Characteristics Behaviors of Coagulation and Fibrinolysis Markers in Acquired Thrombotic Thrombocytopenic Purpura

Introductions: Patients with acquired thrombotic thrombocytopenic purpura (TTP) show no severe abnormalities in coagulation or fibrinolysis. However, the exact extent of the abnormalities is unclear. Materials and Methods: This study analyzed 138 patients with acquired TTP and 46 patients with septic disseminated intravascular coagulation (DIC) who were included in a Japanese registry. Complete blood cell counts and 8 coagulation or fibrinolysis parameters were compared between the 2 groups. Results: Platelet counts in the acquired TTP group were significantly lower than those in the septic DIC group (P < .001). The international normalized ratio of prothrombin time and the activated partial thromboplastin time in the septic DIC group were significantly higher and longer, respectively, than those in the acquired TTP group (P < .01). The antithrombin (AT) values were significantly lower in the septic DIC group than in the acquired TTP group (P < .001), the latter of which were almost normal. Although both groups revealed elevations of fibrinogen degradation product (FDP) and D-dimer, these levels were significantly higher in the septic DIC group than in the acquired TTP group (P < .001). Of 138 patients with acquired TTP, 25 (18.1%) were diagnosed with septic DIC by the diagnostic criteria of the Japanese Ministry Health, Labour and Welfare, and 78 (56.5%) by those of the Japanese Association of Acute Medicine. Receiver operating characteristic curve analysis showed that acquired TTP could be diagnosed based on severe thrombocytopenia (<20 × 109/L), normal AT level (>87%), and mildly elevated FDP (<23 µg/mL). Conclusions: Our results indicate that 3 routine laboratory tests could differentiate between acquired TTP and septic DIC.

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Hemostatic Markers, Adamts-13 Profile and Anti-Sars-Cov-2 Antibody Levels in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving BNT162b2 Vaccination

Blood ◽

10.1182/blood-2021-153606 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1022-1022

Author(s):

Francesca Schieppati ◽

Laura Russo ◽

Marina Marchetti ◽

Elisa Galimberti ◽

Angela Maria Palladino ◽

...

Keyword(s):

Antibody Response ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Remission ◽

