Summary
Background
The burden of severe bleeding in adults and children with immune thrombocytopenia (ITP) has not been established.
Objectives
To describe the frequency and severity of bleeding ...events in patients with ITP, and the methods used to measure bleeding in ITP studies.
Patients/Methods
We performed a systematic review of all prospective ITP studies that enrolled 20 or more patients. Two reviewers searched Medline, Embase, CINAHL and the Cochrane registry up to May 2014. Overall weighted proportions were estimated using a random effects model. Measurement properties of bleeding assessment tools were evaluated.
Results
We identified 118 studies that reported bleeding (n = 10 908 patients). Weighted proportions for intracerebral hemorrhage (ICH) were 1.4% for adults (95% confidence interval CI, 0.9–2.1%) and 0.4% for children (95% CI, 0.2–0.7%; P < 0.01), most of whom had chronic ITP. The weighted proportion for severe (non‐ICH) bleeding was 9.6% for adults (95% CI, 4.1–17.1%) and 20.2% for children (95% CI, 10.0–32.9%; P < 0.01) with newly‐diagnosed or chronic ITP. Methods of reporting and definitions of severe bleeding were highly variable in primary studies. Two bleeding assessment tools (Buchanan 2002 for children; Page 2007 for adults) demonstrated adequate inter‐rater reliability and validity in independent assessments.
Conclusions
ICH was more common in adults and tended to occur during chronic ITP; other severe bleeds were more common in children and occurred at all stages of disease. Reporting of non‐ICH bleeding was variable across studies. Further attention to ITP‐specific bleeding measurement in clinical trials is needed to improve standardization of this important outcome for patients.
Essentials
Heparin‐induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat.
We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT.
...One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery.
Rivaroxaban may be an effective and safe treatment option for HIT.
Summary
Background
Rivaroxaban is a direct oral anti‐Xa inhibitor that has the potential to greatly simplify treatment of heparin‐induced thrombocytopenia (HIT).
Objectives
To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single‐arm, prospective cohort study of patients with suspected or confirmed HIT.
Patients/Methods
Twenty‐two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30.
Results and Conclusions
The primary outcome measure, incidence of new symptomatic, objectively‐confirmed venous and arterial thromboembolism at 30 days, occurred in one HIT‐positive participant (4.5%; 95% confidence interval CI, 0–23.5%) and one HIT‐positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT‐positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.
Summary
Background
Many patients exposed to heparin develop antibodies against platelet factor 4 (PF4) and heparin, yet only those antibodies that activate platelets cause heparin‐induced ...thrombocytopenia (HIT). Patients who produce anti‐PF4/heparin antibodies without developing HIT either have antibodies that do not cause platelet activation or produce pathogenic antibodies at levels that are insufficient to cause HIT. Understanding the differences between anti‐PF4/heparin antibodies with and without HIT will improve test methods and reduce overdiagnosis.
Aims
To investigate the presence of low levels of platelet‐activating antibodies in patients investigated for HIT who had anti‐PF4/heparin antibodies but failed to cause platelet activation in the 14C‐serotonin release assay (SRA).
Materials/methods
We developed a platelet activation assay similar to the SRA using exogenous PF4 without added heparin (PF4‐SRA). This assay was able to detect low levels of platelet‐activating antibodies. We used this PF4‐SRA to test for platelet‐activating antibodies in patients investigated for HIT.
Results
The PF4‐SRA detected platelet‐activating antibodies in seven (100%) of seven SRA‐positive sera even after the samples were diluted until they were no longer positive in the standard SRA. Platelet‐activating antibodies were detected in 14 (36%) of 39 patients who had anti‐PF4/heparin antibodies but tested negative in the SRA and did not have clinical HIT. The clinical diagnosis of HIT was confirmed by chart review and concordant with the SRA results.
Conclusions
A subset of heparin‐treated patients produce subthreshold levels of platelet‐activating anti‐PF4/heparin antibodies that do not cause HIT. An increase in the titer of these pathogenic antibodies, along with permissive clinical conditions, could lead to HIT.
Background: Drug‐induced immune thrombocytopenia (DITP) can be confirmed by the demonstration of drug‐dependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and ...test methods are not standardized. Objective: To identify drugs with the strongest evidence for causing DITP based on clinical and laboratory criteria. Patients/Methods: We developed a grading system to evaluate the quality of DITP laboratory testing. The ‘DITP criteria’ were: (i) Drug (or metabolite) was required for the reaction in vitro; (ii) Immunoglobulin binding was demonstrated; (iii) Two or more laboratories obtained positive results; and (iv) Platelets were the target of immunoglobulin binding. Laboratory diagnosis of DITP was considered definite when all criteria were met and probable when positive results were reported by only one laboratory. Two authors applied the DITP criteria to published reports of each drug identified by systematic review. Discrepancies were independently adjudicated. Results: Of 153 drugs that were clinically implicated in thrombocytopenic reactions, 72 (47%) were associated with positive laboratory testing. Of those, 16 drugs met criteria for a definite laboratory diagnosis of DITP and thus had the highest probability of causing DITP. Definite drugs were: quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin and suramin; the glycoprotein IIbIIIa inhibitors abciximab, tirofiban and eptifibatide; and heparin.Conclusions: We identified drugs with the strongest evidence for an association with immune thrombocytopenia. This list may be helpful for ranking potential causes of thrombocytopenia in a given patient.
Summary
Background
A significant challenge in the management of heparin‐induced thrombocytopenia (HIT) patients is making a timely and accurate diagnosis. The readily available enzyme immunoassays ...(EIAs) have low specificities. In contrast, platelet activation assays have higher specificities, but they are technically demanding and not widely available. In addition, ~ 10% of samples referred for HIT testing are initially classified as indeterminate by the serotonin release assay (SRA), which further delays accurate diagnosis. HIT is characterized by platelet activation, which leads to FcγRIIa proteolysis. This raises the possibility that identification of the proteolytic fragment of FcγRIIa could serve as a surrogate marker for HIT.
