Contemporary Management and Prevention of Vaso-Occlusive Crises (VOCs) in Adults With Sickle Cell Disease
Journal of pharmacy practice. 2021;:8971900211026644
Sickle cell disease (SCD) is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the mediterranean. The main complications leading to hospitalizations include vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). Therefore, the main objective of this paper was to identify and evaluate evidence-based management and prevention of VOCs in patients with SCD. A literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) was performed using the following search terms "vaso-occlusive crises", "sickle cell disease", "hydroxyurea", "L-glutamine", "voxelotor", "crizanlizumab", "treatment" and "prevention" as well as a combination of these terms. All English-language interventional studies assessing the efficacy and safety of VOC outcomes were evaluated. Literature was excluded if published in a language other than English or if it was a review article. A total of 69 articles were identified and there were 7 articles that met the search criteria. Majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to first sickle cell crises, median rates of hospitalizations etc were evaluated as secondary outcomes. After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy.
Adult patients with sickle cell disease (7 studies).
Several comparators, including: L-glutamine, voxelotor and crizanlizumab.
The majority of the studies focused on mean and median annual rates of vaso-occlusive crises (VOCs) as primary outcomes while median time to first sickle cell crises and median rates of hospitalizations were evaluated as secondary outcomes. The literature suggested that many patients with VOCs were still benefitting from hydroxyurea therapy since long term efficacy data and cost was still a concern for newer agents such as: L-glutamine, voxelotor and crizanlizumab.
The Use of Total Thrombus Formation Analysis System as a Tool to Assess Platelet Function in Bleeding and Thrombosis Risk-A Systematic Review
International journal of molecular sciences. 2021;22(16)
BACKGROUND Today there are many devices that can be used to study blood clotting disorders by identifying abnormalities in blood platelets. The Total Thrombus Formation Analysis System is an automated microchip flow chamber system that is used for the quantitative analysis of clot formation under blood flow conditions. For several years, researchers have been using a tool to analyse various clinical situations of patients to identify the properties and biochemical processes occurring within platelets and their microenvironment. METHODS An investigation of recent published literature was conducted based on PRISMA. This review includes 52 science papers directly related to the use of the Total Clot Formation Analysis System in relation to bleeding, surgery, platelet function assessment, anticoagulation monitoring, von Willebrand factor and others. CONCLUSION Most available studies indicate that The Total Thrombus Formation Analysis System may be useful in diagnostic issues, with devices used to monitor therapy or as a significant tool for predicting bleeding events. However, T-TAS not that has the potential for diagnostic indications, but allows the direct observation of the flow and the interactions between blood cells, including the intensity and dynamics of clot formation. The device is expected to be of significant value for basic research to observe the interactions and changes within platelets and their microenvironment.
Comparison of Published Guidelines for the Diagnosis and the Management of Vaccine-Induced Immune Thrombotic Thrombocytopenia
Critical care explorations. 2021;3(9):e0519
The development of thrombocytopenia and thrombosis after the administration of the AstraZeneca and Johnson & Johnson/Janssen vaccines has been recently described. This new condition has been called vaccine-induced immune thrombotic thrombocytopenia. The objective of this review is to summarize the clinical characteristics and therapeutic options of vaccine-induced immune thrombotic thrombocytopenia based on available published case series. Furthermore, we provide a comparison of the diagnostic pathway and treatment recommendations provided by six major medical societies. DATA SOURCES We searched MEDLINE, PubMed, and Cochrane Central Register of Controlled Trials databases. STUDY SELECTION We included case series and case reports on patients who developed vaccine-induced immune thrombotic thrombocytopenia. We also included guidelines for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia from major medical societies. DATA EXTRACTION We examined baseline risk factors, symptoms, physical signs, laboratory and imaging findings, and treatment in patients with vaccine-induced immune thrombotic thrombocytopenia reported in the case series. We also analyzed the diagnostic and treatment recommendations provided by major societal guidelines on the management of vaccine-induced immune thrombotic thrombocytopenia. DATA SYNTHESIS Patients who developed vaccine-induced immune thrombotic thrombocytopenia were more likely to be young women (age 20-50) who were given the AstraZeneca or Johnson & Johnson/Janssen 4-28 days prior to presentation. Patients showed signs, symptoms, and imaging findings consistent with cerebral venous sinus thrombosis and splanchnic thrombosis. Laboratory findings showed thrombocytopenia, low fibrinogen, and elevate d-dimer levels, while positive platelet factor 4 antibodies were always positive. Major societal guidelines recommend avoidance of heparin and platelets. Treatment with nonheparin anticoagulants and IV immunoglobulin is also recommended. CONCLUSIONS Vaccine-induced immune thrombotic thrombocytopenia is a rare but highly morbid complication related to the administration of the AstraZeneca and Johnson & Johnson/Janssen vaccines. Clinicians should be prepared for the early identification of patients with suspicious symptoms and prompt treatment should be initiated to avoid catastrophic deterioration. Major societal guidelines provide useful recommendations for the diagnosis and management of patients with vaccine-induced immune thrombotic thrombocytopenia.
