Thrombotic thrombocytopenic purpura: reducing the risk?

Berndt, Michael C.; Andrews, Robert K.

doi:10.1172/jci46091

Cited by 7 publications

(7 citation statements)

References 21 publications

(29 reference statements)

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“…Endothelial injuries combined with the physiological intravasal shear stress cause a conformation change of the normally compact vWF protein into elongated multimers [6,15]. The elongated form of vWF exposures multiple binding sites for platelets and optimizes the adhesion between aggregated thrombocytes and fibrin resulting in thrombus formation within the injured vessel [6,16-18]. We now suppose that this activated coagulation is also the main reason for the formation of stases by sticking of erythrocytes to the thrombotic material.…”

Section: Discussionmentioning

confidence: 99%

“…The latter is realized by the protease ADAMST13 decreasing the multimer size of vWF by cleaving it within its A2 domain and secondly by reducing intra-multimer disulfide bonds. Both activities lead to a reduction of vWF multimer-size and its pro-thrombotic function [6,19]. …”

Section: Discussionmentioning

confidence: 99%

“…Such a cleavage of vWF disulfide bonds is also performed by NAC [6]. Thus, through the long lasting application of NAC the vWF balance has been shifted to shorter multimers exhibiting a lower number of binding sites for platelets.…”

Section: Discussionmentioning

confidence: 99%

“…Since NAC only attenuates and not extinguishes the prothrombotic function of vWF [6] only a limited amount of blood is leaking into the parenchyma. Therefore, the majority of emerging microbleeds is smaller than 150 μm.…”

Section: Discussionmentioning

confidence: 99%

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NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study

Bueche

Garz

Kropf

et al. 2013

Exp & Trans Stroke Med

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BackgroundN-Acetylcystein (NAC) reduces the reperfusion injury and infarct size in experimental macroangiopathic stroke. Here we now investigate the impact of NAC on the development of the histopathology of microangiopathic cerebrovascular disease including initial intravasal erythrocyte accumulations, blood–brain-barrier (BBB)-disturbances, microbleeds and infarcts.MethodsSpontaneously Hypertensive Stroke-Prone Rats (SHRSP) were treated with NAC (12 mg/kg body weight, daily oral application for three to 30 weeks) and compared to untreated SHRSP. In all rats the number of microbleeds, thromboses, infarcts and stases were quantified by HE-staining. Exemplary brains were stained against von Willebrand factor (vWF), IgG, Glutathione and GFAP.ResultsNAC animals exhibited significant more microbleeds, a greater number of vessels with BBB-disturbances, but also an elevation of Glutathione-levels in astrocytes surrounding small vessels. NAC-treatment reduced the numbers of thromboses, infarcts and arteriolar stases.ConclusionsNAC reduces the frequency of thromboses and infarcts to the expense of an increase of small microbleeds in a rat model of microangiopathic cerebrovascular disease. We suppose that NAC acts via an at least partial inactivation of vWF resulting in an insufficient sealing of initial endothelial injury leading to more small microbleeds. By elevating Glutathione-levels NAC most likely exerts a radical scavenger function and protects small vessels against extended ruptures and subsequent infarcts. Finally, it reveals that stases are mainly caused by endothelial injuries and restricted thromboses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study

Bueche

Garz

Kropf

et al. 2013

Exp & Trans Stroke Med

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“…El uso de N-acetilcisteína se ha propuesto debido a su acció n reductora de los puentes disulfuros de los multímetros del FvW 97,98 .…”

Section: Otros Tratamientosunclassified

Guía diagnóstica y terapéutica de las microangiopatías trombóticas del Grupo Español de Aféresis

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Río-Garma³

et al. 2015

Medicina Clínica

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Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients.

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VWF/ADAMTS13 Imbalance, But Not Global Coagulation or Fibrinolysis, Is Associated With Outcome and Bleeding in Acute Liver Failure

et al. 2021

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Word count 270 Background and Aims: Recent studies of acute liver failure (ALF) in man and animals have suggested that rebalanced hemostasis occurs, with distinct hypercoagulable features clinically evidenced by a low risk of bleeding. Rodent models have shown a link between intrahepatic microthrombus formation and progression of ALF. We sought to confirm these earlier findings in a large series of well-characterized ALF patients from the Acute Liver Failure Study Group (ALFSG). Patients and Methods: Citrated plasma samples taken on admission from 676 patients with ALF or acute liver injury (ALI; INR  2.0 without hepatic encephalopathy) were used to determine levels of VWF, ADAMTS13 activity, thrombomodulin-modified thrombin generation, and clot lysis time (CLT) and compared with levels in 40 healthy controls. Results: Patients had 3-fold increased VWF levels, 4-fold decreased ADAMTS13 activity, similar thrombin generating capacity, and 2.4-fold increased CLT, compared with controls. Increasing disease severity was associated with progressively more elevated VWF levels as well as hypofibrinolysis. Patients who died or underwent liver transplantation within 21 days of admission had higher VWF levels, lower ADAMTS13 activity, but similar thrombin generation and a similar proportion of patients with severe hypofibrinolysis, when compared to transplant-free survivors. Likewise, patients with bleeding complications had higher VWF levels and lower ADAMTS13 activity compared to those without bleeding. Thrombin generation and CLT did not differ significantly between bleeding and non-bleeding patients. Conclusion: Rebalanced hemostatic status was confirmed in a large cohort of patients with ALI/ALF demonstrating that VWF/ADAMTS13 imbalance is associated with poor outcome and bleeding. The association between VWF/ADAMTS13 imbalance and bleeding suggest that bleeding in ALF relates more to systemic inflammation than a primary coagulopathy.

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Thrombotic thrombocytopenic purpura: reducing the risk?

Cited by 7 publications

References 21 publications

NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study

NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study

Guía diagnóstica y terapéutica de las microangiopatías trombóticas del Grupo Español de Aféresis

VWF/ADAMTS13 Imbalance, But Not Global Coagulation or Fibrinolysis, Is Associated With Outcome and Bleeding in Acute Liver Failure

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