Objectives
To determine the specificity of platelet FcγRIIa proteolysis induced by sera from patients with HIT, and to correlate the results with those of the SRA.
Methods/Patients
Sera from HIT patients and control patients with other thrombocytopenic/prothrombotic disorders were tested for their ability to proteolyse FcγRIIa. The results were correlated with anti‐platelet factor 4 (PF4)/heparin antibodies (EIA), and heparin‐dependent platelet activation (SRA).
Results
Only HIT patient samples (20/20) caused heparin‐dependent FcγRIIa proteolysis, similar to what was shown by the SRA. None of the samples from the other patient groups or hospital controls caused FcγRIIa proteolysis. Among nine additional samples that tested indeterminate in the SRA, FcγRIIa proteolysis resolved five samples that had a positive anti‐PF4/heparin EIA result; three had no FcγRIIa proteolysis, and two were shown to have heparin‐dependent FcγRIIa proteolysis
Conclusions
This study suggests that heparin‐dependent FcγRIIa proteolysis is at least as specific as the SRA for the diagnosis of HIT.
Homoserine transacetylase catalyzes one of the required steps in the biosynthesis of methionine in fungi and several bacteria. We have determined the crystal structure of homoserine transacetylase ...from Haemophilus influenzae to a resolution of 1.65 A. The structure identifies this enzyme to be a member of the alpha/beta-hydrolase structural superfamily. The active site of the enzyme is located near the end of a deep tunnel formed by the juxtaposition of two domains and incorporates a catalytic triad involving Ser143, His337, and Asp304. A structural basis is given for the observed double displacement kinetic mechanism of homoserine transacetylase. Furthermore, the properties of the tunnel provide a rationale for how homoserine transacetylase catalyzes a transferase reaction vs hydrolysis, despite extensive similarity in active site architecture to hydrolytic enzymes.
To cite this article: Kelton JG, Warkentin TE, Moore JC, Arnold DM, Nazi I, Arepally GM, Roach JM, Fier I. A prospective study measuring the development of antibodies against platelet factor ...4–heparin in healthy males after exposure to heparins. J Thromb Haemost 2012; 10: 1446–9.
1 Michael G. DeGroote School of Medicine, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2 Michael G. DeGroote School of Medicine, Department of Pathology and Molecular ...Medicine, McMaster University, Hamilton, Ontario, Canada
3 Department of Medical Sciences, Ospedale "Regina Apostolorum", Albano Laziale, Italy
4 Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Correspondence: Donald M. Arnold MD, MSc, FRCP(C), HSC 3V-48, 1200 Main Street West, Hamilton, Ontario, Canada. E-mail: arnold{at}mcmaster.ca
ABSTRACT
Eradication of H. pylori improves thrombocytopenia in some patients with immune thrombocytopenic purpura by mechanisms that remain obscure. Platelet count responses may occur independently of H. pylori infection as a result of the immune modulating effects of macrolide antimicrobials or the removal of other commensal bacteria. We performed a systematic review of the literature to determine the effect of H. pylori eradication therapy in patients with immune thrombocytopenic purpura by comparing the platelet response in patients who were, and who were not infected with H. pylori . MEDLINE, EMBASE, Cochrane central registry and abstracts from the American Society of Hematology (from 2003) were searched in duplicate and independently without language or age restrictions. Eleven studies, 8 from Japan, were included enrolling 282 patients with immune thrombocytopenic purpura who received eradication therapy; 205 were H. pylori -positive and 77 were H. pylori -negative. The odds of achieving a platelet count response following eradication therapy were 14.5 higher (95% confidence interval 4.2 to 83.0) in patients with H. pylori infection (51.2% vs. 8.8%). No study reported bleeding or quality of life. Adverse events were reported in 12 patients. H. pylori eradication therapy was of little benefit for H. pylori -negative patients. These findings strengthen the causal association between H. pylori infection and immune thrombocytopenia in some patients. Randomized trials are needed to determine the applicability of H. pylori eradication therapy across diverse geographical regions.
Key words: helicobacter, autoimmunity, purpura, platelets.
Related Article
Definition, diagnosis and treatment of immune thrombocytopenic purpura
James N. George
Haematologica 2009 94: 759-762.
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•Building thermal performance is governed by a number of national policies.•The focus included attributes, technology and innovation, barriers and reflections.•The perspectives of the stakeholders ...did not fully align with the policies.•The industry had no objection to employing low carbon technology alternatives.•Industry should be consulted continuously in forming future policies.
Current policies have implied that improving thermal performance of the built environment would be included in a strategy to reduce the greenhouse gas emissions in the UK and meet the national targets of the Climate Change Act by 2050. However, the perceptions of the industrial stakeholders in this matter have not, to date, been clear. This study aimed to uncover stakeholder perspectives on thermal performance of the built environment and investigate whether their perspectives aligned well with the national policies. Focusing on attributes of the built environment, technology and innovation, barriers and reflections on reality, technical feedback was gathered from experienced industrial stakeholders via a one-day workshop and emails. The analysis showed that despite being familiar with the national policies, the perspectives of the industrial stakeholders did not fully align with the national policies in most aspects. However, the industry had no objection to employing low carbon technology alternatives in the future. The study concluded that consultation with industry should be carried out continuously to assist in the formation of future national policies to significantly improve the thermal performance of the built environment. Future research should be extended to comparing the stakeholder viewpoints and national policies from environmental and economic perspectives on a European/global scale.
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