Onset Of Thrombotic Thrombocytopenic Purpura Research Articles

Case report of thrombotic thrombocytopenic purpura during pregnancy with a review of the relevant research.

Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by widespread blood vessel clotting and bleeding. It can affect individuals of any age but is more commonly observed in females, particularly during pregnancy. Pregnancy combined with TTP is a critical and rapidly progressing condition that is often misdiagnosed as an obstetric disorder like severe preeclampsia or HELLP syndrome. To deepen the understanding of TTP during pregnancy with the help of a clinical case. A 20-year-old patient, is pregnancy 1 birth 0, 32 weeks dated by her last menstrual period, presented chest tightness, and shortness of breath after physical activity for 3 days. TTP. At present, there are no preventive measures. Timely diagnosis and treatment are useful. Plasma exchange and treat to the patient hinder autoantibodies, such as gamma globulin, methylprednisolone, rituximab, and cyclosporine were effective. The patient exhibited stable vital signs, normal examination results, and experienced no complications. We continued to monitor her progress after she was discharged. The acute onset of TTP is often associated with pregnancy, as it is a triggering factor. Timely identification, accurate diagnosis, and a comprehensive treatment approach involving plasma exchange, immunosuppressants, and the termination of pregnancy can lead to remission and a favorable outlook for the majority of patients.

Sudden coma at the onset of severe refractory thrombotic thrombocytopenic purpura with successful treatment

Most patients develop coma several days after the onset of thrombotic thrombocytopenic purpura (TTP) caused by microvascular occlusion. However, aggravated coma as the first symptom of TTP has rarely been reported. Although plasma exchange (PEX) and steroids have reduced mortality, the prognosis of patients with TTP is still poor. We reported a patient with refractory TTP presenting with aggravated coma on admission. After days of successful PEX, rituximab, and glucocorticoid therapy for clinical remission, the patient regained consciousness and returned to his normal life with a good outcome. Our case highlights that TTP should be considered when coma occurs as the first symptom.

Acquired Thrombotic Thrombocytopenic Purpura and Acute Pancreatitis: Variable and Reciprocal Pathophysiologic Relationships

