Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A Twenty Year Review

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2226-2226
Author(s):  
Zaina Parvez Qureshi ◽  
John Armstrong ◽  
Charles Bennett
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Survival Rates ◽  
Epidemiologic Study ◽  
Phase Iii ◽  
World Health ◽  
First Year ◽  
Thrombocytopenic Purpura ◽  
Pharmaceutical Manufacturers ◽  
Adamts13 Deficiency ◽  
Health Organization

Abstract Abstract 2226 Objective: Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome, with our group having identified the thienopyridines ticlopidine and clopidogrel as the most common drugs associated with TTP in Food and Drug Administration (FDA) databases. We review clinical, epidemiologic, laboratory, and drug safety findings for thienopyridine-associated TTP, including the first reported cases with prasugrel, a thienopyridine approved in 2009. Methods: Data sources included FDA's Adverse Event Reports database, pharmaceutical manufacturers, package inserts, physician surveys, phase III reports, insurance databases, and an epidemiologic study (1989–2011). Causality was assessed with the World Health Organization scale. Results: Since 2002, FDA received reports of 10 ticlopidine-, 140 clopidogrel-, and nine prasugrel-associated TTP cases, including four, 11, and 9 cases respectively, in the first year of marketing of each agent. Surveys of hematologists by our group identified 32 ticlopidine- and ten clopidogrel-associated TTP cases. Thienopyridines were administered for > two weeks for 90% of 93 ticlopidine-associated cases, 26% of 35 cases clopidogrel-associated cases, and none of nine prasugrel-associated cases. In the Phase III setting, one of 2,932 ticlopidine-, none of 27,961 clopidogrel-, and none of 1,769 prasugrel-treated patients developed TTP. Insurance databases identified three clopidogrel-associated TTP case among 15.3 million individuals. Ticlopidine- (n=30) versus clopidogrel-associated TTP patients (n=8) presented with severe ADAMTS13-deficiency (80% versus 0%) and neutralizing auto-antibodies to ADAMTS13 (100% versus 0%) and had higher survival rates following therapeutic plasma exchange (87% versus 50%) (p<0.05). Greater than 95% of ticlopidine-associated TTP cases were assessed as having a probable causal relationship versus none of the clopidogrel- or prasugrel-associated TTP cases. TTP is described in a Black Box warning for ticlopidine (1998, incidence of 1 in 2,000) and as a warning for clopidogrel (2000; 12 per million) and prasugrel (2010; no incidence reported) Conclusion: TTP is associated with all thienopyridines, although causal relationships remain under active investigations. Disclosures: Armstrong: LeadHorse Technologies Inc.: Employment.

Clinical and Outcomes Findings for Thrombotic Thrombocytopenic Purpura among 467 Persons with Severely Versus Not Severely Deficient ADAMTS-13 Levels.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2088-2088 ◽  
Author(s):  
Charles L. Bennett ◽  
Thanh Ha Luu ◽  
Anaadriana Zakarija ◽  
Hau C. Kwaan ◽  
Nicholas Bandarenko ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Neutralizing Antibodies ◽  
Clinical Laboratory ◽  
Survival Rates ◽  
Outcome Data ◽  
Severe Thrombocytopenia ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels. Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007). Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer. Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE. Platelet count mean (x10^9/L) Creatinine mean (mg/dl) ADAMTS13 neutralizing antibodies (%) Survival % Relapse % * &lt;15% ADAMTS13 activity cutoff Severe ADAMTS13 Deficiency (&lt;10–15%) SERF-TTP (n=30) 19 1.3 83 97 41 Zheng (n=16) 19 1.6 44 81 38 Bennett (n=26) 15 85 Oklahoma (n=18) 12 1.8 94 81 38 Raife (n=50) * 13 1.2 92 35 Japan (n=34) 35 91 Canada (n=11) 16 2.4 82 Not Severely Deficient ADAMTS13 Activity (&gt; 15%) SERF-TTP (n=22) 57 3.9 35 90 0 Raife (n=57) * 44 2.7 83 9 Canada (n=17) 57 4.1 88 Zheng (n=13) 40 3.0 0 54 Bennett (n=13) 62 Japan (n=66) 9 62 Oklahoma (n=94 ) 23 47 3

scholarly journals Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 637-643 ◽  
Author(s):  
Paul Coppo ◽  
Antoine Froissart
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Survival Rates ◽  
Therapeutic Plasma Exchange ◽  
Response To Treatment ◽  
Thrombocytopenic Purpura ◽  
Therapeutic Landscape ◽  
Life Threatening ◽  
Adamts13 Deficiency ◽  
Von Willebrand

