Development Of Thrombotic Thrombocytopenic Purpura Research Articles

Case Report of Development of Atypical Hemolytic-Uremic Syndrome in Pregnancy

Atypical hemolytic-uremic syndrome (aHUS) is an ultra-rare (orphan) disease with a progressive course, which is a systemic thrombotic microangiopathy resulting from uncontrolled activation of the alternative complement pathway. There exist the so called obstetric thombotic microangiopathies (pre-eclampsia, HELLP syndrome) which are considered as triggers causing development of aHUS in pregnancy in genetically predisposed female patients. Here, the main peculiarity of these pathologies is the improvement of the condition of the puerpera after delivery. In case of non-obstetric thombotic microangiopathies, delivery does not lead to regress of symptoms, on the contrary, microangiopathic process progresses with rapid development of multiorgan failure. The development of thrombotic thrombocytopenic purpura and aHUS in pregnancy may induce physiological changes in the organism of a pregnant woman. There occurs a build-up of the activity of von Willebrand factor with a parallel reduction of the activity of ADAMTS 13 enzyme (metalloprotease that cleaves its super-large multimers). This is probably a physiological adaptation of the body to minimize blood loss during childbirth. As a result of the imbalance, the risk of developing thrombotic microangiopathy increases by the end of II beginning of III trimester. The concept of chronic uncontrolled activation of the alternative complement pathway implies a genetic defect of regulatory proteins with increased formation of C5 convertase, increased release of C5a a strong chemoattractant, and of membraneattacking complex C5bC9, which leads to damage to endothelial cells, exposure of the subendothelial layer and thrombosis. The currently used drug eculizumab is a recombinant humanized monoclonal antibody that binds to the complement C5 protein and suppresses the activation of complement-mediated cell lysis. The article presents a clinical case of the development of aHUS in a patient during pregnancy, the main stages of diagnostic search are considered, routing is determined and the therapy used is justified.

COVID-19 vaccine (mRNA BNT162b2) and COVID-19 infection-induced thrombotic thrombocytopenic purpura in adolescents.

The mRNA COVID‐19 vaccine and COVID‐19 infection caused by the SARS‐CoV‐2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID‐19 vaccination or infection in pediatric or adolescent patients. We describe three adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID‐19 vaccine or after COVID‐19 infection. Our observations demonstrate that the Pfizer‐BioNTech mRNA vaccine and COVID‐19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.

СЛУЧАЙ ВТОРИЧНОЙ ТРОМБОТИЧЕСКОЙ ТРОМБОЦИТОПЕНИЧЕСКОЙ ПУРПУРЫ, ВЫЗВАННОЙ COVID-19

The article analyzes a clinical case of the development of thrombotic thrombocytopenic purpura (TTP) in a patient with verified COVID-19 infection. The algorithm of TTP diagnosis when ADAMTS13 biomarker test is unavailable is presented. The article presents the scheme of effective treatment of TTP with the use of plasma exchange, methylprednisolone and rituximab administration.

Graves disease-induced thrombotic thrombocytopenic purpura: a case report

BackgroundThrombotic thrombocytopenic purpura is an autoimmune disease that carries a high mortality. Very few case reports in the literature have described a relationship between Graves disease and thrombotic thrombocytopenic purpura. We present a case of a patient with Graves disease who was found to be biochemically and clinically hyperthyroid with concurrent thrombotic thrombocytopenic purpura.Case presentationOur patient was a 30-year-old African American woman with a history of hypertension and a family history of Graves disease who had recently been diagnosed with hyperthyroidism and placed on methimazole. She presented to our hospital with the complaints of progressive shortness of breath and dizziness. Her vital signs were stable. On further evaluation, she was diagnosed with thrombotic thrombocytopenic purpura, depending on clinical and laboratory results, and also was found to have highly elevated free T4 and suppressed thyroid-stimulating hormone. She received multiple sessions of plasmapheresis and ultimately had a total thyroidectomy. The patient’s hospital course was complicated by pneumonia and acute respiratory distress syndrome. Her platelets stabilized at approximately 50,000/μl, and her ADAMTS13 activity normalized despite multiple complications. The patient ultimately had a cardiac arrest with pulseless electrical activity and died despite multiple attempts at cardiopulmonary resuscitation.ConclusionGraves disease is an uncommon trigger for the development of thrombotic thrombocytopenic purpura, and very few cases have been reported thus far. Therefore, clinicians should be aware of this association in the appropriate clinical context to comprehensively monitor hyperthyroid patients during treatment.