Vaccine Dose ◽

Symptomatic Infection ◽

Thrombocytopenic Purpura ◽

Cell Counts ◽

Hemostatic Markers ◽

D Dimer

Abstract Introduction: Patients (pts) with immune thrombotic thrombocytopenic purpura (iTTP) are at high risk of severe COVID-19, therefore protection from SARS-CoV-2 by vaccination is particularly relevant in this setting, although concerns may exist on possible adverse reactions or disease relapse after vaccination. In this study, in a group of iTTP pts who received in-hospital COVID-19 vaccination in a special program for 'fragile patients', we prospectively evaluated over time the antibody response, the clinical and laboratory disease parameters and hemostatic biomarker levels. Methods: Twelve iTTP pts in clinical remission and regularly followed-up in our Center were enrolled in April 2021, all of them received 2 doses of BNT162b2 vaccine (Pfizer-BioNTech) over 21 days, and were followed-up for clinical and laboratory testing for 60 days. Blood samples were collected at enrollment (day 0, D0) before the 1 st vaccine dose; on day 21 (D21) before the 2 nd dose; and on day 60 (D60) after the 1 st dose. Blood cell counts, anti-Spike receptor-binding-domain protein (anti-S/RBD) IgG, ADAMTS-13 activity, and anti-ADAMTS-13 IgG (chromogenic assay and ELISA), were measured at each time point. Additionally, an extensive study of hemostatic markers (i.e. FVIII, von Willebrand Factor (vWF) antigen and activity, fibrinogen, D-dimer, tPA, PAI, and F1+2) was performed. Follow up is currently continuing. Results: Median age of our cohort was 65 years with M/F ratio of 4/8. Median time since last acute iTTP episode was 40 months, median follow up of the cohort was 71 months (95% CI 30-126). All pts were in clinical remission, except one patient (P1) who had an iTTP relapse after contracting SARS-CoV-2 infection, in Dec 2020, and was on low-dose steroids on D0. One patient (P2) had an ADAMTS-13 relapse in Jan 2021, and received pre-emptive rituximab. No other pts were on immunosuppressive therapy. Concerning the status of ADAMTS-13 activity on D0, 6 pts showed normal levels (>50%), while 5 had a moderate (50-20%) and 1 a complete (<10%) ADAMTS-13 deficiency. This latter patient (P3) had normal ADAMTS-13 activity before the pandemic. All patients were negative for anti-ADAMTS-13 inhibitor. Further, on D0, the anti-S/RBD IgG testing was positive in 3/12 pts (median 704,1 AU/mL), due to symptomatic infection in 1 case (P1), and asymptomatic in 2 (P3 and 1 pt with ADAMTS-13 activity of 54%, P4). The study of hemostatic markers on D0 showed an increase in median levels of FVIII and vWF antigen and activity. These parameters were altered in 7/12, 11/12 and 8/12 pts, respectively. Fibrinogen and D-dimer were increased in 3/12 and 2/12, respectively. Notably, P1, P3 and P4 presented the highest levels of FVIII and vWF antigen, associated with high levels of vWF activity in P1 and P3 (mean 233%); moreover, P3 showed higher levels of D-dimer (708 ng/mL) and tPA (13 ng/ml). After the 2 doses of BNT162b2, no significant clinical side effects were reported, and no changes in platelet counts. ADAMTS-13 activity and inhibitors did not significantly change on D21 and D60. A complete ADAMTS-13 activity deficiency persisted in P3 on D21 and D60, associated with anti-ADAMTS-13 IgG titer >15 U/ml, despite clinical remission. Overall, a significant increase in anti-S/RBD IgG level was observed on D21 (p = 0.0005) and D60 (p = 0.0005). Remarkably, only P2 did not show an increase in anti-S/RBD IgG titer after both doses of BNT162b2. Median levels of FVIII and vWF antigen did not significantly change during follow up, while increased vWF activity was seen on D60 (p = 0.05). Fibrinogen levels were stable, and an increase in D-dimer (>1000 ng/mL both on D21 and D60) was seen in P3. There were no changes in the other hemostatic parameters, and no thromboses were observed. Conclusions: In our cohort of iTTP pts, COVID-19 was associated with 1 clinical and 1 ADAMTS-13 relapse. Our data show that SARS-CoV-2 vaccination was effective in inducing an antibody response in all but one patient who received rituximab within 3 months before vaccination, confirming recent findings. Overall, vaccination had no relevant impact on the hemostatic profile of our pts, and did not appear to be a driver of iTTP relapses. However, anti-SARS-CoV-2 antibodies monitoring in iTTP pts may be useful after vaccination, as currently it is unknown how long the antibody titer may persist. Although small, this study is in favor of efficacy and safety of mRNA vaccines in pts with iTTP. Disclosures Falanga: Bayer: Honoraria; Sanofi: Honoraria; Leo Pharma: Honoraria; Pfizer: Honoraria.

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Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management

Journal of Clinical Medicine ◽

10.3390/jcm10030536 ◽

2021 ◽

Vol 10 (3) ◽

pp. 536

Author(s):

Senthil Sukumar ◽

Bernhard Lämmle ◽

Spero R. Cataland

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Initial Therapy ◽

Fresh Frozen Plasma ◽

Organ Injury ◽

Severe Thrombocytopenia ◽

Front Line ◽

Thrombocytopenic Purpura ◽

Fresh Frozen ◽

Biallelic Mutations ◽

Line Setting

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.