Hydroxyurea Adherence Strategies for Persons with Sickle Cell Disease: A Systematic Review
Journal of health care for the poor and underserved. 2021;32(1):99-118
INTRODUCTION Adherence to hydroxyurea is essential to modify the pathology of sickle cell disease. OBJECTIVE To identify best strategies to support adherence to hydroxyurea in persons with sickle cell disease. METHODS A systematic review was conducted. PubMed, Cumulative Index of Nursing and Allied Health Literature, PsycArticles, PsycInfo, Embase databases and Cochrane Library were searched for studies between 1998 to 2018. RESULTS Six studies met inclusion criteria: two randomized controlled trials, three prospective studies, and one retrospective chart review. DISCUSSION Few studies addressed strategies that tested adherence interventions primarily composed of behavioral change resulting in medication adherence. More studies on hydroxyurea adherence are needed.
Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions
Hematology/oncology and stem cell therapy. 2021
Gene therapy (GT) has been reported to improve bone marrow function in individuals with Fanconi anemia (FA); however, its clinical application is still in the initial stages. We conducted this systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess the long-term safety and clinical outcomes of GT in FA patients. Electronic searches from PubMed, Web of Science, Cochrane Library, and Google Scholar were conducted and full texts of articles meeting our inclusion criteria were reviewed. Three clinical trials were included, with a total of nine patients and mean age of 10.7 ± 5.7 years. All patients had lentiviral-mediated GT. A 1-year follow-up showed stabilization in blood lineages, without any serious adverse effects from GT. A metaregression analysis could not be conducted, as very little long-term follow-up data of patients was observed, and the median survival rate could not be calculated. Thus, we can conclude that GT seems to be a safe procedure in FA; however, further research needs to be conducted on the longitudinal clinical effects of GT in FA, for a better insight into its potential to become a standard form of treatment.
Efficacy and Safety of Avatrombopag in Patients with Chronic Immune Thrombocytopenia: A Systematic Literature Review and Network Meta-Analysis
Advances in therapy. 2021
INTRODUCTION A network meta-analysis (NMA) was performed to assess the efficacy and safety of avatrombopag, relative to eltrombopag, romiplostim, and fostamatinib, for patients with chronic immune thrombocytopenia (ITP) not responding adequately to corticosteroids. METHODS A systematic search of publication and clinical trial databases was conducted to identify relevant randomized controlled trials (RCTs) and observational studies. Data from eligible studies were extracted and analyzed in a Bayesian framework using relative effect sizes vs placebo. Outcomes included durable platelet response; need for rescue therapy; reduction in use of concomitant ITP medication; incidence of any or World Health Organization (WHO) grade 2-4 bleeding events, and any adverse events. Results were reported as odds ratios or incidence rate ratios (IRR) with 95% credible intervals (CrIs). RESULTS The NMA included seven phase 3 RCTs. Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs eltrombopag (IRR 0.38 [95% CrI 0.19, 0.75]) and romiplostim (IRR 0.38 [95% Crl 0.17, 0.86]); no other between-treatment differences were observed. CONCLUSION In this NMA, avatrombopag significantly increased the chance of achieving durable platelet response and reducing the use of concomitant ITP medication vs placebo, and significantly reduced the incidence of any bleeding events compared with placebo, eltrombopag, and romiplostim. The study aims to help guide clinicians managing patients with chronic ITP and insufficient response to previous treatment.
Patients with chronic immune thrombocytopenia (ITP), not responding to corticosteroids (7 studies).
Eltrombopag, romiplostim, fostamatinib therapy or placebo.
Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs. placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs. eltrombopag (IRR 0.38) and romiplostim (IRR 0.38); no other between-treatment differences were observed.