INTRODUCTIONAcquired thrombotic thrombocytopenic purpura (TTP) is an aggressive thrombotic microangiopathy (TMA). Central to the pathophysiology is loss of ADAMTS 13 activity, due to inhibitors in the acquired form, allowing circulating ulVWF multimers to activate platelets and produce organ damage from microvascular thromboses. Autopsy studies find frequent pancreatic involvement, but clinically evident acute pancreatitis (AP) is infrequently reported. The relationship of TTP and AP may be variable and complex, with either capable of precipitating, exacerbating or mimicking the other. More so than other organ systems, the pancreas has immense potential for cytokine production and proteolytic enzyme release. This characteristic may contribute to the reciprocal fueling, and thus severity, of TTP in association with pancreatitis.METHODSWe generated a descriptive, retrospective case series, querying the Methodist Environmental for Translational Enhancement and Outcomes Research database, a system that integrates Houston Methodist Hospital patient data into a single, comprehensive warehouse. We included all patients in whom TTP and AP were diagnosed during the same hospitalization between 2006 and 2016. Baseline demographics, laboratory values, time between onset of TTP and AP, complications, treatment, as well as short term morbidity and mortality were analyzed.RESULTSTwelve patients were identified as having TTP and AP in the same hospitalization. Demographics, onset intervals, and laboratory values of all patients are summarized in Table 1. Four patients had likely TTP induced AP with time to AP onset between 3 to 28 days, while eight patients had concurrent TTP and AP at initial presentation. All patients had elevated LDH levels with a range of 1575 U/L to 28,342 U/L and decreased platelet counts with a range of 5 k/µL to 59 k/µL. In the seven cases where ADAMTS13 measurements were performed prior to plasma exchenge (PEX), levels were below 5%. With the exception of case 5 in whom mild disseminated intravascular coagulation may have played a role in addition to TTP, no alternative etiologies were identified for the induction of the AP or the TMA.Gastrointestinal (GI) symptoms were observed in 91% of the patients, with severe cases exhibiting ischemic colitis and GI bleeds. Eighty-one percent experienced neurological symptoms, of which 80% were considered major (coma, stroke seizures, or transient focal abnormalities) and the remaining minor (transient headache or confusion). Occurring more often than in TTP patient without AP, significant renal manifestations were seen in 81% (44% progressing to renal failure requiring dialysis), and acute coronary syndromes were experienced by 50%. All patient received fresh frozen plasma, PEX, and glucocorticoids for their TTP. However, 67% of the patients had refractory TTP, of which two thirds required the addition of rituximab. With the exception of two patients who expired secondary to cardiac arrests, all others achieved normalization of their platelets by discharge. Details of the organ involvements, treatments, and complications are summarized in Table 2.CONCLUSIONWe describe twelve patients with clinically evident acute pancreatitis in association with TTP. Compared to the severely ADAMTS13 deficient (<10%) patients reported in other studies, our patients suffered significantly worse organ involvement (George, 2010). Pancreatic cytokine release observed in other studies may have contributed to ADAMTS13 depletion, contributing to the phenotypic severity (Reiter et al, 2003; Bernardo et al, 2004; Mannucci et al, 2004; Swisher et al, 2007; Morioka et al, 2008). A review of literature also revealed the role of pancreatitis in nitric oxide depletion and complement activation, which may augment micro-thrombi formation and fuel TTP propagation. Whereas the relationship between TTP and other organ systems may be one of cause and effect, the relationship between AP and TTP may be one of reciprocal fueling. As such, early appreciation and treatment of pancreatitis might significantly decrease the severity of TTP and improve patient outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Acute Onset of Thrombotic Thrombocytopenic Purpura after Erenumab Treatment: A Case Report (2888)

Acute Onset of Thrombotic Thrombocytopenic Purpura after Erenumab Treatment: A Case Report (2888)

Histone-induced thrombotic thrombocytopenic purpura in adamts13 -/- zebrafish depends on von Willebrand factor.

Thrombotic thrombocytopenic purpura (TTP) is caused by severe deficiency of ADAMTS13 (A13), a plasma metalloprotease that cleaves endothelium-derived von Willebrand factor (VWF). However, severe A13 deficiency alone is often not sufficient to cause an acute TTP; additional factors may be required to trigger the disease. Using CRISPR/Cas9, we created and characterized several novel zebrafish lines carrying a null mutation in a13−/−, vwf, and both. We further used these zebrafish lines to test the hypothesis that inflammation that results in neutrophil activation and release of histone/DNA complexes may trigger TTP. As shown, a13−/− zebrafish exhibit increased levels of plasma VWF antigen, multimer size, and ability of thrombocytes to adhere to a fibrillar collagen-coated surface under flow. The a13−/−zebrafish also show an increased rate of occlusive thrombus formation in the caudal venules after FeCl3 injury. More interestingly, a13−/− zebrafish exhibit ~30% reduction in the number of total, immature, and mature thrombocytes with increased fragmentation of erythrocytes. Administration of a lysine-rich histone results in more severe and persistent thrombocytopenia and a significantly increased mortality rate in a13−/−zebrafish than in wildtype (wt) ones. However, both spontaneous and histone-induced TTP in a13−/− zebrafish are rescued by the deletion of vwf. These results demonstrate a potentially mechanistic link between inflammation and the onset of TTP in light of severe A13 deficiency; the novel zebrafish models of TTP may help accelerate our understanding of pathogenic mechanisms and the discoveries of novel therapeutics for TTP and perhaps other arterial thrombotic disorders.

