Desmopressin for prevention of bleeding for thrombocytopenic, critically ill patients undergoing invasive procedures: A randomised, double-blind, placebo-controlled feasibility trial.

Thrombocytopenic patients have an increased risk of bleeding when undergoing invasive procedures. In a multicentre, phase II, blinded, randomised, controlled feasibility trial, critically ill patients with platelet count 100 × 109/L or less were randomised 1:1 to intravenous desmopressin (0.3 µg/kg) or placebo before an invasive procedure. Forty-three participants (18.8% of those eligible) were recruited, with 41 eligible for analysis. Post-procedure bleeding occurred in one of 22 (4.5%) in the placebo arm and zero of 19 in the desmopressin arm. Despite liberal inclusion criteria, there were significant feasibility challenges recruiting patients in the critical care setting prior to invasive procedures.

Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway.

BACKGROUND AND AIMS: Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart. METHODS: A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. RESULTS: In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1. CONCLUSIONS: Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.

Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage.

BACKGROUND: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018. OBJECTIVES: To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset. SEARCH METHODS: We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022. SELECTION CRITERIA: We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90. MAIN RESULTS: We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence). AUTHORS' CONCLUSIONS: In this updated Cochrane Review including 20 RCTs involving 4652 participants, rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH. Thirteen RCTs are ongoing and are likely to increase the certainty of the estimates of treatment effect.

Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability.

Background: Factor XIII (FXIII) is an important proenzyme in the hemostatic system. The plasma-derived enzyme activated FXIII cross-links fibrin fibers within thrombi to increase their mechanical strength and cross-links fibrin to fibrinolytic inhibitors, specifically α2-antiplasmin, to increase resistance to fibrinolysis. We have previously shown that cellular FXIII (factor XIII-A [FXIII-A]), which is abundant in the platelet cytoplasm, is externalized onto the activated membrane and cross-links extracellular substrates. The contribution of cellular FXIII-A to platelet activation and platelet function has not been extensively studied. Objectives: This study aims to identify the role of platelet FXIII-A in platelet function. Methods: We used normal healthy platelets with a cell permeable FXIII inhibitor and platelets from FXIII-deficient patients as a FXIII-free platelet model in a range of platelet function and clotting tests. Results: Our data demonstrate that platelet FXIII-A enhances fibrinogen binding to the platelet surface upon agonist stimulation and improves the binding of platelets to fibrinogen and aggregation under flow in a whole-blood thrombus formation assay. In the absence of FXIII-A, platelets show reduced sensitivity to agonist stimulation, including decreased P-selectin exposure and fibrinogen binding. We show that FXIII-A is involved in platelet spreading where a lack of FXIII-A reduces the ability of platelets to fully spread on fibrinogen and collagen. Our data demonstrate that platelet FXIII-A is important for clot retraction where clots formed in its absence retracted to a lesser extent. Conclusion: Overall, this study shows that platelet FXIII-A functions during thrombus formation by aiding platelet activation and thrombus retraction in addition to its antifibrinolytic roles.

Desmopressin for patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs (DASH): a UK-based, phase 2, randomised, placebo-controlled, multicentre feasibility trial.

