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation

Yoshioka

Kawa

et al. 2002

Bone Marrow Transplant

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Summary:Hepatic veno-occlusive disease (VOD) is a life-threatening complication after stem cell transplantation (SCT), characterized by thrombus formation in hepatic venules leading to a symptom triad of hyperbilirubinemia, hepatomegaly, and ascites. Multifactorial defects in the hemostatic system may contribute to its pathogenesis, but its remains to be investigated. Unusually large VWF multimers (UL-VWFMs), produced in and released from vascular endothelial cells, are most biologically active in the interaction with platelets under a high shear stress. UL-VWFMs are cleaved and degraded into smaller VWFMs by a specific liver producing plasma protease, termed VWF-cleaving protease (VWF-CPase), which has recently been identified as a metalloprotease solely produced in liver, termed ADAMTS13. Herein, we studied the correlation between plasma VWF-CPase activity and UL-VWFMs in 21 patients who received SCT, seven patients with VOD and 14 patients without VOD. In non-VOD patients, activities (mean ؎ 1s.d.) of VWF-CPase were 78 ؎ 17% of the control before the conditioning regimen, 76 ؎ 18% on day 0, 64 ؎ 19% on day 7, 57 ؎ 23% on day 14, 68 ؎ 13% on day 21 and 79 ؎ 19% on day 28 after SCT. The respective values in VOD patients were 32 ؎ 19%, 27 ؎ 15%, 18 ؎ 11%, 22 ؎ 18%, 26 ؎ 22% and 12 ؎ 4%. Thus, VWF-CPase activity was significantly reduced in VOD patients, even before the conditioning regimen, and such a difference was not found in other laboratory tests. However, despite such a clear difference, UL-VWFMs were present in plasmas of both patient groups, together with the increase of VWF antigen and ristocetin cofactor activity. These results indicate that the measurement of this enzyme activity is extremely useful in predicting the occurrence of VOD prior to a demonstration of its direct involvement in its pathogenesis.

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“…The size of the multimers is regulated through proteolysis 1,2 by a specific protease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13). [3][4][5] There are 3 pools of VWF: (1) soluble plasma VWF, (2) subendothelial (ECM) VWF, and (3) cellular VWF in storage granules. 6 VWF is a carrier for factor VIII (FVIII) and protects it from inactivation.…”

Section: Introductionmentioning

confidence: 99%

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Chauhan

Kisucka

Lamb

et al. 2006

Blood

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von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using genetargeted mice, we show that in ferric chloride-injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF ؊/؊ mice when compared with wild type (WT). We also observed increased embolization in the VWF ؊/؊ mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF ؊/؊ venules did not occlude. Introductionvon Willebrand factor (VWF) is a large adhesive glycoprotein synthesized in megakaryocytes and endothelial cells and stored in platelet ␣-granules and Weibel-Palade bodies, respectively. VWF circulates in plasma as a series of multimers ranging from 500 to 20 000 kDa. The size of the multimers is regulated through proteolysis 1,2 by a specific protease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13). [3][4][5] There are 3 pools of VWF: (1) soluble plasma VWF, (2) subendothelial (ECM) VWF, and (3) cellular VWF in storage granules. 6 VWF is a carrier for factor VIII (FVIII) and protects it from inactivation. 7 The formation of a thrombus on an injured vessel wall is a complex process that involves multiple adhesion molecules (VWF, collagen, fibrinogen, and fibronectin) and their respective receptors on the platelet surface (GPIb␣, GPVI, ␤1 and ␤3 integrins). VWF has 2 main receptors, GPIb␣ in the GPIb-IX-V complex and the integrin ␣IIb␤3. 8 Pathological thrombosis can occur in arteries and veins. Arterial thrombosis is often linked to inappropriate platelet activation and can result in myocardial infarction and ischemic stroke, while venous thrombosis (eg, deep vein thrombosis) is commonly linked to high procoagulant activity, which produces fibrin-rich thrombi. In the clinical setting, elevated levels of FVIII and VWF are associated with an increased risk of venous thrombosis. The Leiden Thrombophilia Study suggested that the effect of elevated VWF on the risk of venous thrombosis was due to increased FVIII levels. 9 In contrast, the Longitudinal Investigation of Thromboembolism Etiology (LITE) Study showed FVIII and VWF were independently associated with venous thromboembolism. 10 Under high shear, the VWF-GPIb␣ interaction is necessary for initial platelet contact with the subendothelium, while irreversible platelet aggregation also requires interaction between the VWF and integrin ␣IIb␤3. 8,[11][12][13] Although an important role for VWF in platelet-platelet cohesion and thrombus formation at arterial shear rates was demonstrated both in vitro 13,14 and in vivo, 15,...

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Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura

Cited by 85 publications

References 81 publications

Transplantation-associated thrombotic microangiopathy: twenty-two years later

Transplantation-associated thrombotic microangiopathy: twenty-two years later

Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

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