Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy.

The complex relation between thrombotic thrombocytopenic purpura (TTP) and pregnancy is concisely reviewed. Pregnancy is a very strong trigger for acute disease manifestation in patients with hereditary TTP caused by double heterozygous or homozygous mutations of ADAMTS13 (ADisintegrin And Metalloprotease with ThromboSpondin type 1 domains, no. 13). In several affected women disease onset during their first pregnancy leads to the diagnosis of hereditary TTP. Without plasma treatment mother and especially fetus are at high risk of dying. The relapse risk during a next pregnancy is almost 100% but regular plasma transfusion starting in early pregnancy will prevent acute TTP flare-up and may result in successful pregnancy outcome. Pregnancy may also constitute a mild risk factor for the onset of acute acquired TTP caused by autoantibody-mediated severe ADAMTS13 deficiency. Women having survived acute acquired TTP may not be at very high risk of TTP relapse during an ensuing next pregnancy but seem to have an elevated risk of preeclampsia. Monitoring of ADAMTS13 activity and inhibitor titre during pregnancy may help to guide management and to avoid disease recurrence. Finally, TTP needs to be distinguished from the much more frequent hypertensive pregnancy complications, preeclampsia and especially HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome.

Gallbladder and Pancreas in Henoch-Schönlein Purpura: Review of the Literature

OBJECTIVE Involvement of the pancreato-biliary system has been occasionally noted in Henoch-Schönlein purpura. Furthermore, cases of this vasculitis syndrome sometimes develop in the context of a viral hepatitis or after hepatitis vaccination. METHODS We completed a review of the literature. RESULTS Fifty reports published between 1977 and 2015 were retained for the analysis. A pancreato-biliary involvement was recognized in 34 individually well-described patients (♂:♀ = 19:15) with severe abdominal pain: pancreatitis (N = 20), acalculous cholecystitis (N = 11), both pancreatitis and cholecystitis (N = 3). In all of the pancreatitis patients, full recovery occurred (within ≤3 weeks in three-fourths of the patients). Cholecystectomy was performed in 8 cholecystitis patients. Seventeen Henoch-Schönlein patients (♂:♀ = 9:8) were associated with a viral liver disease and 4 (♂:♀ = 1:3) with a hepatitis vaccination. The vasculitis syndrome rapidly remitted in the 7 patients accompanying hepatitis A or E, in 2 patients of hepatitis B, and in the 4 patients preceded by a vaccination. Henoch-Schönlein purpura seemed to be serious in 5 patients with chronic hepatitis B and in 3 with chronic hepatitis C. CONCLUSIONS This analysis indicates that pancreato-biliary involvement is unusual in Henoch-Schönlein purpura. This complication deserves consideration in patients with especially severe abdominal pain. Finally, viral hepatitides and hepatitis vaccinations seem to be rare triggers of Henoch-Schönlein purpura.

Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency.

The congenital form of thrombotic thrombocytopenic purpura (TTP) is caused by genetic mutations in ADAMTS13. Some, but not all, congenital TTP patients manifest renal insufficiency in addition to microangiopathic hemolysis and thrombocytopenia. We included 32 congenital TTP patients in the present study, which was designed to assess whether congenital TTP patients with renal insufficiency have predisposing mutations in complement regulatory genes, as found in many patients with atypical hemolytic uremic syndrome (aHUS). In 13 patients with severe renal insufficiency, six candidate complement or complement regulatory genes were sequenced and 11 missense mutations were identified. One of these missense mutations, C3:p.K155Q mutation, is a rare mutation located in the macroglobulin-like 2 domain of C3, where other mutations predisposing for aHUS cluster. Several of the common missense mutations identified in our study have been reported to increase disease-risk for aHUS, but were not more common in patients with as compared to those without renal insufficiency. Taken together, our results show that the majority of the congenital TTP patients with renal insufficiency studied do not carry rare genetic mutations in complement or complement regulatory genes.

Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND Acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high. METHODS Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses. RESULTS Seventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group. CONCLUSIONS Caplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.).

Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies

Severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 as observed in acquired thrombotic thrombocytopenic purpura (TTP) is caused by inhibitory and non-inhibitory autoantibodies directed against the protease. Current treatment with plasma exchange is considered to remove circulating antibodies and to concurrently replenish the deficient enzyme.

Reticulate eruptions: Part 2. Historical perspectives, morphology, terminology and classification

Reticulate eruptions of vascular origin may represent an underlying arterial, venous, microvascular or combined pathology. In the presence of arterial pathology, individual rings are centred around ascending arterial vessels that supply the corresponding area of skin within an arterial hexagon that clinically presents with a blanched centre. Confluence of multiple arterial hexagons generates a stellate (star-like) pattern. In the presence of a primary venous pathology, individual rings correspond to the underlying reticular veins forming multiple venous rings. Focal involvement of a limited number of vessels presents with a branched (racemosa) configuration while a generalized involvement forms a reticulate (net-like) pattern. 'Livedo' refers to the colour and not the pattern of the eruption. Primary livedo reticularis (Syn. cutis marmorata) is a physiological response to cold and presents with a diffuse blanchable reticulate eruption due to vasospasm of the feeding arteries and sluggish flow and hyperviscosity in the draining veins. Livedo reticularis may be secondary to underlying conditions associated with hyperviscosity of blood. Livedo racemosa is an irregular, branched eruption that is only partially-blanchable or non-blanchable and always signifies a pathological process. Retiform purpura may be primarily inflammatory with secondary haemorrhage or thrombohaemorrhagic, as seen in disseminated intravascular coagulopathy.

Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies

Thrombotic microangiopathies (TMAs) are a group of life-threatening disorders characterized by thrombocytopenia, fragmentation of erythrocytes, and ischemic organ damage. Genetic disorders, autoimmune disease, and cancer are risk factors for TMAs, but an additional, unknown trigger is needed to bring about acute disease. Recent studies suggest that DNA and histones are released during inflammation or infection and stimulate coagulation, thrombosis, thrombocytopenia, and organ damage in mice. We show that extracellular DNA and histones as well as markers of neutrophils are present in acute TMAs. Analysis of plasma from TMA patients of different clinical categories revealed elevated levels of DNA-histone complexes and myeloperoxidase (MPO) from neutrophil granules as well as S100A8/A9, a heterocomplex abundant in neutrophil cytosol. During therapy of thrombotic thrombocytopenic purpura, a subtype of TMAs often associated with severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) deficiency, plasma DNA and MPO were inversely correlated with platelet counts, and their levels indicated amelioration or exacerbation of the disease. ADAMTS13 deficiency together with increased levels of plasma DNA and MPO were characteristic for acute thrombotic thrombocytopenic purpura. A minor infection often precedes acute TMA and extracellular DNA and histones released during the inflammatory response could provide the second hit, which precipitates acute TMA in patients with pre-existing risk factors.

Novel ADAMTS13 mutations in an obstetric patient with upshaw-schulman syndrome

Upshaw-Schulman syndrome (USS) is a rarely reported congenital form of thrombotic thrombocytopenic purpura (TTP) that results from mutations in the ADAMTS13 gene. Many USS patients are diagnosed during the second or third trimester of their first pregnancy. We present a patient diagnosed with USS following retinal detachments and intrauterine fetal demise at 34 weeks of gestation. The patient's plasma was tested for ADAMTS13 activity, inhibitor, and antibody. Subsequently, she and her first-degree relatives had ADAMTS13 gene sequencing. Initially, the patient was found to have an ADAMTS13 activity of <5% in the absence of an ADAMTS13 inhibitor (FRETS assay) or antibody (immunoassay). Repeat studies in the months following hospital discharge showed persistent, undetectable ADAMTS13 activity and she was given a clinical diagnosis of USS. Molecular sequencing demonstrated two novel missense mutations in the ADAMTS13 gene: one in the maternal exon 17 (p.Ala690Thr due to nucleotide substitution c.2068 G>A) and another in the paternal exon 22 (p.Arg915Cys due to nucleotide substitution c.2746 C>T). In addition to being compound heterozygous for two ADAMTS13 mutations, the patient also had two maternally inherited single nucleotide polymorphisms: p.P618A (exon 16) and p.A732V (exon 18). Her parents and only sister had normal or near-normal ADAMTS13 activity. Each was heterozygous for one of the novel missense mutations. This case highlights the importance of molecular analysis of the ADAMTS13 gene in patients and family members when the severe ADAMTS13 deficiency does not appear to be autoimmune in nature. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