Development of Thrombotic Thrombocytopenic Purpura in Association With the Monoclonal Antibody, Golimumab, Used to Treat Rheumatoid Arthritis, in a Case With Literature Review

Cepeda, Jillian DO; Liedke, Christopher DO; Patnaik, Asha MD; Yao, Qingping MD, PhD Author Information

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

Genetic and autoimmune risk factors contribute to the development of thrombotic thrombocytopenic purpura (TTP) but triggers are needed to bring about acute disease. The aim of the study was to investigate the association of neutrophil activation with acute TTP, to assess whether neutrophil activation changes during plasma exchange therapy and to show if complement- and neutrophil activation are parallel, characteristic processes in acute TTP. Altogether 49 EDTA-plasma samples of 21 TTP patients with acute disease and 17 in remission were investigated along with 20 healthy controls. A stable complex of PMNE-proteinase-inhibitor was measured by ELISA (Calbiochem, Merck-Millipore, Darmstadt, Germany). Acute disease was associated with significantly increased PMNE levels, the group medians were similarly low in TTP patients in remission and in healthy controls. Increased PMNE levels were characteristic for hematologically active and ADAMTS13 deficient form of TTP. PMNE concentration inversely correlated to disease activity markers platelet count (r=-0.349, p=0.032) and hemoglobin levels (p=-0.382 p=0.018). Achievement of remission was associated with significant reduction of plasma PMNE levels (p=0.031, Wilcoxon test). There was positive correlation between PMNE levels and complement activation markers C3a and Bb. We report increased PMNE levels in acute TTP and showed its association to activity markers of acute TTP and complement activation. Effective treatment of an acute TTP episode resulted in marked decrease in PMNE levels. Our data support and extend previous observations that neutrophil extracellular traps may be released in acute TTP and potentially contribute to the pathophysiology of this disease.

Serum Neutrophil Extracellular Trap Levels Predict Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation. TA-TMA likely represents the final stage of vascular endothelial injury; however, its pathophysiology is largely unknown, making clinical management difficult. Recently, the association of neutrophil extracellular traps (NETs) with the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been reported. Thus, we explored whether NETs are also relevant to the occurrence of TA-TMA. We retrospectively analyzed post-transplant trends of serum NET levels in 90 patients, 11 of whom developed TA-TMA. Relative to baseline (before the conditioning regimen), elevated serum NET levels either at 4 weeks after transplantation or as early as the day of transplantation were associated with significantly increased risk of TA-TMA. In contrast, thrombomodulin, a potential marker for TA-TMA, was not helpful to predict the occurrence of TA-TMA in our study. In addition, we directly detected glomerular deposition of NETs in 2 TA-TMA patients. Increased NET levels are a significant risk factor for TA-TMA, suggesting that NET level is a useful biomarker for TA-TMA.

Multiple myeloma presenting with a fever of unknown origin and development of thrombotic thrombocytopenic purpura post‐bortezomib

Multiple myeloma rarely presents with a fever of unknown origin and diagnosis may be delayed. We describe a case of myeloma presenting in this way with raised serum-free light chains and TP53 deletion on cytogenetics. The patient developed thrombotic thrombocytopenia purpura (TTP) following bortezomib therapy but recovered spontaneously and was successfully re-challenged. We believe this is only the second case to describe this phenomenon post-bortezomib and the first to rechallenge the patient successfully without further recurrence of TTP. Possible mechanisms for this successful rechallenge are discussed.