BACKGROUND: The risk of death from spontaneous intracerebral haemorrhage is increased for people taking antiplatelet drugs. We aimed to assess the feasibility of randomising patients on antiplatelet drug therapy with spontaneous intracerebral haemorrhage to desmopressin or placebo to reduce the antiplatelet drug effect. METHODS: DASH was a phase 2, randomised, placebo-controlled, multicentre feasibility trial. Patients were recruited from ten acute stroke centres in the UK and were eligible if they had an intracerebral haemorrhage with stroke symptom onset within 24 h of randomisation, were aged 18 years or older, and were taking an antiplatelet drug. Participants were randomly assigned (1:1) to a single dose of intravenous desmopressin 20 µg or matching placebo. Treatment allocation was concealed from all staff and patients involved in the trial. The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. The trial was prospectively registered with ISRCTN (reference ISRCTN67038373), and it is closed to recruitment. FINDINGS: Between April 1, 2019, and March 31, 2022, 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned to receive desmopressin (n=27) or placebo (n=27). The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). The recruitment rate increased after the enrolment period was extended from 12 h to 24 h, but it was then impaired due to the COVID-19 pandemic. Of the 54 participants included in the analysis (mean age 76·4 years [SD 11·3]), most were male (36 [67%]) and White (50 [93%]). 53 (98%) of 54 participants received all of their allocated treatment (one participant assigned desmopressin only received part of the infusion). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 (modified Rankin Scale score >4) occurred in six (22%) of 27 participants in the desmopressin group and ten (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group. The most common adverse events were expansion of the haemorrhagic stroke (four [15%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group) and pneumonia (one [4%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group). INTERPRETATION: Our results show it is feasible to randomise patients with spontaneous intracerebral haemorrhage who are taking antiplatelet drugs to desmopressin or placebo. Our findings support the need for a definitive trial to determine if desmopressin improves outcomes in patients with intracerebral haemorrhage on antiplatelet drug therapy. FUNDING: National Institute for Health Research.

Acquired haemophilia A diagnosed during pregnancy.

Pregnancy-associated haemophilia A is an uncommon, acquired bleeding disorder which usually presents post-partum; very rarely it may present during pregnancy. No consensus guidelines exist on the management of this condition in pregnancy and very few cases have been reported in the literature. Here we describe the case of a woman presenting with acquired haemophilia A during pregnancy and outline the management of her bleeding disorder. We contrast her case with that of two other women, presenting to the same tertiary referral centre, with acquired haemophilia A presenting post-partum. These cases highlight the heterogeneous management of this condition and how it may be successfully managed in pregnancy.

Real world reduction in red cell transfusion with restrictive transfusion threshold in haematology inpatients.

OBJECTIVES: The aim of this study was to assess the reduction in red cell transfusions following a change in the red cell transfusion threshold for haematology inpatients from 80 to 70 g/L. BACKGROUND: Haematology patients are among the high users of red blood cells. We reduced the threshold for transfusion of haematology inpatients to 70 g/L. This was based on evidence provided by randomised controlled trial published in 2020 that showed restrictive transfusion is non-inferior to liberal transfusion. METHOD: We assessed red cell transfusions for haematology inpatients at Oxford University Hospitals NHS Foundation Trust for 9 months before and 9 months after a change in red cell transfusion threshold from 80 to 70 g/L. RESULTS: After the change in threshold to 70 g/L or less from 80 g/L, the median number of red cell transfusions per month reduced to 88 from 111. This was a 23% reduction in the total number of red cells administered per month. CONCLUSION: These results show the real-world reductions in transfusion that can be made by putting local transfusion guidelines in line with the international recommendations. This is of particular importance at a time of national blood shortage.

Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data.

Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug-induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug-induced TTP (DI-TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI-TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty-seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI-TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.

Intraoperative cell salvage using swab wash and serial thromboelastography in elective abdominal aortic aneurysm surgery involving massive blood loss.

The loss of 50% blood volume is one accepted definition of massive haemorrhage, which ordinarily would trigger the massive transfusion protocol, involving the administration of high ratios of fresh frozen plasma and platelets to allogeneic red cells. We investigated 53 patients who experienced >50% blood loss during open elective abdominal aortic aneurysm surgery to assess allogeneic blood component usage and coagulopathy. Specialist patient blood management practitioners used a tailored cell salvage technique including swab wash to maximise blood return. We assessed the proportion of patients who did not require allogeneic blood components and develop evidence of coagulopathy by thromboelastography (TEG) parameters. Blood loss was 50%-174% (mean [SD] 68% [27%]) of blood volume. The mean (SD) intraoperative decrease in haemoglobin concentration, assessed by arterial blood gas analysis, was 5 (13) g/l. No patient received allogeneic red cells intraoperatively. Four of the 53 (8%) patients received blood components in the first 24 h postoperatively at the anaesthetists' discretion. No patient had intraoperative TEG changes indicative of fibrinolysis or coagulopathy. The 30-day mortality was 2% (one of 53). Reduction of allogeneic transfusion is one aim of patient blood management techniques. We have demonstrated virtual avoidance of allogeneic blood product transfusion despite massive blood loss. These data show possible alternatives to the current massive transfusion protocols to the management of elective vascular surgical patients.

