Measuring Factor XIII Inhibitors in Patients with Factor XIII Deficiency: A Case Report and Systematic Review of Current Practices in Japan
Journal of clinical medicine. 2022;11(6)
Factor XIII (FXIII) deficiency is a rare but serious coagulopathy. FXIII is critical in blood coagulation, and FXIII deficiencies can lead to uncontrolled or spontaneous bleeding. FXIII deficiencies can be congenital or acquired; acquired FXIII deficiency can be categorized as autoimmune and non-autoimmune. Immunological tests to measure FXIII inhibitors are required to diagnose acquired FXIII deficiency; however, appropriate test facilities are limited, which increases the turnaround time of these tests. In the case of critical bleeding, delayed test results may worsen prognosis due to delayed treatment. Here, we report a case of acquired FXIII deficiency, followed by a review of FXIII deficiency cases in Japan. We performed a systematic review to investigate the present conditions of the diagnosis and treatment of FXIII deficiency, including the measurement of FXIII inhibitors in Japan. FXIII inhibitor testing was only performed in 29.7 of acquired FXIII deficiency cases. Clinical departments other than internal medicine and pediatrics were often involved in medical treatment at the time of onset. Therefore, it is important for doctors in clinical departments other than internal medicine and pediatrics to consider FXIII deficiency and perform FXIII inhibitor testing when examining patients with prolonged bleeding of unknown cause or persistent bleeding after trauma.
Systemic therapy of necrobiotic xanthogranuloma: a systematic review
Orphanet journal of rare diseases. 2022;17(1):132
BACKGROUND Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. OBJECTIVE To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. METHODS All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. RESULTS The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. CONCLUSIONS Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG.
Factor VIII concentrate dosing with lean body mass, ideal body weight and total body weight in overweight and obesity: A randomized, controlled, open-label, 3 × 3 crossover trial
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
INTRODUCTION Obesity alters the pharmacokinetic (PK) properties of drugs making it difficult to determine the appropriate dose when administering weight-based medications. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight (IBW), are sometimes used in these situations. METHODS We performed a single-centre, randomized, controlled, open-label, 3 × 3 crossover trial to determine whether recombinant factor VIII (rFVIII) dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on total body weight (TBW) in overweight and obese, adult males with haemophilia A. Participants were randomized to 1 of 6 possible FVIII concentrate dosing sequence scenarios (TBW, LBM and IBW). Recombinant FVIII was administered on 3 separate weeks following a washout period of at least 72 hours. RESULTS A total of 19 participants were randomized and completed the study. FVIII recovery was lower at 30 minutes post-rFVIII infusion in LBM vs TBW and IBW vs TBW-based dosing, mean difference -0.38 (95% CI: -0.56, -0.20) and -0.28 (95% CI: -0.47, -0.10) IU/dL per IU/kg, respectively. In LBM vs TBW and IBW vs TBW-based dosing, there was a non-significant increase in the proportion of participants with a targeted FVIII recovery of 2.00 ± 0.20 IU/dl per IU/kg, OR = 1.93 (95% CI: 0.44, 8.55) and OR = 3.65 (0.80, 16.72), respectively. DISCUSSION Based on our study's findings, overweight and obese patients with haemophilia A may benefit from an individualized PK analysis using LBM and IBW to determine the most accurate, and potentially cost-effective, method of achieving targeted FVIII recovery.