[Glomerulonephritis and vasculitis as causes of arterial hypertension]

The various types of glomerulonephritis, including many forms of vasculitis, are responsible for about 15% of cases of end-stage renal disease (ESRD). Arterial hypertension represents a frequent finding in patients suffering from glomerulonephritis or vasculitis and hypertension also serves as an indicator for these severe types of diseases. In addition, there are symptoms and signs like hematuria, proteinuria and renal failure. Especially, rapidly progressive glomerulonephritis (RPGN) constitutes a medical emergency and must not be missed by treating physicians. This disease can either occur limited to the kidneys or in the context of a systemic inflammatory disorder, like a vasculitis. If left untreated, RPGN can lead to a necrotizing destruction of glomeruli causing irreversible kidney damage within several months or even weeks. With respect to the immunologically caused vasculitis, there are - depending upon the severity and type of organ involved - many clinical warning signs to be recognized, such as arterial hypertension, hemoptysis, arthalgias, muscle pain, palpable purpura, hematuria, proteinuria and renal failure. In addition, constitutional signs, such as fever and loss of body weight may occur concurrently. Investigations of glomerulonephritis or vasculitis must contain a careful and complete examination of family history and medications used by the respective patient. Thereafter, a thorough clinical examination must follow, including skin, joints and measurement of arterial blood pressure. In addition, a spectrum of laboratory analyses is required in blood, such as full blood screen, erythrocyte sedimentation rate, CRP, creatinine, urea and glucose, and in urine, including urinalysis looking for hematuria, red cell casts and proteinuria. Importantly, proteinuria needs to be quantified by the utilization of a random urine sample. Proteinuria > 3g/d is diagnostic for a glomerular damage. These basic tests are usually followed by more specialized analyses, such as a screening for infections, including search for HIV, hepatitis B or C and various bacteria, and for systemic inflammatory diseases, including tests for antibodies, such as ANA, anti-dsDNA, ANCA, anti-GBM and anti-CCP. In cases of membranous nephropathy, antibodies against phospholipase-A2-receptor need to be looked for. Depending upon the given clinical circumstances and the type of disease, a reasonable tumor screening must be performed, especially in cases of membranous and minimal-change nephropathy. Finally, radiological examinations will complete the initial work-up. In most cases, at least an ultrasound of the kidney is mandatory. Thereafter, in most cases a renal biopsy is required to establish a firm diagnosis to define all treatment options and their chance of success. The elimination of a specific cause for a given glomerulonephritis or vasculitis, such as an infection, a malignancy or a drug-related side-effect, remains the key principle in the management of these diseases. ACE-inhibitors, angiotensin receptor-blockers, aldosteron antagonists and renin-inhibitors remain the mainstay in the therapy of arterial hypertension with proteinuria. Only in cases of persistently high proteinuria, ACE-inhibitors and angiotensin receptor blockers can be prescribed in combination. Certain types of glomerulonephritis and essentially all forms of vasculitis require some form of more specific anti-inflammatory therapy. Respective immunosuppressive drug regimens contain traditionally medications, such as glucocorticoids (e. g. prednisone), cyclosporine A, mycophenolate mofetil, cyclophosphamide, and azathioprine. With respect to more severe forms of glomerulonephritis and vasculitis, the antibody rituximab represents a new and less toxic alternative to cyclophosphamide. Finally, in certain special cases, like Goodpasture's syndrome or severe ANCA-positive vasculitis, a plasma exchange will be useful and even required.