Outcomes and management of pregnancy in women with bleeding disorder of unknown cause.

BACKGROUND: Patients with a bleeding tendency with normal laboratory tests have been described as having an unclassified bleeding disorder or bleeding disorder of unknown cause (BDUC). There are very little data available on how to manage pregnancy. OBJECTIVES: To study management and outcomes of these patients at four United Kingdom hemophilia comprehensive care centers. METHODS: Retrospective case note review from 2010-2020. RESULTS: Sixty deliveries in 36 patients were recorded. The median International Society on Thrombosis and Haemostasis bleeding assessment tool score was 9. In 54 cases for which data were available, the odds ratio for post partum hemorrhage (PPH) was 6.3 for no primary hemostatic prophylaxis versus prophylaxis (95% confidence interval 1.2-34.2, p < .05); 7/9 (78%) versus 16/45 (36%) PPH incidence for the groups, respectively. Hemostatic prophylaxis was with tranexamic acid but some patients received desmopressin or platelet infusions. Secondary PPH was seen in 5/60 (8%) of cases. No neonatal bleeding complications or maternal thromboembolic complications were noted. Avoidance of regional anesthesia and fetal delivery precautions were commonly advised, but in the small number of cases in which they occurred no complications were noted. CONCLUSIONS: Despite hemostatic prophylaxis PPH was commonly seen. Further prospective studies of BDUC patients are required to determine optimal management in pregnancy as well as determine the pathophysiological basis of bleeding.

Platelet transfusion and anticoagulation in hematological cancer-associated thrombosis and thrombocytopenia: The CAVEaT multicenter prospective cohort.

BACKGROUND: Venous thromboembolism (VTE) in patients with thrombocytopenia represents a complex management challenge. OBJECTIVES: To describe practice, document outcomes, and compare management to national guidelines. METHODS: We present a prospective multicenter cohort of 105 patients with hematological cancer, VTE within 28 days, and platelets <50 × 109 /L from May 14, 2019 to April 24, 2021 from 20 sites. RESULTS: Median age was 64 and median initial platelet count 28 × 109 /L. Thromboses were: 46% catheter-associated, 11% lower limb, 33% pulmonary emboli (PE), and 10% other sites. Management was according to International Society on Thrombosis and Haemostasis (ISTH) guidance in 30 (47%) of 64 patients with high-risk thrombosis and 2 (5%) of low-risk thrombosis (catheter-associated or asymptomatic subsegmental PE). Twelve patients (11%) received no anticoagulation. At 28 days mortality was 15%, 8% experienced VTE progression, 7% experienced major bleeding, and 25% experienced clinically relevant non-major bleeding. Four inferior vena cava filters were placed, two were later removed. The median number of platelet units transfused was 5 (range 0-53). Twenty-seven percent of patients had a change of management strategy by 28 days. There was no clear relationship among platelet transfusion threshold, anticoagulant dose reduction threshold, and risk of thrombosis progression or major bleeding. CONCLUSIONS: This data set demonstrates the heterogeneity of approaches used in patients presenting with severe thrombocytopenia and acute thrombosis and confirms the high rates of bleeding in this cohort with thrombosis progression rates similar to the wider cancer-associated thrombosis population. Randomized data is required to inform the optimal management.

Risk of thrombosis with thrombocytopenia syndrome after COVID-19 vaccination prior to the recognition of vaccine-induced thrombocytopenia and thrombosis: A self-controlled case series study in England.