Lysine Histone-Induced Thrombocytopenia in Zebrafish Depends on Endothelial Von Willebrand Factor

Thrombotic thrombocytopenic purpura (TTP), a potentially fatal blood disorder, is caused by severe deficiency of plasma ADAMTS13 activity, primarily resulting from acquired autoantibodies that inhibit ADAMTS13's ability to cleave von Willebrand factor (VWF). However, severe deficiency of plasma ADAMTS13 activity alone is often not sufficient to cause an acute episode of TTP; additional environmental or genetic factors may be required for the development of acute TTP. Here, we report a creation and characterization of a novel zebrafish model of TTP and use the model to identify a potential mechanistic link between an innate immunity and onset of TTP. Using CRISPR/cas9, we generated adamts13-/-,vwf-/-, and adamts13-/-vwf-/-zebrafish on a double transgenic (Fli1-eGFP/Gata1-dsRed) background in which erythrocytes, thrombocytes, and endothelial cells were uniquely labeled with an endogenously expressed fluorescent protein. Our results demonstrated that adamts13-/-zebrafish larvae (5-dpf) had an increased rate of developing occlusive thrombi in the caudal venues after FeCl3 injury; also, adamts13-/- adult zebrafish (3-4 months) exhibited ~27% reduction of their total or mature thrombocyte counts with a significantly increased number of fragmented erythrocytes; moreover, an intraperitoneal administration of a lysine-rich histone resulted in severe and more persistent thrombocytopenia with an increased mortality in adamts13-/-zebrafish than their wild-type littermate; finally, both spontaneous and histone-induced thrombocytopenia and thrombotic microangiopathy in adamts13-/-was eliminated when endothelial vwf was genetically deleted from zebrafish. Together, these results provide experimental evidences to support a mechanistic link of acute infection or inflammation to acute onset of TTP in patients lacking plasma ADAMTS13 activity. DisclosuresZheng:Alexion: Research Funding, Speakers Bureau.

Proteolytic inactivation of ADAMTS13 by plasmin in human plasma: risk of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is caused by inactivation of a von Willebrand factor (VWF)-cleaving enzyme, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which leads to platelet-rich thrombi comprising unusually large VWF multimers. We have found that ADAMTS13 can bind to the inactivated form of plasmin. In addition, plasmin cleaves purified ADAMTS13 into several fragments and inactivates it. Hence, we hypothesized that activation of plasminogen to plasmin becomes a new-onset factor for TTP due to ADAMTS13 inactivation. Plasmin was added exogenously or activated from plasminogen by streprokinase addition in human plasma (HP). ADAMTS13 digestion and effects of the digestion on ADAMTS13 activity were evaluated. Exogenous plasmin cleaved ADAMTS13 into several fragments, but a portion of ADAMTS13 remained in full-length form. Digestion profile of ADAMTS13 with streprokinase added exogenously in HP was similar to that of ADAMTS13 with exogenous plasmin. ADAMTS13 activity measured using FRETS-VWF73 decreased to ∼40% compared with that for normal plasma. Endogenous VWF multimer-cleaving activity was attenuated more severely (∼10%). These data suggest that endogenous plasmin cleaves ADAMTS13 into fragments and reduces its activity to ∼10%. We suggest that endogenous plasmin activation alone is not sufficient to cause TTP, but plasmin activation with ADAMTS13 deficiency might increase the risk of TTP onset.

Rituximab for Prevention of Recurrent Pregnancy Related Thrombotic Thrombocytopenic Purpura in High Risk Patients with Previous Episodes of Thrombotic Thrombocytopenic Purpura during Pregnancy