A common origin of the 4143insA ADAMTS13 mutation

Severely deficient activity of the von Willebrand Factor (VWF) cleaving metalloprotease, ADAMTS13, is associated with thrombotic thrombocytopenic purpura (TTP). The mutation spectrum ofADAMTS13 is rather heterogeneous, and numerous mutations spread across the gene have been described in association with congenital TTP. The 4143insA mutation is unusual with respect to its geographic concentration. Following the initial report from Germany in which the 4143insA mutation was detected in four apparently unrelated families, we have now identified this mutation in a further eleven patients from Norway, Sweden, Poland, Germany, the Czech Republic and Australia. Confirmation that the Australian patient is of German ancestry, together with the Northern and Central European origin of most of the other patients, suggests that the 4143insA mutation has a common genetic background. We established ADAMTS13 haplotypes by analyzing 17 polymorphic intragenic markers. The haplotypes linked to 4143insA were identical in all informative families. Three novel candidate mutations, C347S, P671L and R1060W, as well as the known mutation R507Q, were also identified during the course of the study. We conclude that 4143insA has a common genetic background and is frequent among patients with hereditary ADAMTS13 deficiency in Northern and Central European countries.

ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock

BACKGROUND: Insufficient control of von Willebrand factor (VWF) multimer size as a result of severely deficient ADAMTS-13 activity results in thrombotic thrombocytopenic purpura associated with microvascluar thrombosis and platelet consumption, features not seldom seen in severe sepsis and septic shock. METHODS: ADAMTS-13 activity and VWF parameters of 40 patients with severe sepsis or septic shock were compared with those of 40 healthy controls of the same age and gender and correlated with clinical findings and sepsis outcome. RESULTS: ADAMTS-13 activity was significantly lower in patients than in healthy controls [median 60% (range 27-160%) vs. 110% (range 63-200%); P < 0.001]. VWF parameters behaved reciprocally and both VWF ristocetin cofactor activity (RCo) and VWF antigen (VWF:Ag) were significantly (P < 0.001) higher in patients compared with controls. Neither ADAMTS-13 activity nor VWF parameters correlated with disease severity, organ dysfunction or outcome. However, a contribution of acute endothelial dysfunction to renal impairment in sepsis is suggested by the significantly higher VWF propeptide and soluble thrombomodulin levels in patients with increased creatinine values as well as by their strong positive correlations (creatinine and VWF propeptide r(s) = 0.484, P < 0.001; creatinine and soluble thrombomodulin r(s) = 0.596, P < 0.001). CONCLUSIONS: VWF parameters are reciprocally correlated with ADAMTS-13 activity in severe sepsis and septic shock but have no prognostic value regarding outcome.

A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13

Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by occlusive microvascular thrombosis, consumptive thrombocytopenia, and microangiopathic hemolytic anemia. Homozygous or compound heterozygous mutations in the ADAMTS13 gene result in a congenital severe ADAMTS13 deficiency and subsequent accumulation of ultra-large von Willebrand factor multimers, which tend to form platelet thrombi in the microcirculation. We report a first case of congenital TTP on the African continent with a new, homozygous mutation in the metalloprotease domain of ADAMTS13. An initially oligo-symptomatic presentation was followed by acute exacerbation with ischemic stroke and acute renal failure highlighting the severity of this syndrome.

[Childhood Henoch-Schönlein syndrome--common and uncommon features, complications, Finkelstein-Seidlmayer variant and management]

Although Henoch-Schönlein syndrome can occur at any age, it is overwhelmingly a disease of childhood. Indeed, Henoch-Schönlein syndrome is the most common vasculitis that affects children. The clinical features of this vasculitis are well documented, and the diagnosis is generally not difficult. This article briefly reviews both common and uncommon clinical aspects of the condition and information concerning therapy. A further focus of this review is recent information concerning abnormalities of immunoglobulin IgA1 glycosylation and the role of aberrantly glycosylated immunoglobulins in the development of Henoch-Schönlein syndrome. The final focus of the article is acute hemorrhagic edema, a benign vasculitis limited to the skin, which is characterized by circinate, medallion-like purpura, and ecchymoses and occurs in children younger than 4 years of age. The nosologic position of acute hemorrhagic edema, which has also been called Finkelstein-Seidlmayer syndrome, as a variant of Henoch-Schönlein syndrome is the subject of considerable debate, but most authors agree that there are sufficient clinical and prognostic differences to consider it a separate entity.