A Case Report of Gemcitabine Treatment for Duodenal Cancer: The Good (A Sustained Response) and The Bad (Life Threatening Refractory Thrombotic Thrombocytopenic Purpura)

Adenocarcinoma of the duodenum is a rare cancer and not submitted to the type of clinical trials that guide chemotherapy treatments in other gastrointestinal malignancies. This case demonstrates the potential use for gemcitabine, a chemotherapy typically used in pancreas and biliary tract tumors, in this difficult to treat disease as this patient had a partial response to single agent gemcitabine. Unfortunately, this case also demonstrates one of the rare potential adverse reactions to gemcitabine, which is the development of thrombotic thrombocytopenic purpura (TTP). In this case, the TTP was extremely difficult to treat but was resolved with splenectomy.

Development of thrombotic thrombocytopenic purpura after a single dose of gemcitabine

Development of thrombotic thrombocytopenic purpura after a single dose of gemcitabine

Pronounced Reduction in ADAMTS13 Activity Occurs in Heparin Induced Thrombocytopenia but Is Not Due to IgG ANTI-ADAMTS13.

Although severe deficiency in ADAMTS13 activity (<5%) can result in the development of thrombotic thrombocytopenic purpura (TTP), a less marked reduction in ADAMTS13 occurs in the acute phase reaction of sepsis and DIC, and may promote thrombosis in various disease states. Heparin induced thrombocytopenia (HIT) shares many important similarities with TTP. Both are autoimmune prothrombotic disorders characterised by pathogenic antibodies, marked endothelial cell activation, thrombocytopenia, and the development of thrombosis. ADAMTS13 parameters in HIT have not been well characterised and there is no consensus on the severity of the reduction in ADAMTS13 activity. We hypothesize that a pronounced reduction in ADAMTS13 activity can occur in HIT and investigated potential mechanisms underlying ADAMTS13 depletion. We evaluated ADAMTS13 activity, anti-ADAMTS13 IgG and VWF:Ag in double-spun citrated plasma from 20 patients (median age 64, Male:Female = 14:6). 15 were HIT positive (of whom 10 were cardiothoracic cases) and 5 were suspected HIT thrombocytopenic cases, but HIT negative. HIT antibodies were measured by ELISA (either: PF4 enhanced, GTI Diagnostics; or Asserachrom HPIA, Diagnostica Stago) and platelet aggregation (heparin dependence was demonstrated using a known responder as the platelet donor). ADAMTS13 activity was determined by a modified residual collagen binding assay, and anti-ADAMTS13 IgG by an in-house ELISA using recombinant ADAMTS13-coated microtitre plates. VWF:Ag was measured using an immunoturbidimetric assay (Dade Behring). The median HIT antibody concentration in the 15 HIT cases was 1.57 OD using PF4-enhanced ELISA (range 0.91–2.44), and 143% using HPIA (range 69–181%). The median platelet nadir was 57×109/L (range 6–132×109/L). ADAMTS13 activity (normal range (NR): 66–126%) was reduced in 15/15 (100%) HIT positive patients (median 17%, range 0–55%), but also in 4/5 (80%) HIT negative thrombocytopenic patients (median 31%, range 18–76%). There was no statistically significant difference between these two groups (p=0.12). Furthermore, the ADAMTS13 activity of the 10 cardiothoracic patients was not significantly different from the remaining HIT positive cases. Anti-ADAMTS13 IgG was detected in 3/15 HIT positive patients (with IgG levels of 12%, 28% and 69% [NR <4%]) and 1/5 HIT negative cases (IgG of 21%). VWF:Ag was elevated (>200 iu/dL) in 18/20 with a median VWF:Ag of 297 iu/dL (range 165–606 iu/dL). These observations show that ADAMTS13 activity is often low in HIT patients, and can be markedly reduced in some cases. However, ADAMTS13 IgG autoantibodies were only detected in 3 cases, suggesting that autoantibody production is not the predominant mechanism for reduced ADAMTS13 function. The high VWF:Ag observed in HIT is an acute phase reactant and represents excess ADAMTS13 substrate, which drives the process of VWF proteolysis and causes circulating ADAMTS13 depletion. This may ultimately promote the prothrombotic milieu seen in HIT.