IntroductionWe describe the use of rituximab for the successful prophylaxis and delivery of a multiparous female with a history of pregnancy related thrombotic thrombocytopenic purpura (TTP) now presenting with a high risk of relapse during subsequent pregnancy.Case PresentationA 33 year-old African American female with a history of post-partum TTP diagnosed two years prior was referred to the hematology clinic for suspected recurrence of her TTP at 22 weeks gestation.Two years ago the patient had presented with symptoms of severe headache and hypertension which began 1 week after the delivery of her 3rd child. She was referred to the emergency department where she was found to have microangiopathic hemolytic anemia with a hemoglobin of 7.6g/dL, platelets of 10k/uL and abundant schistocytes on peripheral smear. Her blood chemistry revealed renal failure with an elevated creatinine of 2.7mg/dL, LDH of 2001 IU/L. She was found to have a moderately low ADAMTS13 level of 16% (normal >66%) and an inhibitor was detected (1.0 BEU). Her ANA, HIV, hepatitis and lupus serologies were all negative. Her C3 level was 105 (normal 70-225mg/dL) and C4 was 20 mg/dL (normal 14-55 mg/dL). She was promptly initiated on plasma exchange in addition to magnesium supplementation and strict blood pressure control. She underwent 11 days of daily plasma exchange and steroids with improvement of her platelets and resolution of schistocytes on peripheral smear. Despite this, she again had rise in her parameters and rituximab was added to the regimen which she responded to with continued normalization of her hematologic parameters and clinical resolution of symptoms.Approximately 2 years later, the patient presented again at 22 weeks gestation of her fourth pregnancy for suspected recurrence of her TTP. Blood chemistry revealed a low ADAMTS13 (<3%), anemia (Hb 10.8g/dL) and moderate thrombocytopenia (platelets 156k/uL). Her liver and renal functions were unaffected and she had no evidence of bruising or bleeding on physical exam. Serial repeat testing showed persistently low ADAMTS13 level (<3%) and worsening thrombocytopenia (platelets decreased to 113k/uL) without development of other clinical manifestation of TTP.Prophylactic plasma exchange was offered to the patient however the patient declined due to its associated risks. She was initiated on weekly rituximab (375mg/m2) with decadron (6mg weekly) from 27th to 30th weeks of pregnancy. After 4 infusions, her platelets improved to 190k/uL along with an increase in ADAMTS13 level to 62%. A healthy male child weighing 3.2 kilograms was delivered by C-section at 36 weeks without complications. Post-partum, the patient's CBC remained stable with platelets above 100k/dL along with her LDH, haptoglobin and renal function and was subsequently discharged with no further documentation of relapse in her TTP.DiscussionTTP is a severe, and often life threatening condition characterized clinically by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, neurologic changes and fever.Pregnancy is a known trigger for onset of TTP and has been well described in literature, usually presenting in the third trimester or post-partum period with a constellation of symptoms that may mimic other thrombotic microangiopathies (Martin JN Jr, et al. Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955-2006. Am J Obstet Gynecol.2008; 199(2):98-104). Recurrent TTP complicating subsequent TTP is uncommon (George. JN, et al.Blood, 2014; 123 (11):1674-1680). Patients with a history of pregnancy related TTP continue to be at high risk of relapse with subsequent pregnancies and their management often presents as a challenge to both hematologist as well as obstetricians .While plasma exchange and immunosuppression is a cornerstone of successful treatment of confirmed pregnancy related TTP, literature regarding optimal prophylaxis to prevent the onset of subsequent TTP in women with a history of pregnancy related TTP is lacking. Rituximab for the prevention of TTP relapse during pregnancy may be a viable option. DisclosuresNo relevant conflicts of interest to declare.

Plasma ADAMTS13, von Willebrand Factor (VWF), and VWF Propeptide Profiles in Patients With Connective Tissue Diseases and Antiphospholipid Syndrome.

Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

Plasma Levels of Human Neutrophil Peptides and Complement Activation Markers in Patients with Acquired Autoimmune Thrombotic Thrombocytopenic Purpura

Acquired thrombotic thrombocytopenic purpura (TTP) is a potentially fatal syndrome, resulting from autoantibodies against the metalloprotease ADAMTS13. Autoantibodies bind and inhibit plasma ADAMTS13 activity, leading to exaggerated platelet agglutination and thrombus formation in small arteries and capillaries. However, plasma ADAMTS13 deficiency or the presence of anti-ADAMTS13 autoantibodies is not sufficient to cause the disease. Infection or inflammation often precedes the acute onset of TTP. We hypothesize that neutrophil activation or complement activation vial alternative pathway may be the trigger for TTP. In this study, plasma samples were collected prior to plasma exchange from 58 adult patients with acute TTP between 2006 and 2015 at the University of Alabama at Birmingham Medical Center. All patients were diagnosed having TTP on the basis of severe thrombocytopenia, microangiopathic hemolytic anemia, and severe deficiency of plasma ADAMTS13 activity (less than 10%) and the presence of ADAMTS13 inhibitors. All patients were treated by plasma exchange. Thirty plasma samples from healthy individuals were collected for controls. Plasma levels of human neutrophil peptides (HNP-1, -2, and -3) released from activated neutrophils and alternative pathway complement activation markers (iC3b, C4d, C5b-9, and Bb) were determined by enzyme-linked immunosorbent assays (ELISAs). We showed that plasma levels of HNP-1, -2, and -3 in TTP patients were elevated on average by 10-fold when compared with those in the healthy controls (44.12 ± 39.53 ng/ml vs. 3.54 ± 2.97 ng/ml, means ± SD) (p <0.0001). Whereas plasma levels of Bb and iC3b were only modestly increased in TTP patients (2.94 ± 1.82 µg/ml vs. 1.39 ± 0.34 µg/ml for Bb, p <0.0001, and 16.21 ± 9.71 µg/ml vs. 12.13 ± 3.07 µg/ml for iC3b, p =0.028). No significant difference was detected in the plasma levels of C4d and C5b-9 between TTP patients and healthy controls (p >0.05). To differentiate HNP-1 from HNP-2 or HNP-3, we developed a LC/MS mass spectrometric assay and showed that all subtypes of HNPs in TTP patients were significantly elevated when compared with those in the healthy controls (p<0.001). In general, there was good concordance between ELISA and LC/MS MS in the measurement of all three HNPs. These results demonstrate that innate immunity (i.e. activation of neutrophils) and to a lesser degree the activation of complements via alternative pathway may play a role in pathogenesis of TTP in light of severe ADAMTS13 deficiency. Our findings provide rationales for developing novel targeted therapies for acquired TTP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post-partum management in a patient affected by thrombotic thrombocytopenic purpura: case report and review of literature

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially lethal syndrome characterized by severe thrombocytopenia, microangiopathichaemolytic anaemia, and aspecific neurologic symptoms. This syndrome is the result of an abnormal intravascularplatelet aggregation which induces transient ischemia in various organs, especially in the central nervous system. Platelet aggregationcauses also fragmentation of erythrocytes, thus leading to the characteristic anaemia. The exact cause of TTP is unknown, but a largebody of evidence suggest that this syndrome might be due to acquired (immunological) or congenital ADAMTS13 deficiency. The dysregulationof ADAMTS13 activity could promote massive release of high molecular weight multimers of von Willebrand factor (VWF)from endothelium and, as a consequence, could cause intravascular platelet aggregation. Pregnancy is commonly associated with numerousmetabolic, immunological, and haemostatic changes which could increase thrombotic risk: during pregnancy, in fact, it is generallyobserved an increase of procoagulant activity and a decrease of fibrinolytic activity; moreover, at the end of pregnancy, it is notrare to find thrombocytopenia. All these reasons lead us to consider pregnancy itself as a triggering event for the onset of TTP. The authorsdescribe a case of TTP occurred during puerperium, in a patient who underwent caesarean section.

