Acquired Haemophilia A in four north European countries: survey of 181 patients.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5-99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.

A Case Report of Severe Coagulopathy in Antenatal COVID-19.

Pregnancy is a naturally occurring hypercoagulable state, and COVID-19 can cause profound changes in the coagulation system associated with thromboinflammation. We report a case of a pregnant woman with moderate symptoms of COVID-19 and a severe coagulopathy with unexpected low levels of fibrinogen and factor VIII as well as atypical thrombelastometry results. She developed a severe placental dysfunction with intrauterine fetal distress and perinatal death. The case did not fulfil the criteria for preeclampsia or sepsis, and the adverse outcome was assessed as a direct effect of the COVID-19 infection with placental insufficiency, despite absence of serious maternal pulmonary symptoms. Atypical persistent coagulopathy may serve as an important marker of a serious obstetrical situation in COVID-19.

Conditioning with melphalan 200 mg/m2 and subsequent ASCT improves progression-free and overall survival in elderly myeloma patients compared to standard of care.

OBJECTIVES: Despite the effectiveness of newer drugs for the treatment of multiple myeloma (MM), the outcomes are further improved by subsequent autologous stem cell transplantation (ASCT). Data on effectiveness in older patients are limited. We compared outcomes in patients aged 65-75 years depending on whether they were treated with ASCT or not and compared those to outcomes in patients <65 years. METHODS: This was a retrospective, single-center study. We compared progression-free survival (PFS) and overall survival (OS) for all MM patients below and above the age of 65 years treated ± ASCT at the Karolinska University Hospital between 2010 and 2020. PFS and OS were calculated by the Kaplan-Meier method. Variables affecting PFS and OS were evaluated using Cox regression model. RESULTS: Both PFS and OS were improved in the group 65-75 years treated +ASCT compared to those treated pharmacologically (p = 0.008 and p < 0.001, respectively). There were no significant differences between patients <65 years and those 65-75 years treated with ASCT. CONCLUSION: The findings indicate that even patients >65 years should be evaluated as candidates for ASCT. An individualized approach supported by a frailty/geriatric assessment score could assist clinicians to select the appropriate treatment for each patient.

In patients hospitalized for COPD exacerbation, a PE diagnostic strategy + usual care did not improve outcomes.

SOURCE CITATION: Jiménez D, Agustí A, Tabernero E, et al. Effect of a pulmonary embolism diagnostic strategy on clinical outcomes in patients hospitalized for COPD exacerbation: a randomized clinical trial. JAMA. 2021;326:1277-85. 34609451.

The presence of lupus nephritis additionally increases the risk of preeclampsia among pregnant women with systemic lupus erythematosus.

INTRODUCTION: Pregnant women with systematic lupus erythematosus (SLE) have an increased risk of obstetric complications, such as preeclampsia and premature births. Previous studies have suggested that renal involvement could further increase the risk for adverse obstetric outcomes. Aims: The aim of this study was to compare the obstetric outcomes in a Swedish cohort of patients with SLE with and without lupus nephritis (LN). PATIENTS AND METHODS: The study was conducted as a retrospective observational study on 103 women with SLE, who gave birth at the Karolinska University Hospital between the years 2000-2017. Thirty-five women had previous or active LN and 68 women had non-renal lupus. Data was collected from digital medical records. The outcomes that were analysed included infants born small for gestational age (SGA), premature birth, preeclampsia, SLE- or nephritis flare and caesarean section. RESULTS: Women with LN, both with previous and with renal flare during pregnancy suffered from pre-eclampsia more often compared to women with non-renal lupus (25.7% vs 2.9%, p = 0.001) and this complication was associated with premature birth (p = 0.021) and caesarean section (p = 0.035). CONCLUSIONS: Lupus nephritis is a significant risk factor for adverse obstetric outcomes in women with SLE, including preeclampsia. Those patients could benefit from more frequent antenatal controls and more vigorous follow-up.

Obstetric and neonatal outcomes in pregnant women treated with high-dose thromboprophylaxis: a retrospective, single-center study.