Famciclovir and Development of Thrombotic Thrombocytopenic Purpura

Famciclovir and Development of Thrombotic Thrombocytopenic Purpura

The Role of ADAMT-13 in Platelet Adhesion in Flow: methods for Diagnosis of Thrombotic Thrombocytopenic Purpura

Von willebrand factor (VWF) is synthesized and released from endothelial cells and megakaryocytes. VWF multimers that are immobilized on the activated endothelial cells and unfolded by high shear stress, undergo proteolysis by specific VWF-cleaving protease, ADAMTS-13. Severe deficiency of ADAMTS-13 is followed by accumulation of ultralarge VWF multimers and development of thrombotic thrombocytopenic purpura (TTP). Several methods for detection of ADAMTS-13 activity are proposed. However, all these assays are lacking the condition of shear stress, in which rapid cleavage of VWF multimeric strings by the ADAMTS-13 occurs. Impact- R method testing the effect of plasma on normal platelet adhesion under shear stress allows rapid screening of acute TTP and discrimination from other thrombotic microangiopathies.

Simultaneous Development of Thrombotic Thrombocytopenic Purpura and Immune Thrombocytopenia in a Pediatric Patient with Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus can experience multiple hematological complications. Autoimmune hemolytic anemia, immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP) have been described in patients with this disease. Hematologic abnormalities may precede joint or renal manifestations of the disease. In TTP, decrease in the level of von Willebrand cleaving protease (ADAMTS13) activity and the presence of an inhibitor to this enzyme have been shown to correlate with disease activity. For the diagnosis of ITP, the presence of platelet antibodies is not required, but they are strongly suggestive of the diagnosis in combination with a falling platelet count. We present a young lady who developed multiple hematological abnormalities simultaneously against a background of well-controlled SLE. WC is a 13 yo female who was diagnosed with SLE after developing lupus nephritis at the age of 12. She was treated successfully with immunosuppression and had been maintained on cyclophosphamide every three months. At a routine clinic visit, a CBC was obtained that showed a hemoglobin of 6.7 g/dL, white blood cells of 7,500/mm3 and platelets of 22,000/mm3. Reticulocyte count was 18.8%. Direct antiglobulin test was negative. The patient complained of fatigue and headache of one week's duration. The peripheral blood smear showed 7–10 schistocytes per high power field and thrombocytopenia. A complete blood count performed one month prior to this visit showed a hemoglobin of 11.6 gm/dL and a platelet count of 353,000/mm3. The patient underwent plasmapheresis for 5 days for a presumptive diagnosis of TTP. She responded to plasmapheresis with increase in her hemoglobin level to 10.2 gm/dL and platelets to 153,000/mm3. On laboratory examination obtained prior to beginning plasmapheresis therapy, anti-platelet IgM antibody titer was elevated; ADAMTS13 inhibitor was elevated at 0.9 inhibitor units, and ADAMTS13 activity was decreased at 30%. After cessation of plasmapheresis the patient's platelet count decreased over one week to a nadir of 74,000/mm3. However, the patient's hemoglobin increased to 11.1 gm/dL over that same time period. Haptoglobin was normal at this time at 142 mg/dL. Lactate dehydrogenase was also normal at 204 U/L. No schistocytes were evident on peripheral blood smear. Therefore, we felt that the patient at this point was experiencing autoimmune destruction of her platelets only, without active TTP. The patient was monitored closely and her platelet count increased to 214,000/mm3 without intervention. She currently has stable blood counts in the normal range. This case is an unusual example of the hematological complications of SLE with the simultaneous development of two abnormalities in one patient. In this situation, presence of anti-platelet antibody and the stability of the patient's hemoglobin prevented reinitiation of plasmapheresis. The measurement of anti-platelet antibody was obtained as part of the screening laboratory examination for lupus and would not normally have been obtained in a patient with this clinical picture who presented to our clinic. This raises the questions of how often multiple autoantibodies coexist in these complex patients with SLE and whether we should consider examining for them more closely at the time of development of hematological abnormalities or at diagnosis of their rheumatologic disease.