The novel ADAMTS13‐p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice

Congenital thrombotic thrombocytopenic purpura (TTP) is characterized by mutations in the ADAMTS13 gene, which either impair protein secretion or influence ADAMTS13 (A Disintegrin-like And Metalloprotease domain with ThromboSpondin type-1 motif, member 13) activity. Phenotypic consequences of these mutations have not yet been evaluated in animal models for TTP. To identify the in vitro effect of a novel ADAMTS13 mutation and to investigate whether this mutation induces TTP in vivo. All 29 ADAMTS13 exons with exon-intron boundaries of a patient with pregnancy-onset TTP were sequenced. Wild-type and mutant ADAMTS13 proteins were both transiently and stably expressed in human embryonic kidney cells, and their activity was evaluated in vitro using fluorescence resonance energy transfer and flow assays. Molecular dynamics simulations were performed to study Ca(2+) stability. Adamts13(-/-) mice were hydrodynamically injected with wild-type and mutant expression plasmids and triggered with recombinant human von Willebrand factor. We identified a novel heterozygous c.559G>C mutation in exon 6 of the proposita's ADAMTS13 gene. This mutation resulted in a p.Asp187His substitution (p.D187H), which was located in the high affinity Ca(2+) -binding site in the metalloprotease domain of ADAMTS13. The homozygous p.D187H mutation down-regulated ADAMTS13 activity in vitro. Impaired proteolytic activity was linked to unstable Ca(2+) binding as visualized using a molecular dynamics simulation. In addition, the p.D187H mutation affects protein secretion in vitro. In Adamts13(-/-) mice, the homozygous p.D187H mutation reduced ADAMTS13 secretion and activity and contributed to TTP when these mice were triggered with recombinant human von Willebrand factor. Our data indicate that the p.D187H mutation impairs ADAMTS13 activity and secretion and is responsible for TTP onset in mice.

Inhibition of ADAMTS13 Activity By Human Neutrophil Peptide 1 (HNP-1): Potential Link Between Inflammation, Onset of Thrombotic Thrombocytopenic Purpura, and Other Thrombosis

Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal syndrome associated with severe deficiency of plasma ADAMTS13 activity resulting from either mutations or autoantibodies. However, patients with severe ADAMTS13 deficiency do not always develop TTP. Rather, a trigger, such as infection or inflammation, often precedes the onset of the TTP syndrome. We hypothesized that antimicrobial human neutrophil peptides 1-3 (HNPα1-3) or α-defensins, the most abundant proteins in the granules of neutrophils, which are released at site of inflammation, activate platelets, and inhibit fibrinolysis, might help to initiate TTP. This question arose because we noted that the amino acid sequences of HNPα1-3, which are nearly identical except for one residue at the N-terminus, all contain a motif (RRY) similar to exosite 3 (659RRYGEEY665) in the spacer domain of ADAMTS13 (Fig. 1) that was shown to be critical for recognition of von Willebrand factor (VWF). Here, we found that both purified and synthetic HNPα1 bind to FRETS-VWF73 and plasma-derived VWF and inhibit proteolytic cleavage of these substrates in a concentration-dependent manner. At the final concentrations of 10 micro mol/L and 150 micro mol/L, HNPα1 completely abolished the cleavage of FRETS-VWF73 (IC50=3.5 micro mol/L) (Fig. 2) and VWF (IC50=75 micro mol/L) (not shown), respectively. Such concentrations are readily attained locally after systemic infection. Deletion or alanine substitution within the RRY motif of HNPα1 completely abolished its ability to inhibit ADAMTS13 activity assessed by FRETS-VWF73 and VWF multimer analysis. This suggests that an interaction of the RRY motif in HNPα1 with the central A2 domain of VWF is required to mediate its inhibition. In support of this hypothesis, HNPα1 interacts with a human monoclonal antibody against ADAMTS13 scFv (the single chain fragment of variable region) designated 4-20, but not scFv3-1, both isolated by phage display from patients with acquired autoimmune TTP. Hydrogen-deuterium exchange mass spectrometry has shown that the binding site for scFv4-20, but not scFv3-1, contains the RRY sequence. These results suggest that HNPα1-3 released from neutrophils following infection or inflammation may inhibit residual plasma ADAMTS13 activity in vivo similar to anti-ADAMTS13 autoantibodies by interfering with its interaction with VWF, thereby triggering the onset of hereditary and acquired autoimmune TTP. Our findings suggest a potential novel link between systemic inflammation and the pathogenesis of TTP and possibility other thrombotic sequelae. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Complement Activation May Trigger the Onset of Thrombotic Thrombocytopenic Purpura in Patients with Severe ADAMTS13 Deficiency