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The occurrence of thrombotic thrombocytopenic purpura during treatment of HCV with direct-acting antiviral agents

african journal of gastroenterology and hepatology ◽

10.52378/kxkq8987 ◽

2018 ◽

Vol 1 (1) ◽

pp. 1-9

Author(s):

Amr Hanafy ◽

◽

Waseem Seleem ◽

Salem Mohamed ◽

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Hemolytic Anemia ◽

Peripheral Blood Smear ◽

Hcv Infection ◽

Severe Thrombocytopenia ◽

Direct Acting Antivirals ◽

Thrombocytopenic Purpura ◽

Direct Acting Antiviral ◽

Chronic Hcv ◽

Direct Acting

Background and aim Experts have reported thrombocytopenia linked to chronic liver disease in up to 70% in patients with advanced fibrosis and portal hypertension. Thrombotic thrombocytopenic purpura (TTP) occurrence with HCV infection is a rare and life-threatening event. We aimed to investigate the cause of disturbed conscious level, acute hemolytic anemia, and severe thrombocytopenia in a male patient with chronic HCV and under treatment with direct-acting antivirals. Case report: Development of severe thrombocytopenia, acute hemolytic anemia, neurological symptoms in the form of fits and coma in a 32- year- old man with chronic HCV infection after one week of treatment with direct-acting antivirals (sofosbuvir 400mg PO daily, and daclatasvir 60 mg PO daily). Brain CT was normal, with a negative Coombs test and the presence of schistocytes in the peripheral blood smear. The patient presentation was suggestive of thrombotic thrombocytopenic purpura (TTP). Conclusion: This is a case of TTP after one week of direct-acting antiviral drugs despite the safety profile of these medications. Studying the pathophysiology of TTP after DAAs needs more clarifications.

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Exome Sequencing Identifies Glycosylation Defects As a Probable Cause of Immune Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood-2019-131511 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 217-217

Author(s):

Felipe Massicano ◽

Elizabeth M. Staley ◽

Konstantine Halkidis ◽

Nicole K. Kocher ◽

Lance A. Williams ◽

...

Keyword(s):

Exome Sequencing ◽

Thrombotic Thrombocytopenic Purpura ◽

Potential Contribution ◽

Severe Thrombocytopenia ◽

Adamts13 Activity ◽

Genomic Alterations ◽

Autoantibody Production ◽

Thrombocytopenic Purpura ◽

Long Term Outcome ◽

Clinical Presentations

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal syndrome, resulting primarily from autoantibodies against ADAMTS13. However, the mechanism underlying the autoantibody formation and the contribution of other genomic alterations to the pathogenesis of iTTP are largely unknown. Methods: Whole exome sequencing (WES) and bioinformatic analyses were performed to determine the genetic variations in 40 patients with iTTP who had ADAMTS13 activity <10 IU/dL and a positive inhibitor or an elevated anti-ADAMTS13 IgG in concordance with clinical presentations of severe thrombocytopenia and microangiopathic hemolytic anemia with various degrees of organ injury. WES was also performed at the same time in fifteen age-, gender-, and ethnicity- matched individuals who did not have a history of iTTP or other hematological disorders as controls. Results: WES identified variants or mutations in the genes involving in glycosylation, including O-linked glycosylation, to be the major pathway affected in patients with iTTP. We propose that the altered glycosylation may be responsible for the development of autoantibodies against ADAMTS13 which impair the proteolytic cleavage of von Willebrand factor, accelerate the clearance of ADAMTS13 from circulation, and result in severe thrombocytopenia platelets in patients with iTTP. We also identified defects in ankyrin repeat containing protein ANKRD36C, a protein with hitherto unknown function, as the most statistically significant genomic alterations associated with iTTP (p < 10-5). Moreover, candidate gene analysis revealed that various genes involving in hemostasis, complement activation, platelet function and signaling pathway, and inflammation were all affected in patients with iTTP, which may contribute to the onset, progress, severity, and long-term outcome of iTTP. Finally, we also identified two patient subgroups where the disease mechanism might be different. Conclusion: Our findings provide novel insight into the pathogenic mechanism underlying ADAMTS13 autoantibody production and the potential contribution of other genetic abnormalities in modifying the iTTP clinical presentations in the individuals with severe deficiency of plasma ADAMTS13 activity. Disclosures Zheng: Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Research Funding; Clotsolution: Other: Co-Founder.