Therapy of Hereditary TTP with ADAMTS13 Deficiency - A Case Report and Review of the Literature.

Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 is associated with the development of thrombotic thrombocytopenic purpura (TTP). ADAMTS13 gene mutations cause the hereditary TTP. We describe a patient with relapsing TTP, who failed to achieve sustained remission despite therapies with plasma exchange, steroids, vincristine and ATG. There was lower ADAMTS13 inhibitor titre and lower activity of ADAMTS13 enzyma in the patient's plasma. Sequence analysis of DNA amplified by polymerase chain reaction showed that the patient was homozygous for two novel missense mutations in TSP1 repeated motif domain of ADAMTS13. In both mutations cytisine were subtituded by thymine. One was a Serine to Leucine substitution in NT 3152, exon21(codon S903L); the other is a Arginine to a Tryptophan substitution in NT3727, exon 25(codon R1094W), while both parents were heterozygous for the same mutation. The patient was dialogue as hereditary TTP. The patient receives 600 to 800 ml plasma transfusion every 3 weeks and now she is very well and works again.Hereditary TTP with ADAMTS13 deficiency could be treated with the infusion of only a few units of plasma, without plasma exchange. Gene therapy may eventually cure hereditary TTP.

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome Associated with High-Dose Interleukin-2 for the Treatment of Metastatic Melanoma

Various drugs have been associated with the development of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Among the biologic agents, alpha-interferon therapy, used for treatment of hepatitis B and chronic myelogenous leukemia, has been associated with TTP in a few recent reports. The authors report the first case of TTP/HUS occurring in a metastatic melanoma patient receiving treatment with high-dose interleukin-2 (IL-2). A 57-year-old patient with malignant melanoma presented with seizures 3 days after completing the first week of high-dose IL-2, and the characteristic hematologic picture revealed TTP/HUS. This occurrence is unlikely to be explained by the association with malignant melanoma, which was not presenting with widespread visceral disease at the time of the occurrence, or by the use of other medications. Similar cytokine release profiles are encountered in TTP, HUS caused by Shiga toxin-1, HUS caused by E. coli O157, after IL-2 or IL-2-containing biochemotherapy, as well as in TTP caused by interferon-alpha. This cytokine profile could reflect a common cause, or just the presence of similar pathways involved.

Why Do We Need ADAMTS13?

ADAMTS13 is a member of a newly recognized zinc metalloprotease family that has been the subject of intense interest in recent years. Cleavage of von Willebrand factor by this protease is essential for preventing the development of thrombotic thrombocytopenic purpura (TTP) Von Willebrand factor (VWF), synthesized in vascular endothelial cells and megakaryocytes, supports platelet adhesion and aggregation at sites of vessel injury under high shear stress conditions. VWF exists in the circulation as a series of multimers, which were once believed to be released directly from vascular endothelial cells. By late 1980’s, much was known about the physiology and genetics of VWF. Nevertheless, three characteristics of VWF-platelet interaction in hemostasis had resisted efforts to unravel their molecular mechanisms (Table 1). First, VWF-platelet binding occurs only at sites of vessel injury but not in the circulation. There are two receptors on platelet surface that are engaged in VWF binding: glycoproteins αIIbβ3 and Ib/IX/V. Much is known about the regulation of VWF–αIIbβ3: αIIbβ3, normally in an inactive conformation, is transformed upon platelet activation to a competent form for ligand binding. In contrast, the regulation of VWF–Ib/IX/V remained mostly unclear. There is no definitive evidence that Ib/IX/V requires activation. What processes prevent VWF-platelet binding in the circulation but allows it to occur at sites of vessel injury? Second, several lines of evidence suggest that the large VWF multimers arc hemostatically more effective than small multimers. What is the molecular basis of this size dependence? Third, in experimental models, high levels of shear stress enhance the VWF-mediated platelet aggregation. What are the molecular features of VWF that enable VWF to become more effective under high shear stress conditions? Table 1 Characteristics of VWF-platelel interaction and their causes

Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13

AbstractSevere deficiency of the von Willebrand Factor (VWF)–cleaving proteinase, ADAMTS13, is associated with the development of thrombotic thrombocytopenic purpura (TTP). Several mutations spread across the ADAMTS13 gene have been identified in association with a deficiency of VWF-cleaving proteinase activity in patients with congenital TTP. The spread of these dysfunctional mutations and the domain structure of ADAMTS13 are suggestive of a complex interaction between the enzyme and its substrate. We have studied a patient with congenital TTP who is a compound heterozygote for the Thr196Ile mutation in the metalloproteinase domain and a frameshift mutation (4143-4144insA) in the second CUB domain that results in loss of the last 49 amino acids of the protein. The VWF-cleaving proteinase activity of the truncated enzyme was comparable to that of the wild-type enzyme but its secretion from transfected COS-7 cells was about 14% of the wild type.

Thienopyridine-linked thrombotic microangiopathy: association with endothelial cell apoptosis and activation of MAP kinase signalling cascades.

The thienopyridine platelet antagonist ticlopidine is associated with development of thrombotic thrombocytopenic purpura (TTP) but the pathophysiology of this link is unclear. Severe deficiency of disintegrin and metalloproteinase with thrombospondin motif-13 (ADAMTS13), described in familial cases and a significant fraction of idiopathic TTP, has been reported in only a few ticlopidine-linked cases. As ticlopidine can disrupt production of extracellular matrix (ECM) components critical to microvascular endothelial cell (MVEC) integrity in vitro, we explored the hypotheses that ticlopidine and ticlopidine-linked TTP plasmas induce MVEC apoptosis in a manner similar to that of idiopathic TTP plasmas, and that ECM components and related mitogen-activated protein kinase (MAPK) signalling cascades may be involved in this process. Replicating the activity of plasmas from patients with idiopathic TTP, plasma from five ticlopidine-linked TTP patients induced apoptosis of primary human dermal, glomerular and hepatic MVEC, but had no effect on pulmonary MVEC or large vessel endothelial cells (EC). Pharmacological levels of ticlopidine initiated apoptosis with similar EC lineage restriction. In parallel, ticlopidine and plasmas from idiopathic and ticlopidine-TTP patients decreased transcripts for the ECM component thrombospondin-1 in MVEC, but not in large vessel EC. These changes were accompanied by prolonged induction of MAPKs extracellular signal-related kinase (ERK)-1/2 and p38 only in TTP susceptible MVEC. Induction of apoptosis by ticlopidine and TTP plasma was abrogated by inhibitors of ERK-1/2 and p38 phosphorylation. In conclusion, MVEC apoptosis related to altered ECM-MVEC interactions may be a key part of the pathology of ticlopidine-linked and idiopathic TTP.

ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity

AbstractDeficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 is associated with the development of thrombotic thrombocytopenic purpura (TTP). A case of congenital TTP that was previously reported to have normal ADAMTS13 activity was analyzed at the molecular level. Reanalysis of plasma VWF cleaving protease activity using a different assay revealed that the patient had less than 0.1 U/L ADAMTS13 protease activity, while the parents were both partially deficient. Sequence analysis of DNA amplified by polymerase chain reaction showed that the patient was homozygous for a novel TT deletion in exon 15 of the ADAMTS13 gene resulting in a frameshift, while both parents were heterozygous for the same mutation. Taken together with other recent reports, all the cases of hereditary TTP studied by DNA sequence analysis to date appear to be due to mutations within the ADAMTS13 gene.