Thrombotic thrombocytopenic purpura (TTP), a potential fatal syndrome, is often associated with severe deficiency of plasma ADAMTS13 activity, either resulting from ADAMTS13 mutations or acquired anti-ADAMTS13 autoantibodies that inhibit plasma ADAMTS13 activity. Patients with severe ADAMTS13 do not always have TTP signs and symptoms, which often occur following infections or inflammatory responses. The mechanism of TTP flare is not fully understood. In the present study, complement activation markers (iC3b, C5b, Bb, and C4b) were determined by enzyme-linked absorbent assays (ELISA) in the initial plasmas (prior to plasma exchange) of 20 patients with acquired TTP with severe ADAMTS13 deficiency (less than 20% of normal) and plasmas from 20 healthy controls. Of 20 TTP patients, 19 exhibited positive inhibitor in the 50:50 mixing study. Plasma levels of iC3b (1,000 ± 1,062 ng/ml), sC5b-9 (1,342±867 ng/ml), and Bb (38.2±47.7 ng/ml), as well as C4b (74.3±49.5 ng/ml) in acquired TTP patients were significantly higher than those in healthy controls (p value less than 0.01) These results indicate that complement activation in both classic and alternative pathways is a common phenomenon in patients with acquired autoimmune TTP. To demonstrate the causative effect of complement activation in TTP, we turned to our Adamts13 null mice. C57BL/6 (Adamts13-/-) mice are resistant to the development of spontaneous and Shigatoxin-induced TTP syndrome. When injected with a murine specific monoclonal antibody against complement factor H (CFH) (800 micro grams/mouse), which inhibits binding of circulating CFH to endothelial cells and C3b, Adamts13-/- mice (C57BL/6) developed more severe thrombocytopenia and anemia than wild type mice did within 6 days without additional challenge. However, renal insufficiency manifested by the increase of plasma BUN concentration was similar in both groups (Fig. 1). These results indicate that complement activation through an alternative pathway, following antibody-mediated inhibition of CFH or other complement regulatory components, may trigger the onset of TTP in light of severe ADAMTS13 deficiency. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Successful management of thrombotic thrombocytopenic purpura associated with pregnancy

Thrombotic thrombocytopenic purpura (TTP) is an uncommon, severe, potentially life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, altered mental status, fever, and renal abnormalities. It can be seen at any age or sex but affects women of childbearing age more commonly. Pregnancy is known as one of the most common precipitating events for the onset of TTP and occurs mostly in the late third trimester or during the puerperium. Because of relatively low prevalence of pregnancy-related TTP, here we report the clinical characteristics and successful outcomes of 7 women with pregnancy-related TTP. Median age of patients was 25 (19-32). While 4 out of 7 women were primiparous, others were multiparous. Total plasma exchange (TPE) procedure was started within 24h after admission to our hospital. All patients got into complete remission without any maternal mortality. Fetal mortality was found to be 28%. Pregnancy-related TTP is still associated with high maternal and fetal mortality rates. However, the prognosis of TTP has improved dramatically with early diagnosis and plasma- based therapies.