INTRODUCTION: It is well established that women with very high risk of developing antenatal thrombosis benefit from high-dose thromboprophylaxis, however data on outcomes and the safety and efficacy of thromboprophylaxis are scarce. The aim of the study was to evaluate the safety and effectiveness of the Swedish guidelines for high-dose thromboprophylaxis and the obstetric outcomes in a single-center patient cohort. PATIENTS AND METHODS: Forty-seven women treated at the Department of Obstetrics and Gynecology, Karolinska University Hospital, Solna, Sweden, between 2004 and 2017 were included in this retrospective study. Data on treatment, obstetric, and neonatal outcomes and medical history were collected. Data derived from the Swedish Medical Birth Registry on women giving birth in Stockholm County 2004-2016 were used as controls. The protocol of the study was approved by the Regional Ethics Committee in Stockholm, Sweden. RESULTS: The initial thromboprophylaxis dose was 5000 IU dalteparin twice daily. No patient developed ablatio placentae or preeclampsia. One patient suffered antenatal muscle vein thrombosis. Six patients (12.7%) suffered postpartum hemorrhage (PPH); however only one patient had severe PPH. Forty-eight children were born. Three children (6%) were diagnosed with intrauterine growth retardation, five (10%) were born small for gestational age and seven (15%) were born premature, the majority of which (except for two premature) to women with thrombophilia. DISCUSSION: High-dose thromboprophylaxis was effective and safe. The incidence of preeclampsia and ablatio was lower than in controls; however, neonatal outcomes were worse, especially among mothers with thrombophilia. Due to the diversity of the thrombophilic traits, no thrombophilia-specific conclusion could be drawn. Stricter adherence to the guidelines could further decrease the risk for bleeding, whereas more frequent antenatal controls could possible improve neonatal outcomes.

Genetics and Hemostatic Potential in Persons with Mild to Moderate Hemophilia A with a Discrepancy between One-Stage and Chromogenic FVIII Assays.

BACKGROUND: Factor VIII (FVIII) activity (FVIII:C) can be measured by different methods including one-stage clotting assays (OSAs) and chromogenic assays (CSAs). Discrepancy between FVIII:C assays is known and associated with genetic variations causing mild and moderate hemophilia A (HA). We aimed to study the discrepancy phenomenon and to identify associated genetic alterations. Further, we investigated if hemostatic global assays could discriminate the group with discrepant FVIII:C from them. METHODS: The study contained plasma samples from 45 patients with HA (PwHA) from Hemophilia Centers in Stockholm, Sweden, and Belgrade, Serbia. We measured FVIII:C with OSA and CSA, sequenced the F8 gene, and performed two global hemostatic assays; endogenous thrombin potential and overall hemostatic potential. RESULTS: Nineteen of 45 PwHA had a more than twofold higher FVIII:C using OSA compared to CSA and were considered discrepant. Thirty-four causal mutations were detected, where of five had not previously been associated with assay discrepancy. These novel mutations were p.Tyr25Cys, p.Phe698Leu, p.Met699Leu, p.Ile1698Thr, and Ala2070Val. We found no difference between discrepant and nondiscrepant cases with either of the global assays. CONCLUSION: There was a discrepancy between FVIII:C assays in almost half of the PwHA, which for some could lead to missed HA diagnoses or misclassification of severity. Genotyping confirmed that mutations associated with FVIII:C discrepancy cluster in the A domains of F8, and five mutations not previously associated with FVIII:C discrepancy was identified. Global hemostatic assays did not contribute to distinguish assay discrepancy in PwHA.

Management and outcomes of newborns at risk for inherited antithrombin deficiency.

BACKGROUND: As levels of antithrombin (AT) are low at birth, diagnosing inherited AT deficiency in newborns is challenging. In Stockholm, Sweden, pregnant women with known AT deficiency are referred to the Karolinska University Hospital, where local guidelines for management of newborns at risk of inherited AT deficiency have been established. Data on pregnancy, obstetric, and neonatal outcomes are recorded in a registry. OBJECTIVES: We aimed to evaluate the current practice at the Karolinska University Hospital for managing delivery of newborns at risk for AT deficiency, the predictive value of AT levels at birth, and the neonatal outcomes of newborns with AT deficiency. PATIENTS/METHODS: This was an observational, retrospective study. All children born to mothers with AT deficiency at the Karolinska University Hospital 2003-2018 were identified from the registry and included in the study. Data were collected from the medical records and the registry. AT activity was measured postnatally and after 6 months of age. RESULTS: The total study cohort included 41 newborns. There was a significant association between low AT values postnatally and after 6 months of age (P = .001). Half (21/41) of the children were diagnosed with AT deficiency; two suffered from sinus thrombosis, which presented at 10 days of age. Both children with sinus thrombosis were delivered using vacuum extraction. CONCLUSIONS: The current practice of testing newborns can in most cases predict inherited AT deficiency. The risk for thrombosis during the neonatal period is enhanced by the use of instrumental delivery.

Phosphatidylserine positive microparticles improve hemostasis in in-vitro hemophilia A plasma models.