Prothrombin complex concentrates and andexanet for management of direct factor Xa inhibitor related bleeding: a meta-analysis
European review for medical and pharmacological sciences. 2021;25(6):2637-2653
There are potential concerns related to bleeding caused by oral anticoagulants, especially in the elderly. Andexanet alfa has been authorized for use to reverse the effects of oral anticoagulants. Off-label use of four factor prothrombin complex concentrate (4F-PCC) for the reversal of oral factor Xa inhibitors is common. However, not much is known about their efficacy and safety profile. The intent of this meta-analysis was to evaluate the efficacy and safety of 4F-PCC and andexanet alfa for management of major bleeding due to oral factor Xa inhibitors. Comprehensive searches were done systematically through PubMed, Scopus and Google scholar databases. Studies that were retrospective record based or adopted prospective cohort approach and reported either of the three main outcomes, i.e., achieved hemostasis rate or rate of thrombotic events or mortality rate were included in the meta-analysis. Statistical analyses were done using STATA version 13.0. A total of 22 studies were included in the meta-analysis. All the studies had a single arm with no control/comparator group. The pooled rate of good to excellent hemostatic control upon use of andexanet was 80% (95% CI; 72% to 88%) and for 4F-PCC, it was 76% (95% CI; 70% to 83%). A comparatively higher pooled rate of thrombotic complications upon use of andexanet [13% (95% CI; 5% to 20%) was noted, compared to use of aPCC/4F-PCC [4% (95% CI; 3% to 5%). The pooled all-cause mortality rate within 30 days of administration was 24% (95% CI; 12% to 35%) with andexanet use and 19% (95% CI; 14% to 25%) for aPCC/4F-PCC. The findings suggest that use of both andexanet and aPCC/4F-PCC achieves a good hemostasis but there is an associated risk of thrombotic events and mortality. Future studies should have a control group to better establish evidence on efficacy and safety of these agents.
Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B
The Cochrane database of systematic reviews. 2021;8:Cd014201
BACKGROUND The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. OBJECTIVES To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia. DATA COLLECTION AND ANALYSIS Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence. MAIN RESULTS Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect. AUTHORS' CONCLUSIONS There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI. When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons. Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.
Hydroxyurea and blood transfusion therapy for Sickle cell disease in South Asia: inconsistent treatment of a neglected disease
Orphanet journal of rare diseases. 2021;16(1):148
BACKGROUND Hydroxyurea and blood transfusion therapies remain the main therapeutic strategies for Sickle cell disease. Preliminary data suggest substantial variation and inconsistencies in practice of these two therapeutic modalities in South Asia. In this systematic review we searched Medline, Cochrane library and Scopus for articles on usage of hydroxyurea and blood transfusion therapies for sickle cell disease in South Asia published in English between October 2005 and October 2020. RESULTS We selected 41 papers: 33 from India, 3 from Sri Lanka, 2 each from Pakistan and Bangladesh and one from Nepal. Only 14 prospective trials focused on hydroxyurea therapy from which majority (n = 10; 71.4%) adopted fixed low dose (10 mg/kg/day) regimen. With hydroxyurea therapy, 12 and 9 studies reported significant reductions in vaso-occlusive crises and transfusion requirement respectively. Severe anaemia (haemoglobin level < 6-7 g/dl) was the commonest indicator (n = 8) for transfusion therapy followed by vaso-occlusive crisis. CONCLUSIONS Published data on the hydroxyurea and transfusion therapies in South Asia are limited and heterogeneous. A clear gap of knowledge exists about the nature of the sickle cell disease in the Indian subcontinent particularly from countries outside India necessitating further evidence-based assessments and interventions.
A scoping review of transition interventions for young adults with sickle cell disease
Pediatric blood & cancer. 2021;:e29135
Standardized programming for individuals with sickle cell disease (SCD) transitioning from pediatric to adult-centered care does not currently exist, resulting in high rates of mortality and morbidity. This scoping review examines and evaluates the current literature on SCD transition programs and interventions. Eligible studies described an existing program for individuals with SCD aged 12-29 years preparing to transition. The Evidence Project risk-of-bias tool was used to assess article quality. We identified 30 eligible articles, of which, only two were randomized controlled trials. Many studies have incomplete reports of feasibility information, such as completion rates, patient characteristics, and attrition; all studies were limited to a single institution; and most studies were rated high for risk of bias. Progress has been made in designing and gathering initial evaluation data for SCD transition programs; however, there is a need for higher quality studies, consistent assessment, and better dissemination of programs.