Matching-Adjusted Indirect Comparison of Efficacy and Consumption of rVIII-SingleChain Versus Two Recombinant FVIII Products Used for Prophylactic Treatment of Adults/Adolescents with Severe Haemophilia A
Advances in therapy. 2021
INTRODUCTION Given the relatively small number of patients with haemophilia A, head-to-head comparisons between recombinant FVIII (rFVIII) products are difficult to conduct. This study compared the efficacy and consumption of rVIII-SingleChain (lonoctocog alfa, AFSTYLA(®)) with rAHF-PFM (octocog alfa, Advate(®)) and rFVIIIFc (efmoroctocog alfa, Elocta(®)), for the prophylaxis and treatment of bleeding episodes in previously treated adolescents/adults with severe haemophilia A, through a matching-adjusted indirect comparison (MAIC). METHODS A systematic literature review identified published clinical trials for rAHF-PFM and rFVIIIFc. Individual patient data for rVIII-SingleChain were used to match baseline patient characteristics to those from published trials, using an approach similar to propensity score weighting. After matching, annualized bleeding rates (ABR), percentage of patients with zero bleeds, and rFVIII consumption were compared across trial populations. RESULTS Published data were identified from two rAHF-PFM trials and one rFVIIIFc trial. rVIII-SingleChain had similar ABR (risk ratio [RR]: 0.74 [0.16; 3.48]; RR: 1.18 [0.85; 1.65]) and percentage of patients with zero bleeds (odds ratio [OR]: 1.34 [0.56; 3.22]; OR: 0.78 [0.47; 1.31]) versus rAHF-PFM and rFVIIIFc, respectively. Annual rVIII-SingleChain consumption was significantly lower than rAHF-PFM (mean difference: - 1507.66 IU/kg/year [- 2011.71; - 1003.61]) and equivalent to rFVIIIFc (RR: 0.96 [0.62; 1.49]). CONCLUSION Although limited to published information for comparator trials, these results suggest that with an annualized rFVIII consumption comparable to rFVIIIFc, but significantly lower than rAHF-PFM, routine prophylaxis with rVIII-SingleChain is able to maintain a similar ABR and percentage of patients with zero bleeds, attesting to the long-acting nature of rVIII-SingleChain.
Effectiveness of ankle fusion in patients with hemophilia, advanced ankle degeneration, and unbearable pain for whom nonsurgical and surgical treatments have been ineffective
Expert review of hematology. 2021
INTRODUCTION In underdeveloped countries, patients with hemophilia often experience repetitive ankle joint hemorrhages due to a shortage of coagulation factors (factor VIII [FVIII] and factor IX [FIX] for hemophilia A and B, respectively). AREAS COVERED This is a narrative literature review in which we searched the Cochrane Library and MEDLINE for articles related to ankle arthrodesis in patients with hemophilia. The searches covered the period from the databases´ inception to February 28, 2021. In the event of unsuccessful hematologic prophylaxis and conservative measures (e.g., analgesics, cyclooxygenase-2 inhibitors, taping, intra-articular injections of hyaluronic acid and corticosteroids, physical and rehabilitation medicine, orthoses, radiosynovectomy, and joint-preserving surgery (e.g., removal of the distal tibia by open surgery or by arthroscopic surgery, joint debridement by arthroscopic surgery), the only surgical solution is ankle arthrodesis, which does not preserve the ankle joint. EXPERT OPINION Ankle pain is reduced after ankle arthrodesis (75% of patients experience no pain). Approximately 5% of patients require reoperation due to lack of fusion, and deep infection occurs in 2.5%. After tibiotalar fusion, a self-reported activity scale shows that approximately 12% of patients improve, 9% worsen, and 79% show no improvement. The results of ankle arthrodesis therefore appear to be poor.
Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review
Frontiers in medicine. 2021;8:759914
Background: Thymoma-associated haematological diseases (HDs), such as pure red cell aplasia (PRCA) and Good's syndrome, are extremely rare, and due to the paucity of large-scale studies, the characteristics, remission after thymectomy, and long-term evaluation remain undetermined. Methods: We retrospectively assessed patients with thymoma and associated HDs from Jan 2005 to Dec 2020. All patients received thymectomy and/or additional treatments for HDs. A comparison with thymoma-associated myasthenic gravis (MG), and a systematic review from PubMed/MEDLINE and Embase were conducted. Results: In the median follow-up of 56 months, 130 patients were enrolled. Patients with thymoma-associated MG (n = 46) and HDs [n = 8; PRCA (n = 5), PRCA and Good's syndrome (n = 2) and autoimmune haemolytic anaemia (n = 1)] were evaluated. Patients with MG had a significantly higher remission rate after thymectomy (50 vs. 17%; p = 0.0378) as compared to those with other autoimmune diseases. Two of seven patients with PRCA experienced remission with thymectomy alone, and an additional two patients achieved remission with thymectomy plus immunosuppressive therapy (IST). In the systematic review, 60 studies (case reports, n = 46; case series including the present study, n = 14) were evaluated. Forty-four percent of patients were diagnosed with PRCA after thymoma, and 61% achieved remission with thymectomy plus IST; however, Good's syndrome was unaffected. Conclusions: Our study indicates that patients with thymoma-associated autoimmune diseases other than MG have a lower remission rate than those with MG. Remission of thymoma-associated PRCA can be achieved by thymectomy and IST. This study provides insight into extremely rare but puzzling autoimmune manifestations.