Circulating microparticles (MPs) are procoagulant due to the surface containing phosphatidylserine (PS), which facilitates coagulation. We investigated if MPs improve hemostasis in HA plasma models. MPs isolated from pooled normal human plasma were added to severe, moderate and mild HA plasma models (0%, 2.5%, 20% FVIII). The MPs' effect on hemostasis was evaluated by calibrated automated thrombogram (CAT) and overall hemostasis potential (OHP) assays, while fibrin structure was imaged by standard confocal, stimulated emission depletion (STED) microscopy and scanning electron microscopy (SEM). MPs partially restored thrombin generation and fibrin formation in all HA plasma models. The procoagulant effect of MPs requires PS exposure, to a less extent of contact pathway activation, but not tissue factor exposure or in vitro stimulation of MPs. MPs partially normalized the fibrin structure, and using super-resolution STED, MPs attached to fibrin were clearly resolved. In summary, our results demonstrate that PS positive MPs could improve hemostasis in HA plasma models.

Substantial prevalence of subclinical cardiovascular diseases in patients with hemophilia A evaluated by advanced electrocardiography.

BACKGROUND: Patients with hemophilia A (PWHA) have reportedly lower mortality due to cardiovascular disease (CVD) compared to the general population. AIM: To evaluate signs of CVD in asymptomatic PWHA using advanced electrocardiography (A-ECG). METHODS: PWHA (n = 29, median [interquartile range] age 57 [47-70] years) and age-matched male controls (n = 29, 59 [48-68] years) were evaluated. Digital resting 12­lead ECGs were retrospectively analysed using both conventional and A-ECG techniques including derived vectorcardiography and waveform complexity. Previously validated multivariate A-ECG scores designed to detect: 1) cardiac disease in general, 2) left ventricular systolic dysfunction (LVSD), 3) coronary artery disease or coronary microvascular disease (CAD/CMVD), or 4) left ventricular hypertrophy defined as left ventricular electrical remodelling (LVH/LVER), were quantified and compared between PWHA and controls. RESULTS: Compared to controls, PWHA had a higher probability of having cardiac disease (median [interquartile range] 84.6 [32.5-99.5] vs. 0.6 [0.2-8.2]%), LVSD (4.1 [1.3-12.9] vs. 0.9 [0.5-3.2]%), CAD/CMVD (84.3 [35.6-96.6] vs. 6.7 [0.8-24.4]%), and LVH/LVER (17 [5/29] vs. 0 [0/29]%). Compared to patients with non-severe HA (n = 20), patients with severe HA (n = 9) showed a non-significant trend towards lower probability of cardiac disease, CAD/CMVD, LVSD and LVH/LVER. CONCLUSION: In PWHA, A-ECG exhibits changes more indicative of overt or subclinical CVD compared to controls, and there is a tendency for lower scores for CVD in patients with severe compared to non-severe HA. These results suggest that PWHA ≥ 40 years could be at higher risk for CVD than age-matched controls and that A-ECG could potentially be used for early detection.

Correlation of thromboelastography and thrombin generation assays in warfarin-treated patients.

Venous thromboembolism (VTE) affects approximately 1 per 1000 persons annually. Although patients are increasingly treated with direct oral anticoagulants, many patients continue to be anticoagulated with vitamin K antagonists (VKA). The most important adverse events during VKA treatment, bleeding and the risk of recurrent VTE, are difficult to predict. Global haemostatic assays, such as thrombin generation assays and the viscoelastic whole blood tests thromboelastography (TEG) and thromboelastometry (ROTEM), allow a comprehensive assessment of haemostasis and could potentially predict such side effects. In the present study we compared results from thrombin generation (Calibrated Automated Thrombogram and Innovance ETP assays) and TEG and ROTEM in 84 warfarin-treated patients with primary or recurrent VTE and 87 healthy controls. VKA treatment lead to lagtime prolongation and a lower overall thrombin production, which correlated strongly with INR (Pearson r = 0.89 and r = -0.85, respectively). The reduced thrombin generation of VKA-treated patients was accurately reflected by tissue-factor activated ROTEM (EXTEM) clotting time prolongation (vs. CAT lagtime, r = 0.87). Clot strength or clot formation kinetics were only weakly affected by thrombin generation. Intrinsic pathway activated TEG or ROTEM (INTEM) were not sensitive to the reduced thrombin generation. In conclusion, patients anticoagulated with VKA after VTE showed a reduced plasma thrombin generation that was accurately reflected by tissue factor activated ROTEM. ROTEM provided additional information to thrombin generation, including clot formation kinetics and strength.

Evaluation of a standardized protocol for thrombin generation using the calibrated automated thrombogram: A Nordic study.

