Hereditary thrombotic thrombocytopenic purpura and COVID-19: Impacts of vaccination and infection in this rare disease.

Introduction Severe COVID-19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune-mediated TTP associated with COVID-19 or SARS-CoV-2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. Method We conducted a survey among adult patients of the International Hereditary TTP Registry about SARS-CoV-2 vaccination, COVID-19, and occurrence of acute hTTP episodes. Results Of 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty-five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA-1273 vaccine. Twelve (14%) patients had COVID-19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. Discussion The risk of an acute episode triggered by COVID-19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS-CoV-2

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized

Prevention and Management of Bleeding Episodes in Patients with Acquired Hemophilia A

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies inhibiting the function of coagulation factor VIII. It is characterized by spontaneous bleeding in patients with no previous family or personal history of bleeding. Although several large registries have collected clinical data on AHA, limited information is available on the optimal management of AHA because controlled clinical trials are lacking. AHA can easily be diagnosed if the problem (prolonged activated partial thromboplastin time in a bleeding patient) is recognized. After the effects of anticoagulants are excluded, low factor VIII activity and the detection of circulating inhibitors confirms the diagnosis. However, lack of familiarity with this rare condition may delay diagnosis and adequate therapy. Treatment of AHA is based on measures for prompt hemostatic control to stop (and prevent) bleeding, immunosuppression to eradicate the autoantibodies, and supportive care for the adverse effects of that treatment and patients often complex comorbidities. This article gives a comprehensive overview of the current knowledge about the pathophysiology, diagnosis, and treatment of AHA.(VLID)362008

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a clearly defined entity of the thrombotic microangiopathies (TMA), a heterogeneous group of disorders characterized by microangiopathic hemolytic anemia with red cell fragmentation, thrombocytopenia and organ dysfunction due to disturbed microcirculation. TTP is characterized by a severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme responsible for physiological cleavage of von Willebrand factor (VWF). Organ dysfunction can be severe and life-threatening, and immediate start of appropriate therapy is necessary to avoid permanent damage or death. Until recently, therapeutic options were limited to symptomatic measures, which were not standardized or based on high scientific evidence. In recent years, not only considerable progress has been made in better diagnosis of TTP, but also new therapeutic strategies have been established. Initial treatment is still based on plasma exchange and symptomatic measures to protect organ function, but new concepts (immunosuppression, targeted anti-VWF or anti-complement therapy, replacement with recombinant enzymes) have recently demonstrated impressive advantages.(VLID)362075

Thrombopenie auf der Intensivstation : Diagnose, Differenzialdiagnose und Therapie

Thrombozytopenie ist ein häufiges Phänomen in der Intensivmedizin. Eine Vielzahl von Ursachen kann für erniedrigte Plättchenzahlen verantwortlich sein. Da Plättchen Teil der primären Hämostase sind, ist Blutungsneigung die wichtigste Komplikation einer Thrombopenie. Strukturiertes Aufarbeiten der Differenzialdiagnose und Identifikation der Ursache ist essenziell, da die verschiedenen Krankheitsbilder unterschiedliche diagnostische und therapeutische Maßnahmen erfordern. Eine erniedrigte Thrombozytenzahl ist ein starker Prädiktor der Mortalität kritisch kranker Patienten. Dieser Artikel fasst die Differenzialdiagnose und die diagnostische Aufarbeitung der Thrombopenie in der Intensivmedizin zusammen und gibt einen Überblick über die wichtigsten Krankheitsbilder und die therapeutischen Optionen.Thrombocytopenia is a frequent phenomenon in intensive care medicine. A variety of conditions can be responsible for low platelet counts. As platelets are part of the primary hemostatic system, bleeding is the most important complication of thrombocytopenia. Proper workup of the differential diagnosis to identify the cause of thrombocytopenia is essential because the various underlying disorders require different diagnostic and therapeutic management strategies. A low platelet count is a strong predictor of outcome in critically ill patients. This article summarizes the differential diagnosis and diagnostic workup of thrombocytopenia in the critically ill, describes the most important conditions, and gives an overview on therapeutic options and strategies.(VLID)346795

Thrombopenie auf der Intensivstation : Diagnose, Differenzialdiagnose und Therapie

Thrombozytopenie ist ein häufiges Phänomen in der Intensivmedizin. Eine Vielzahl von Ursachen kann für erniedrigte Plättchenzahlen verantwortlich sein. Da Plättchen Teil der primären Hämostase sind, ist Blutungsneigung die wichtigste Komplikation einer Thrombopenie. Strukturiertes Aufarbeiten der Differenzialdiagnose und Identifikation der Ursache ist essenziell, da die verschiedenen Krankheitsbilder unterschiedliche diagnostische und therapeutische Maßnahmen erfordern. Eine erniedrigte Thrombozytenzahl ist ein starker Prädiktor der Mortalität kritisch kranker Patienten. Dieser Artikel fasst die Differenzialdiagnose und die diagnostische Aufarbeitung der Thrombopenie in der Intensivmedizin zusammen und gibt einen Überblick über die wichtigsten Krankheitsbilder und die therapeutischen Optionen.Thrombocytopenia is a frequent phenomenon in intensive care medicine. A variety of conditions can be responsible for low platelet counts. As platelets are part of the primary hemostatic system, bleeding is the most important complication of thrombocytopenia. Proper workup of the differential diagnosis to identify the cause of thrombocytopenia is essential because the various underlying disorders require different diagnostic and therapeutic management strategies. A low platelet count is a strong predictor of outcome in critically ill patients. This article summarizes the differential diagnosis and diagnostic workup of thrombocytopenia in the critically ill, describes the most important conditions, and gives an overview on therapeutic options and strategies.(VLID)349865