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The Optimal Cutoff Value of D-dimer Levels to Predict in Hospital Mortality in Severe Cases of Coronavirus Disease 2019

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2021.7600 ◽

2021 ◽

Vol 9 (B) ◽

pp. 1561-1564

Author(s):

Ngakan Ketut Wira Suastika ◽

Ketut Suega

Keyword(s):

Hospital Mortality ◽

Receiver Operating Characteristic Curve ◽

Receiver Operating Characteristic ◽

Operating Characteristic ◽

Characteristic Curve ◽

Area Under The Curve ◽

Optimal Cutoff ◽

Cutoff Value ◽

Operating Characteristic Curve ◽

D Dimer

Introduction: Coronavirus disease 2019 (Covid-19) can cause coagulation parameters abnormalities such as an increase of D-dimer levels especially in severe cases. The purpose of this study is to determine the differences of D-dimer levels in severe cases of Covid-19 who survived and non-survived and determine the optimal cut-off value of D-dimer levels to predict in-hospital mortality. Method: Data were obtained from confirmed Covid-19 patients who were treated from June to September 2020. The Mann-Whitney U test was used to determine differences of D-dimer levels in surviving and non-surviving patients. The optimal cut-off value and area under the curve (AUC) of the D-dimer level in predicting mortality were obtained by the receiver operating characteristic curve (ROC) method. Results: A total of 80 patients were recruited in this study. Levels of D-dimer were significantly higher in non-surviving patients (median 3.346 mg/ml; minimum – maximum: 0.939 – 50.000 mg/ml) compared to surviving patients (median 1.201 mg/ml; minimum – maximum: 0.302 – 29.425 mg/ml), p = 0.012. D-dimer levels higher than 1.500 mg/ml are the optimal cut-off value for predicting mortality in severe cases of Covid-19 with a sensitivity of 80.0%; specificity of 64.3%; and area under the curve of 0.754 (95% CI 0.586 - 0.921; p = 0.010). Conclusions: D-dimer levels can be used as a predictor of mortality in severe cases of Covid-19.

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Utility of Thrombin Time in Management of Patients with Green Pit Vipers Bite

SAGE Open Medicine ◽

10.1177/2050312120966468 ◽

2020 ◽

Vol 8 ◽

pp. 205031212096646

Author(s):

Achara Tongpoo ◽

Pimjai Niparuck ◽

Charuwan Sriapha ◽

Winai Wananukul ◽

Satariya Trakulsrichai

Keyword(s):

Positive Predictive Value ◽

Predictive Value ◽

Operating Characteristic ◽

Fibrinogen Level ◽

Characteristic Curve ◽

International Normalized Ratio ◽

Thrombin Time ◽

Coagulation Tests ◽

Sensitivity Specificity ◽

Gold Standards

Objectives: GGreen pit vipers (GPV) envenomation causes consumptive coagulopathy mainly by thrombin-like enzymes. Fibrinogen levels are generally investigated to help evaluate systemic envenomation. However, tests of fibrinogen levels may not be available in every hospital. This study aimed to determine the sensitivity, specificity and accuracy for a range of various coagulation tests (20 minute whole blood clotting test (20WBCT), prothrombin time, international normalized ratio and thrombin time (TT)), comparing to the two gold standards performed in patients with GPV bite. Methods: This was the pilot study which we retrospectively reviewed fibrinogen level results including the hospital records of 24 GPV ( Trimeresurus albolabris or macrops) bite patients visiting Ramathibodi Hospital, Thailand during 2013–2017 with 65 results of fibrinogen levels. The fibrinogen levels <164 and <100 mg/dL were used as the standard cut-off points or gold standards as the abnormal low and critical levels, respectively. Results: Most were male. All had local effects. For fibrinogen levels <164 and <100 mg/dL, prolonged TT had the highest sensitivity of 57.1% and 82.4%; the negative predictive value of 74.5% and 93.6%; the accuracy of 81.0% and 92.1%; and the area under a receiver operating characteristic curve of 0.762 and 0.873, respectively. For fibrinogen levels <164, unclotted 20WBCT and prolonged TT had the highest specificity and positive predictive value of 100% all. For fibrinogen levels <100, unclotted 20WBCT had the highest specificity and positive predictive value of 100% both, while prolonged TT had the specificity and positive predictive value of 95.7% and 87.5%, respectively. One patient developed isolated thrombocytopenia without hypofibrinogenemia and coagulopathy. Conclusions: Among four coagulation tests, TT was the most sensitive and accurate test to indicate hypofibrinogenemia in GPV bite patients. In case of unavailable fibrinogen levels thrombin time might be investigated to help evaluate patients’ fibrinogen status. Isolated thrombocytopenia could occur in GPV envenomation.