Ticlopidine‐associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)

Ticlopidine‐associated <scp>ADAMTS</scp>13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (<scp>SONAR</scp>)

Drug-induced Thrombotic Thrombocytopenic Purpura Successfully Treated with Recombinant Human Soluble Thrombomodulin

A 61-year-old woman with recurrent non-small cell lung cancer presented with thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal failure and a fever that appeared during chemotherapy with gemcitabine and bevacizumab. She was diagnosed with drug-induced thrombotic thrombocytopenic purpura (TTP). After the discontinuation of chemotherapy, the administration of recombinant human soluble thrombomodulin and fresh-frozen plasma rapidly ameliorated the TTP. Hypertension preceded the onset of TTP and required the administration of quadruple therapy on admission. However, after three months, the hypertension was controllable without anti-hypertensive drugs. Twelve months later, the ninth course of vinorelbine was administered safely, preventing the patient's lung cancer from progressing.

Deficient ADAMTS13 Activity in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura (TTP) in Populations From Japan in 2012: Validation of Findings Initially Reported in the United States in 1998 and 2000.

AbstractAbstract 2203 Background:Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan. Methods:We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008.Severe ADAMTS13 deficiency was characterized by activity levels < 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States. Results:Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and USMatsumoto (n= 186)Bennett (n=22)Bennett (n= 98)Tsai (n=7)Steinhubl (n=19)SourcePLOS One 2011This paperArch Int Med 1999Ann Int Med 2000JAMA 1999CountryJapanJapanUSUSUSEtiologyIdiopathicTiclopidineTiclopidineTiclopidineTiclopidine% female55.1%45.5%46.6%70.0%30.0%Median Age (yrs)54 (8 mos-87)69 (41-89)64.2 (11.1= SD)57 (42-89)62 (38-75)Plt < 20k/mm3100.0%96.0%71.9%100.0%89.4%Hgb < 9 g/dlNA72.7%26,9%42.3%66.7%Cr > 2.0 mg/dl75.8%31.2%30.1%NA47.0%Neuro abn79.0%63.6%73.1%70.0%73.7%Median days ticlopidine (range)NA27.5 (14-36)21 (7-112)21 (14-56)21 (14-28)% w/ coronary stentNot applicable13.6%42.3%57.1%100.0%% w/ other CAD indicationNA31.2%0.0%14.3%0.0%% CVA preventionNot applicable55.8%57.7%14.3%0.0%Survival84.3%91.0%84.9%100.0%78.9%% TPENA63.6%74.2%100.0%68.4%Survival w/o TPENot available75.0%42.1%NA33.3%Survival w/ TPE83.9%100.0%81.7%100.0%100.0%% w/ ADAMTS13:AC deficiency (<5%)100.0%100.0%100.0%83.3%NA% with ADAMTS13 inhibitors97.8%100.0%100.0%100.0%NA Conclusions:These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment. Disclosures:Ortel:Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

Inhibition of von Willebrand factor–platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons

AbstractThe pathophysiology of thrombotic thrombocytopenic purpura (TTP) can be explained by the absence of active ADAMTS13, leading to ultra-large von Willebrand factor (UL-VWF) multimers spontaneously interacting with platelets. Preventing the formation of UL-VWF–platelet aggregates therefore is an attractive new treatment strategy. Here, we demonstrate that simultaneous administration of the inhibitory anti-VWF monoclonal antibody GBR600 and the inhibitory anti-ADAMTS13 antibody 3H9 to baboons (prevention group) precluded TTP onset as severe thrombocytopenia and hemolytic anemia were absent in these animals. In addition, partial VWF inhibition was not enough to prevent thrombocytopenia, demonstrating the specificity of this therapeutic strategy. GBR600 treatment of baboons during acute TTP (treatment group) resulted in a rapid recovery of severe thrombocytopenia similar to the platelet count increases observed in TTP patients treated by plasma exchange. Baboons in the control group only injected with 3H9 developed early stages of TTP as previously described. Hence, inhibiting VWF-GPIb interactions is an effective way to prevent and treat the early symptoms of acquired TTP in baboons.

Acquired Idiopathic ADAMTS13 Activity Deficient Thrombotic Thrombocytopenic Purpura in a Population from Japan

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.