Background: Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)-based studies. Objectives: To assess for an association between clinically validated TTS and COVID-19 vaccination. Methods: We used the self-controlled case series method to assess the risks of clinically validated acute TTS after a first COVID-19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results: One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02-31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18- to 39-year-olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4- to 27- and 28- to 41-day periods (RI, 1.52; 95% CI, 0.88-2.63; and (RI, 1.70; 95% CI, 0.73-3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS-CoV-2 test occurred across all age groups and exposure periods. Conclusions: We demonstrate an increased risk of TTS in the 4 to 27 days following COVID-19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS-CoV-2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

Acquired Bernard-Soulier syndrome and hypodysfibrinogenaemia because of multiple myeloma.

We describe a case of a patient with multiple myeloma with initial presentation simulating a bleeding disorder. Detailed coagulation work-up showed hypodysfibrinogenaemia along with a platelet function defect consistent with acquired Bernard-Soulier syndrome (BSS). Multiple plasma exchanges led to significant improvement in his bleeding symptoms. To the best of our knowledge, this is the first described case of simultaneous presentation of hypodysfibrinogenaemia and BSS secondary to multiple myeloma.

Current practice and registration patterns among United Kingdom Haemophilia Centre Doctors' Organisation centers for patients with unclassified bleeding disorders.

BACKGROUND: Bleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management. OBJECTIVES: To examine UK haemophilia centre registration patterns and current practice for UBD patients. METHODS: In a two-step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD. RESULTS/DISCUSSION: Overall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients. CONCLUSION: This study provides a snapshot of current practice and real-world data in this area. Future studies need to address the gaps in evidence.

Management of surgery, menorrhagia and child-birth for patients with unclassified bleeding disorders: a systematic review of cohort studies.

Unclassified bleeding disorders account for 2.6% of all new bleeding disorder registrations in the UK. The management of the bleeding phenotype associated with these disorders is poorly described. Systematic review and meta-analysis to determine the bleeding rates associated with tranexamic acid, desmopressin, platelet transfusion, plasma transfusion and recombinant activated factor VII, for patients with unclassified bleeding disorders undergoing surgery, childbirth or with menorrhagia. We searched for randomized controlled trials in MEDLINE, Embase, The Cochrane Central Register of Controlled Trials, PubMed, ISI Web of Science and the Transfusion Evidence Library from inception to 24 February 2020. Wherever appropriate, data were pooled using the metaprop function of STATA. Two studies with 157 participants with unclassified bleeding disorders were identified. The pooled risk of minor bleeding for patients undergoing surgery treated with peri-operative tranexamic acid was 11% (95% confidence interval 3--20%; n = 52; I2 = 0%); the risk for desmopressin and tranexamic acid in combination was 3% (95% confidence interval 0--7%; n = 71; I2 = 0%). There were no instances of major bleeding. In one procedure, 1 of 71 (1.4%), treated with a combination of desmopressin and tranexamic acid, the patient had a line-related deep vein thrombosis. There were too few patients treated to prevent postpartum haemorrhage or for menorrhagia to draw conclusions. The GRADE quality of evidence was very low suggesting considerable uncertainty over the results. However, both tranexamic acid, and the combination of tranexamic and desmopressin have high rates of haemostatic efficacy and have few adverse events. PROTOCOL REGISTRATION: PROSPERO CRD42020169727.

Factor VIII levels and bleeding according to factor 8 (F8) mutation in pregnant carriers of haemophilia A: a multicentre retrospective cohort study.

This retrospective cohort study investigated the association between factor 8 (F8) genotype severity and factor VIII (FVIII) levels during pregnancy for 52 women (64 pregnancies) who were heterozygous carriers of mild, moderate or severe haemophilia A. There were no significant differences in FVIII levels for carriers of mild, moderate or severe haemophilia A at baseline [mean (SD) level: mild, 0·78 (0·22); moderate, 0·83 (0·33); severe, 0·70 (0·25) iu/ml; P = 0·81] or in the third trimester [mean (SD) level: mild, 1·42 (0·28); moderate, 1·47 (0·41); severe, 1·37 (0·49) iu/ml; P = 0·80). Post-partum haemorrhage rates were higher for carriers of severe haemophilia A (13/24; 54·2%) compared to carriers of mild haemophilia A (four of 14; 28·6%).