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Combination of D-dimer and simplified pulmonary embolism severity index to improve prediction of hospital death in patients with acute pulmonary embolism

Journal of International Medical Research ◽

10.1177/0300060520962291 ◽

2020 ◽

Vol 48 (10) ◽

pp. 030006052096229

Author(s):

Hai-Di Wu ◽

Zi-Kai Song ◽

Xiao-Yan Xu ◽

Hong-Yan Cao ◽

Qi Wei ◽

...

Keyword(s):

Pulmonary Embolism ◽

Acute Pulmonary Embolism ◽

Operating Characteristic ◽

Troponin T ◽

Characteristic Curve ◽

Severity Index ◽

Hospital Death ◽

Operating Characteristic Curve ◽

Death Group ◽

D Dimer

Objective To investigate whether the combination of D-dimer and simplified pulmonary embolism severity index (sPESI) could improve prediction of in-hospital death from pulmonary embolism (PE). Methods Patients with PE (n = 272) were divided into a surviving group (n = 249) and an in-hospital death group (n = 23). Results Compared with surviving patients, patients who died in hospital had significantly higher rates of hypotension and tachycardia, reduced SaO2 levels, elevated D-dimer and troponin T levels, higher sPESI scores, and were more likely to be classified as high risk. Elevated D-dimer levels and high sPESI scores were significantly associated with in-hospital death. Using thresholds for D-dimer and sPESI of 3.175 ng/mL and 1.5, respectively, the specificity for prediction of in-hospital death was 0.357 and 0.414, respectively, and the area under the receiver operating characteristic curve (AUC) was 0.665 and 0.668, respectively. When D-dimer and sPESI were considered together, the specificity for prediction of in-hospital death increased to 0.838 and the AUC increased to 0.74. Conclusions D-dimer and sPESI were associated with in-hospital death from PE. Considering D-dimer levels together with sPESI can significantly improve the specificity of predicting in-hospital death for patients with PE.

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Thrombotic Thrombocytopenic Purpura Following Honeybee Envenomation: A Case Report

International Journal of Medical Toxicology and Forensic Medicine ◽

10.32598/ijmtfm.v10i2.28794 ◽

2020 ◽

Vol 10 (2) ◽

Author(s):

Zahra Khalighi ◽

Golnaz Azami ◽

Elham Shafiei ◽

Ali Sahebi ◽

Aliashraf Mozafari

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Case Reports ◽

Major Complication ◽

The Body ◽

Severe Thrombocytopenia ◽

Thrombocytopenic Purpura ◽

Toxic Reaction ◽

Bee Sting ◽

Life Threatening ◽

Underlying Diseases

Background: Thrombotic Thrombocytopenic Purpura (TTP) is a rare and life-threatening disorder characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, fever, renal dysfunction, and neurological deficient. TTP leads to the formation of blood clots in small blood vessels throughout the body. TTP is associated with many risk factors such as pregnancy, HIV, cancer, lupus, and infections. Recently there have been few published case reports of bee sting associated TTP.Methods: A 67-year-old man from a rural area of the Southwest Province of Iran, Ilam, was referred to the academic general hospital because of fever, chills, sweating, vomiting and dizziness following the honeybee sting on his body. Results: this study showed that,multiple co-morbidities including CVD and diabetes, along with coagulation abnormalities after honeybee stings, seriously exacerbated patient hemodynamic status.Conclusion: TTP, as a major complication due to the toxic reaction of a large number of bee stings with underlying diseases in patients, should be given more attention.