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.
Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis
Journal of Cancer. 2021;12(17):5164-5172
Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages. Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes. Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR) (RR=1.22 [1.04-1.43], P=0.01) as well as non-inferiority compared with sb-PTX in disease control rate (DCR) (RR=1.01 [0.98-1.04], P=0.44), overall survival (OS) (HR=0.99 [0.93-1.05], P=0.81) and disease free survival/progression free survival (DFS/PFS) (HR=0.92 [0.81-1.05], P=0.21). However, when it comes to toxicities (fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation), results favored sb-PTX (RR=2.89 [1.07-7.8], 3.15 [1.78-5.59], 2.11 [1.32-3.37], 2.02 [1.61-2.53]; P<0.05). Patients with metastatic tumors or undergoing conventional schedule responses better to nab-PTX than the compared groups (RR of ORR in metastatic vs early or locally advanced patients: 1.46 [1.09-1.96] vs 1.01 [0.94-1.08]; conventional vs dose dense group: 1.59 [1.23-2.06] vs 1.01 [0.91-1.12]). Conclusions: Nab-PTX can improve ORR compared with paclitaxel and should be given priority to when aiming to reduce tumor load in breast cancer. Sb-PTX of dose dense schedule is recommended when toxicity of nab-PTX is hard to bear for breast cancer patients.
Biological stratification of clinical disease courses in childhood immune thrombocytopenia
Journal of thrombosis and haemostasis : JTH. 2021
BACKGROUND In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes. OBJECTIVE To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers. METHODS Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies. RESULTS In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10(9) /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses. CONCLUSIONS The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
Neuromuscular Complications of Targeted Anticancer Agents: Can Tyrosine Kinase Inhibitors Induce Myasthenia Gravis? Getting Answers From a Case Report up to a Systematic Review
Frontiers in oncology. 2021;11:727010
More than 40 tyrosine kinase inhibitors (TKIs) have received hematological or oncological indications over the past 20 years, following the approval of imatinib, and many others are currently being tested in clinical and preclinical level. Beyond their common toxicities, no certain agent from this large class of molecularly targeted therapies was strongly associated with "off-target" impairment of neuromuscular transmission, and although myasthenia gravis (MG) is a well-characterized autoimmune disorder, only few sporadic events proven by serologically detected causative autoantibodies and/or by positive electrophysiological tests are reported in the literature. Herein, we present the first case of anti-MUSK (+) MG in a woman with metastatic BRAF-mutant melanoma after long-term treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Triggered by this report, a systematic literature review was conducted, summarizing all other cancer cases that developed MG, after exposure to any type of targeted agent and regardless of the underlying malignancy. All available data on the clinical diagnosis, the potential of administered TKIs to induce a seropositive myasthenic syndrome, the immune and non-immune-mediated pathogenesis of postsynaptic damage, and the challenging management of this neuromuscular toxicity were collected and discussed. In the presented case, MG was confirmed by both autoantibodies and nerve-conduction tests, while its reactivation after TKIs rechallenge supports a more than coincidental association. The following review identified 12 cancer cases with TKI-related MG in six case reports and one case series. In most of them, the myasthenia diagnosis was challenging, since the clinical symptomatology of fatigable weakness was not corroborating with consistent laboratory and electrophysiological findings. In fact, anti-AchR titers were positive in five and anti-MuSK only in the abovementioned individual. The symptomatology corresponded to TKI discontinuation and standard treatment with pyridostigmine and prednisolone; intravenous immunoglobulin was added only in three, and two required mechanical ventilation. In an era where TKIs will be prescribed more frequently for various malignancies, even in combinations with immune-checkpoint inhibitors, this report synthesizes their risk for neuromuscular complications and increases the clinicians' awareness in order to extend the on-treatment and overall survival of TKI-treated cancer patients.