Abstract Daily therapeutic plasma exchange (TPE) transformed the historically fatal prognosis of acquired, anti-ADAMTS13 antibody-mediated thrombotic thrombocytopenic purpura (TTP), leading to the current overall survival rates of 80%-85%. However, relapses occur in ∼40% of patients and refractory disease with fatal outcomes still occurs. In this context, the introduction of rituximab has probably been the second major breakthrough in TTP management. Rituximab is now routinely recommended during the acute phase, typically in patients with a suboptimal response to treatment, or even as frontline therapy, with high response rates. In more severe patients, salvage strategies may include twice-daily TPE, pulses of cyclophosphamide, vincristine, as well as splenectomy in more desperate cases. In this life-threatening disease, relapse prevention represents a major goal. Persistent severe acquired ADAMTS13 deficiency in patients who are otherwise in remission is associated with a high risk of relapse and preemptive treatment with rituximab may be considered in this context. In the coming years, the TTP therapeutic landscape should be enriched by original strategies stemming from clinical experience and new agents that are currently being evaluated in large, ideally international, clinical trials. Promising agents under evaluation include N-acetylcysteine, bortezomib, recombinant ADAMTS13, and inhibitors of the glycoprotein-Ib/IX-von Willebrand factor axis.

scholarly journals Annual Incidence and Severity of Acute Episodes in Hereditary Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Author(s):  
Erika Tarasco ◽  
Lukas Bütikofer ◽  
Kenneth D. Friedman ◽  
James N George ◽  
Ingrid V Hrachovinova ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Premature Death ◽  
Annual Incidence ◽  
Prospective Data ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Survival Frequency ◽  
Overt Disease ◽  
Plasma Infusions

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children &lt;10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients &gt;40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

scholarly journals Global Governance and the WHO’s Mandate Post-COVID-19 Crisis

2021 ◽  
Author(s):  
Jean Vilbert
Keyword(s):  
Global Health ◽  
Negative Relationship ◽  
World Health ◽  
First Year ◽  
Health Crisis ◽  
Nation States ◽  
Democratic Principle ◽  
The World ◽  
Distribution Of Power ◽  
Health Organization

The COVID-19 has renovated the debate about global health governance. A number of scholars have proposed that the World Health Organization should assume the position of a central coordinator with hierarchical powers, demanding nation-states to “share their sovereignty”. This article presents four main objections to this project. First, when international institutions receive leverage, they use to impose “one-size-fits-all” policies, which conflicts with the characteristic heterogeny across countries. Second, geopolitical questions and the distribution of power in multilateral institutions put developing countries in a position of vulnerability within a hierarchical order. Third, the risk of crowding out parallel initiatives, especially from non-state actors. Fourth, decisions about health can have a major impact on countries, which may thwart the internal democratic principle. A Pareto improvement would be possible by strengthening the WHO’s operational capacity and its ability to issue technical guidance and coordinate with countries. To test this hypothesis, this study analyses the possible influence of the WHO’s guidance in the first year of the coronavirus health crisis, from January 2020 to January 2021, in 37 countries reported in the World Values Survey Wave 7 (2017-2020). The OLS regression performed shows a statistically significant negative relationship between the trust in the WHO, assumed as a proxy for the level of the organization's penetration, and the number of cases of COVID-19 (per million people) in the countries of the sample. These findings reinforce the hypothesis that there is a valid case for the countries to strengthen the WHO’s mandate post-COVID-19, but they should enhance the operations of provision of reliable information and support. Nation-states, in particular the developing ones, should eschew the temptation to create a hierarchical global health structure, which may not only fail due to countries’ asymmetries but is likely to create losers in the process.

Drug control: a prerequisite for health

1980 ◽  
Vol 209 (1174) ◽  
pp. 159-163
Keyword(s):  
Health Care ◽  
Rural Areas ◽  
Third World ◽  
Health Care Expenditure ◽  
World Health ◽  
Health Care Needs ◽  
Care Needs ◽  
Pharmaceutical Manufacturers ◽  
Health Organization ◽  
Limited List

The purchase of drugs employs an increasingly large part of the health budget of many Third World countries. Like health care expenditure as a whole, drug spending is heavily biased in favour of urban hospitals, often for expensive proprietary drugs that offer little benefit over cheaper preparations. As a result, because limited funds are available, vaccines and drugs for prevention and primary care are sometimes unavailable, especially in rural areas. The World Health Organization and many individual countries have responded to the problem of drug costs by creating a limited list of drugs considered essential for health care needs. Other methods of curtailing spending on drugs have included tendering for supplies and the establishment of plants to manufacture and formulate drugs. Controls of this type meet enormous resistance from doctors and pharmaceutical manufacturers, but are vital for the implementation of policies for appropriate health care.