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Therapeutic Efficacy of Anfibatide in a Murine Model of Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood.v126.23.659.659 ◽

2015 ◽

Vol 126 (23) ◽

pp. 659-659

Author(s):

Liang Zheng ◽

Yingying Mao ◽

Mandy Li ◽

Xiangrong Dai ◽

Benjamin Li ◽

...

Keyword(s):

Body Weight ◽

Hong Kong ◽

Thrombotic Thrombocytopenic Purpura ◽

Snake Venom ◽

Murine Model ◽

Saline Control ◽

Severe Thrombocytopenia ◽

Dependent Manner ◽

Thrombocytopenic Purpura ◽

Blood Disorder

Abstract Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal blood disorder, resulting from severe deficiency of plasma ADAMTS13 activity. Plasma infusion or exchange is the mainstay of treatment. However, complications associated with the administration of blood products and with the placement of a central venous line remain to be a major concern. To address the unmet clinical need, we test hypothesis that anfibatide, a novel snake venom-derived glycoprotein (GP) Ib antagonist, may be efficacious in treating TTP. Here, we show that purified anfibatide from snake venom inhibited murine platelet agglutination induced by botrocetin in the presence of recombinant murine VWF in a concentration-dependent manner. At 6-9 micro grams per ml (final concentrations), anfibatide nearly completely abolished botrocetin-induced murine platelet agglutination (Fig. 1A). As expected, anfibatide at the same concentrations showed little or no inhibitory effect on the protease-activating receptor 4 (PAR4) agonist (AYPGKF)-induced murine platelet aggregation. In vivo, an intravenously infused radiolabeled anfibatide exhibited a half-life of 5-7 hours depending on the initial loading dose. This information provided pharmacokinetic basis for therapeutic strategy for TTP in the murine model. An infusion of purified anfibatide at the dose of 60-90 ng per gram of body weight twice daily significantly reduced the rate of thrombocytopenia in Adamts13-/- mice triggered by intravenous infusion of a bacterial toxin, i.e. shigatoxin-2 (Stx2) (250 pg per gram body weight). As shown, 5/5 (100%) Adamts13-/- mice after being challenged with Stx2 and but treated with normal saline (control) exhibited severe thrombocytopenia (defined by 50% reduction of platelet counts from the baseline). Similarly, treatment of Adamts13-/- mice with anfibatide at the dose of 30 ng per gram body weight twice daily had little or no effect in preventing thrombocytopenia. However, treatment of the same mice with anfibatide at doses of 60-90 ng per gram body weight twice daily resulted in significantly reduced rate of severe thrombocytopenia to 11%-37.5% (Fig. 1B). Our ongoing effort is to determine the efficacy of anfibatide in treatment of acquired TTP associated with inhibitors. We conclude that anfibatide when given at the optimal doses and interval can efficiently prevent Stx2-induced TTP syndrome in the murine model. These findings support a rationale for further development of anfibatide as a novel therapeutic for TTP in humans. Disclosures Li: 3Lee's Pharmaceutical Holdings Limited, Shatin, Hong Kong: Employment. Dai:4Zhaoke Pharmaceutical Co. Limited, Hefei, Anhui, China: Employment. Li:3Lee's Pharmaceutical Holdings Limited, Shatin, Hong Kong, China: Employment.

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

Blood ◽

10.1182/blood-2012-04-421248 ◽

2012 ◽

Vol 120 (17) ◽

pp. 3611-3614 ◽

Cited By ~ 29

Author(s):

Hendrik B. Feys ◽

Jan Roodt ◽

Nele Vandeputte ◽

Inge Pareyn ◽

Harald Mottl ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Von Willebrand Factor ◽

Platelet Glycoprotein ◽

Control Group ◽

Severe Thrombocytopenia ◽

Thrombocytopenic Purpura ◽

Platelet Aggregates ◽

New Treatment ◽

Von Willebrand ◽

Willebrand Factor

Abstract The 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.

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