INTRODUCTION: The thrombin generation assay-calibrated automated thrombogram (TGA-CAT) method is used to measure the overall coagulation capacity in plasma. However, the method is still considered to be a research tool, mainly because of its' lack of standardization. AIM: Our study aimed to further raise the standardization level for the TGA-CAT method by evaluating a detailed standardization protocol and three reference plasmas' (RP)s ability to normalize results. METHODS: Six Nordic centres participated in the study, and with input from all centres a detailed laboratory standardization protocol based on the TGA-CAT manual of the manufacturer was established. Three types of plasma, hypo-,normal and hypercoagulable plasma were assessed. Three commercial lyophilized RPs were used for normalization of data. All samples were aliquoted at the Malmö centre and sent frozen at -20˚C to participating centres. RESULTS: Before normalization, all results under all testing conditions showed inter-laboratory coefficient of variability of 10% or lower except for endogenous thrombin potential (12%) and peak (14%) in hypo-plasma with 1 pmol/L tissue factor as starting agent. Successful normalization, improving variability in results, was obtained with two of the three evaluated RPs (HemosIL RP and Affinity RP). CONCLUSION: With our standardization concept, we were able to produce TGA-CAT results as robust as standard coagulation assays used in the routine laboratories. Normalization with HemosIL RP may be considered in populations with low or unknown coagulability, while when analysing plasma samples from populations where hypercoagulability is known or suspected, normalization with Affinity RP may be preferred.

Blood inflammatory and endothelial markers in women with von Willebrand disease.

INTRODUCTION: VWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls. MATERIALS AND METHODS: The study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI. RESULTS: Within the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle. CONCLUSIONS: Higher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia-common complication of VWF deficiency. The latter statement requires confirmation in larger studies.

Thrombin generation during a regular menstrual cycle in women with von Willebrand disease.

Fluctuations of the sex steroids during the menstrual cycle might significantly influence hemostasis. This association, derived from a number of the observations on healthy women, is yet to be described in females affected by bleeding disorders. The aim of the current study was to assess the changes in hemostatic variables in women with vWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with healthy controls. The study group included 12 vWD-affected females with regular menstrual cycle, with none of them being prescribed any hormonal treatment. The control group consisted of 102 healthy females, matched for age and BMI. Within the vWD group FVIII and FX were both significantly higher during follicular phase than in luteal phase (p = 0.013 and p = 0.033 respectively). AT, FII, FVII and FX were higher in women with vWD, compared with controls during both phases of the menstrual cycle (p < 0.0005, p < 0.0005, p = 0.001 and p < 0.0005). In women with vWD, lag time and time to peak were prolonged during both phases of the menstrual cycle(p < 0.0005), while peak thrombin concentration was reduced (p = 0.003 and p = 0.002 during follicular and luteal phase respectively) compared to healthy peers. Lower levels of FVIII and FX during luteal phase may predispose women to the development of the menorrhagia - common complication of vWD. Women with vWD need more time to reach the peak thrombin concentration, while the latter still remains less than in healthy women. Higher levels of AT in vWD-affected females, compared to controls, may also contribute to the existing bleeding tendency in this cohort.

Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study.

There is uncertainty regarding the effectiveness and occurrence of thromboembolic events in patients treated with prothrombin complex concentrates (PCCs) for the management of major bleeding events (MBEs) on rivaroxaban or apixaban. We investigated the effectiveness of PCCs given for the management of MBEs in patients on rivaroxaban or apixaban. Between 1 January 2014 and 1 October 2016, we prospectively included patients on rivaroxaban or apixaban treated with PCCs for the management of MBEs. The effectiveness of PCCs was assessed by using the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria for the assessment of the effectiveness of major bleeding management. The safety outcomes were thromboembolic events and all-cause mortality within 30 days after treatment with PCCs. A total of 84 patients received PCCs for the reversal of rivaroxaban or apixaban due to a MBE. PCCs were given at a median (interquartile range) dose of 2000 IU (1500-2000 IU). Intracranial hemorrhage (ICH) was the most common site of bleeding requiring reversal (n = 59; 70.2%), followed by gastrointestinal bleeding in 13 (15.5%) patients. Management with PCCs was assessed as effective in 58 (69.1%) patients and ineffective in 26 (30.9%) patients. Most patients with ineffective hemostasis with PCCs had ICH (n = 16; 61.5%). Two patients developed an ischemic stroke, occurring 5 and 10 days after treatment with PCC. Twenty-seven (32%) patients died within 30 days after a MBE. The administration of PCCs for the management of MBEs associated with rivaroxaban or apixaban is effective in most cases and is associated with a low risk of thromboembolism. Our findings are limited by the absence of a control group in the study.

Correction: Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study.

[This corrects the article DOI: 10.1371/journal.pone.0164683.].