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

2009 ◽  
Vol 24 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Chantal Loirat ◽  
Jean-Pierre Girma ◽  
Céline Desconclois ◽  
Paul Coppo ◽  
Agnès Veyradier
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

scholarly journals Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 539-547 ◽  
Author(s):  
Kathryn Dane ◽  
Shruti Chaturvedi
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Relapse Prevention ◽  
Tissue Injury ◽  
Novel Therapies ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Adamts13 Deficiency ◽  
Prophylactic Use ◽  
Von Willebrand

Abstract The advent of plasma exchange has dramatically changed the prognosis of acute thrombotic thrombocytopenic purpura (TTP). Recent insights into TTP pathogenesis have led to the development of novel therapies targeting pathogenic anti-ADAMTS13 antibody production, von Willebrand factor (VWF)–platelet interactions, and ADAMTS13 replacement. Retrospective and prospective studies have established the efficacy of rituximab as an adjunct to plasma exchange for patients with acute TTP, either upfront or for refractory disease. Relapse prevention is a major concern for survivors of acute TTP, and emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. Capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF–platelet aggregates, recently completed phase 2 (TITAN) and 3 (HERCULES) trials with encouraging results. Compared with placebo, caplacizumab shortened the time to platelet recovery and may protect against microthrombotic tissue injury in the acute phase of TTP, though it does not modify the underlying immune response. Other promising therapies including plasma cell inhibitors (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and inhibitors of the VWF–glycoprotein Ib/IX interaction (anfibatide) are in development, and several of these agents are in prospective clinical studies to evaluate their efficacy and role in TTP. In the coming years, we are optimistic that novel therapies and international collaborative efforts will usher in even more effective, evidence-based approaches to address refractory acute TTP and relapse prevention.

scholarly journals Efficacy and safety of tetramethylpyrazine phosphate on pulmonary hypertension: study protocol for a randomized controlled study

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuqin Chen ◽  
Wenjun He ◽  
Haiping Ouyang ◽  
Chunli Liu ◽  
Cheng Hong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Treatment Group ◽  
Phase Iii ◽  
World Health ◽  
Controlled Study ◽  
Stable Phase ◽  
Control Group ◽  
Efficacy And Safety ◽  
Traditional Chinese Herbal Medicine ◽  
Health Organization

Abstract Background Tetramethylpyrazine (TMP), an active ingredient in the traditional Chinese herbal medicine Rhizoma Chuanxiong, has been used clinically for the prevention and treatment of cardiovascular disease. The benefits of TMP are largely attributed to its anti-oxidative and vasodilative properties. However, the efficacy of TMP in the treatment of pulmonary hypertension (PH) is unknown. We hypothesized that TMP may have a therapeutic effect in patients with PH. Methods/design A randomized, single-blinded, clinical study with a TMP treatment group and a control group will be conducted to evaluate the efficacy and safety of TMP intervention in patients with PH. The recruitment target is 120 subjects meeting the following criteria: (i) at rest and at sea level, mean pulmonary artery pressure above 20 mmHg and pulmonary capillary wedge pressure below 15 mmHg; (ii) type 1 or 4 PH in the stable phase; (iii) age 15–70 years; (iv) 6-min walk distance between 100 and 450 m; (v) World Health Organization (WHO) functional classification of pulmonary hypertension of II, III, or IV. Subjects will be assigned randomly into two groups at a ratio of 1:2 (control:TMP). Both groups will receive routine treatment, and the treatment group will also receive oral TMP (100 mg) three times a day for 16 weeks. All patients will be followed up for 4, 8, 12, and 16 weeks; symptoms and patient compliance will be recorded. Discussion We aimed to determine the efficacy and safety of TMP for the treatment of PH. Trial registration Chinese Clinical Trial Register, ChiCTR1800018664. Registered on 2 October 2018.

Practice-Changing Abstracts From the 2016 Society for Neuro-Oncology Annual Scientific Meeting

2017 ◽  
pp. 187-191
Author(s):  
Marta Penas-Prado
Keyword(s):  
Progression Free Survival ◽  
Scientific Meeting ◽  
Annual Scientific ◽  
Phase Iii ◽  
World Health ◽  
Annual Scientific Meeting ◽  
Tumor Treating Fields ◽  
Precise Diagnosis ◽  
Health Organization

The most relevant practice-changing presentations at the 2016 Society for Neuro-Oncology (SNO) Annual Scientific Meeting revolved around the topic of the new 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The most notable change in this new classification is the introduction of molecular markers into the morphologic classification of diffuse gliomas (isocitrate dehydrogenase [IDH] mutation, 1p19q codeletion, and H3K27M mutation), ependymomas (RELA fusion), medulloblastomas (WNT- and sonic hedgehog–activated), and other embryonal tumors (C19MC amplification), thus allowing for more precise diagnosis of these entities compared with the use of morphologic features alone. Among the clinical trials presented, only one phase III trial evaluating a device therapy for treatment of newly diagnosed glioblastoma (EF14; tumor-treating fields) met prespecified statistical criteria for success, showing a modest benefit in progression-free survival and overall survival in patients without progression after radiation and concurrent temozolomide. Other topics of interest included the spatial and temporal heterogeneity of primary brain tumors and the prevalence of burnout among neuro-oncologists.

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