Use of n-acetylcysteine therapy in patients with relapsed refractory thrombotic thrombocytopenic purpura.

There is limited data on the use of NAC in the literature. We would like to present the satisfactory results we obtained in our resistant and relapsed patients as a case series.Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by ADAMTS13 (a disintegrin with thrombospondin type 1 motif and metalloprotease activity, member13) deficiency. Von Willebrand factor (vWF) initiates platelet aggregation and thus thrombus formation. The multimers of vWF are cleaved by ADAMTS13. Because of the decreased activity of ADAMTS13, ultra-large multimers accumulate and end-organ damage occurs. TTP is characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and organ ischemia resulting from vascular occlusion caused by thrombi. Plasma exchange therapy (PEX) remains the mainstay of TTP therapy. Patients who do not respond to PEX and corticosteroids require additional treatments such as rituximab and caplacizumab. NAC reduces disulfide bonds in mucin polymers through its free sulfhydryl group. Thus, the size and viscosity of the mucins are reduced. VWF is structurally similar to mucin. Based on this similarity, Chen and colleagues showed that NAC can reduce the size and reactivity of ultralarge multimers of vWF, such as ADAMTS13. Currently, there is not much information to suggest that NAC has any clinical value in the treatment of TTP. In this case series of 4 refractory patients, we would like to present the responses we obtained with the addition of NAC therapy. NAC can be added to PEX and glucocorticoid therapy as supportive therapy, especially in unresponsive patients.

Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease.

Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.

Post-traumatic thrombotic microangiopathy: What trauma surgeons need to know?

Thrombotic microangiopathy (TMA) is characterized by systemic microvascular thrombosis, target organ injury, anemia and thrombocytopenia. Thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome and Shiga toxin E-coli-related hemolytic uremic syndrome are the three common forms of TMAs. Traditionally, TMA is encountered during pregnancy/postpartum period, malignant hypertension, systemic infections, malignancies, autoimmune disorders, etc. Recently, the patients presenting with trauma have been reported to suffer from TMA. TMA carries a high morbidity and mortality, and demands a prompt recognition and early intervention to limit the target organ injury. Because trauma surgeons are the first line of defense for patients presenting with trauma, the prompt recognition of TMA for these experts is critically important. Early treatment of post-traumatic TMA can help improve the patient outcomes, if the diagnosis is made early. The treatment of TMA is also different from acute blood loss anemia namely in that plasmapheresis is recommended rather than platelet transfusion. This article familiarizes trauma surgeons with TMA encountered in the context of trauma. Besides, it provides a simplified approach to establishing the diagnosis of TMA. Because trauma patients can require multiple transfusions, the development of disseminated intravascular coagulation must be considered. Therefore, the article also provides different features of disseminated intravascular coagulation and TMA. Finally, the article suggests practical points that can be readily applied to the management of these patients.

A critical evaluation of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura.

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy caused by inhibitory autoantibodies against ADAMTS13 protein. Until recently, the combination of plasma exchange (PEX) and immunosuppression has been the standard front-line treatment in this disorder. However, aTTP-related mortality, refractoriness, and relapse are still a matter of concern. Areas covered: The better understanding of the pathophysiological mechanisms of aTTP has allowed substantial improvements in the diagnosis and treatment of this disease. Recently, the novel anti-VWF nanobody caplacizumab has been approved for acute episodes of aTTP. Caplacizumab is capable to block the adhesion of platelets to VWF, therefore inhibiting microthrombi formation in the ADAMTS13-deficient circulation. In this review, the characteristics of caplacizumab together with the available data of its efficacy and safety in the clinical setting will be analyzed. Besides, the current scenario of aTTP treatment will be provided, including the role of other innovative drugs. Expert opinion: With no doubt, caplacizumab is going to change the way we treat aTTP. In combination with standard treatment, caplacizumab can help to significantly reduce aTTP-related mortality and morbidity and could spare potential long-term consequences by minimizing the risk of exacerbation.

Advances in the treatment of thrombotic thrombocytopenic purpura: repurposed drugs and novel agents.

Introduction: Thrombotic thrombocytopenic purpura (TTP) is an infrequent but fatal disease. Plasma exchange and corticosteroids continue to be the mainstay of treatment; however, repurposed drugs and novel agents are emerging as efficient treatment options.Areas covered: In this review, new therapeutic developments in immune-mediated TTP including rituximab, bortezomib, N-acetylcysteine, caplacizumab, and recombinant ADAMTS13, among others, are summarized.Expert opinion: Evidence on the use of rituximab in first and second-line settings is accumulating showing promising potential for avoiding relapses in patients in remission but with low circulating levels of ADAMTS13 in a preemptive fashion. Other repurposed drugs such as bortezomib and N-acetylcysteine are increasingly used off-label. Recombinant ADAMTS13 is slowly emerging. Caplacizumab, a humanized anti-von Willebrand factor-directed nanobody that blocks platelet adhesion and avoids microthrombi formation, was approved by regulatory agencies based on the positive results of a phase-III clinical trial, adding a new drug to the therapeutic arsenal in TTP.

The role of ADAMTS-13 in the coagulopathy of sepsis.

The interaction between platelets and the vessel wall is mediated by various receptors and adhesive proteins, of which von Willebrand factor (VWF) is the most prominent. The multimeric size of VWF is an important determinant of a more intense platelet-vessel wall interaction, and is regulated by the VWF-cleaving protease ADAMTS-13. A deficiency in ADAMTS-13 leads to higher concentrations of ultralarge VWF multimers and pathological platelet-vessel wall interactions, in its most typical and extreme form leading to thrombocytopenic thrombotic purpura, a thrombotic microangiopathy characterized by thrombocytopenia, non-immune hemolysis, and organ dysfunction. Thrombotic microangiopathy associated with low levels of ADAMTS-13 may be a component of the coagulopathy observed in patients with sepsis. Here, we review the potential role of ADAMTS-13 deficiency and ultralarge VWF multimers in sepsis, and their relationship with sepsis severity and prognosis. In addition, we discuss the possible benefit of restoring ADAMTS-13 levels or reducing the effect of ultralarge VWF as an adjunctive treatment in patients with sepsis.

Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics.

Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS-13. In general, severe deficiency of plasma ADAMTS-13 activity (< 10 IU dL-1 ) with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP. A patient usually presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS-13 activity (> 10 IU dL-1 ) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. Although plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS-13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with demonstrable autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide and splenectomy, etc., should be considered to eliminate autoantibodies for a sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS-13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS-13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis and diagnosis of, and current and potential novel therapies for, hereditary and acquired TTP.