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Severe hemophilia A is managed with factor VIII replacement or hemostatic products that stop or prevent bleeding. Data on gene therapy with hematopoietic stem-cell (HSC)-based expression of factor VIII for the treatment of severe hemophilia A are lacking. We conducted a single-center study involving five participants 22 to 41 years of age with severe hemophilia A without factor VIII inhibitors. Autologous HSCs were transduced with CD68-ET3-LV - a lentiviral vector including a new transgene ( ) with a myeloid-directed CD68 promoter - either without transduction enhancer (group 1) or with transduction enhancer (group 2). Transduced HSCs were transplanted into recipients after myeloablative conditioning. The treatment was assessed for safety (engraftment and regimen-related toxic effects) and efficacy (factor VIII activity and annualized bleeding rate). Participants received CD68-ET3-LV-transduced autologous CD34+ HSCs at doses of 5.0×10 to 6.1×10 per kilogram of body weight. The vector copy numbers in the final drug product were 1.0 and 0.6 copies per cell for the two participants in group 1 and 1.5, 0.6, and 2.2 copies per cell for the three participants in group 2. The duration of severe neutropenia was 7 to 11 days and of severe thrombocytopenia was 1 to 7 days. The median factor VIII activity level, measured with the use of a one-stage assay, after day 28 until the last follow-up visit was 5.2 IU per deciliter (range, 3.0 to 8.7) and 1.7 IU per deciliter (range, 1.0 to 4.0) with a peripheral-blood vector copy number of 0.2 and 0.1 copies per cell, respectively, in the two group 1 participants, and 37.1 IU per deciliter (range, 18.3 to 73.6), 19.3 IU per deciliter (range, 6.6 to 34.5), and 39.9 IU per deciliter (range, 20.6 to 55.1) with a peripheral-blood vector copy number of 4.4, 3.2, and 4.8 copies per cell, respectively, in the three group 2 participants. The annualized bleeding rate was zero for all five participants over a cumulative follow-up of 81 months (median follow-up, 14 months; range, 9 to 27). Gene therapy for hemophilia A with the use of lentiviral vector-transduced autologous HSCs resulted in stable factor VIII expression, with factor VIII activity correlating to vector copy number in the peripheral blood. (Funded by the Ministry of Science and Technology, Government of India, and others; ClinicalTrials.gov number, NCT05265767; Clinical Trials Registry-India number, CTRI/2022/03/041304.).

Patients with first venous thromboembolism (VTE) and high factor VIII (FVIII) are at increased risk of recurrence. It is unknown whether these patients benefit from prolonged secondary thrombophrophylaxis. In a prospective trial patients with first spontaneous VTE and FVIII levels >230 IU/dl were randomized to discontinue vitamin K Antagonist (VKA) after 6 months or to continue VKA for additional 24 months. Patients were excluded if they had a natural inhibitor deficiency, lupus anticoagulant, cancer, were pregnant, required long-term antithrombotic therapy or had acute-phase reaction. Primary study endpoints were symptomatic recurrent VTE or major bleeding within 2 years. Follow-up was continued beyond 2 years. Of 3,219 screened patients 34 met the inclusion criteria. Mean observation time was 37 months. Two of 17 patients allocated to discontinue VKA and two of 17 patients randomized to prolonged anticoagulation had recurrent VTE within 2 years. In the prolonged treatment group, one patient had recurrence during VKA therapy and one patient 4 weeks after voluntary discontinuation of VKA. One major nonfatal bleeding (severe epistaxis) after 10 months of VKA occurred in the prolonged treatment group. Five patients allocated to prolonged anticoagulation had recurrent VTE after discontinuation of VKA. The probability of recurrence at 2 years after discontinuation of VKA was 30% (95% CI 13-46%). Patients with high FVIII are at increased risk of recurrence. Our findings in a small number of patients indicate that prolonged anticoagulation seems to be effective but that the benefit is not maintained after discontinuation of anticoagulation.

ABO blood groups are known to influence the plasma level of von Willebrand factor (VWF), but little is known about the relationship between ABO and coagulation factor VIII (FVIII). We analyzed the influence of ABO genotypes on VWF antigen, FVIII activity, and their quantitative relationship in 11,673 participants in the Atherosclerosis Risk in Communities (ARIC) study. VWF, FVIII, and FVIII/VWF levels varied significantly among O, A (A1 and A2), B and AB subjects, and the extent of which varied between Americans of European (EA) and African (AA) descent. We validated a strong influence of ABO blood type on VWF levels (15.2%), but also detected a direct ABO influence on FVIII activity (0.6%) and FVIII/VWF ratio (3.8%) after adjustment for VWF. We determined that FVIII activity changed 0.54% for every 1% change in VWF antigen level. This VWF-FVIII relationship differed between subjects with O and B blood types in EA, AA, and in male, but not female subjects. Variations in FVIII activity were primarily detected at low VWF levels. These new quantitative influences on VWF, FVIII and the FVIII/VWF ratio help understand how ABO genotypes differentially influence VWF, FVIII and their ratio, particularly in racial and gender specific manners.

Established reference intervals (RIs) of coagulation parameters generally based on the general population are not applicable to specific women. In order to accurately evaluate the coagulation status of non-pregnant women and pregnant women, specific RIs should be established. Our study recruited 465 non-pregnant women and 1972 pregnant women aged 20–45 years. Eight tests including antithrombin (AT), protein C (PC), free protein S (fPS), lupus anticoagulant (LA), D-dimer, fibrin/fibrinogen degradation products (FDP), coagulation factor VII (FVII), and factor VIII (FVIII) were performed on ACL TOP automated coagulation instrument. The RIs for these tests were established in non-pregnant and pregnant women at different gestational weeks. Compared to the non-pregnant group, the medians of AT and fPS were lower, while the medians of PC, LA normalized ratio, D-dimer, FDP, FVII, and FVIII were higher. During pregnancy, AT and fPS activity showed a decreasing trend, with the increase of gestational age. PC activity, LA normalized ratio, D-dimer concentrations, FDP concentrations, FVII, and FVIII activity presented an increasing trend, with the increase of gestational age. The non-pregnant women-specific RIs and the gestational age-specific RIs of AT, PC, fPS, LA normalized ratio, D-dimer, FDP, FVII, and FVIII needed to be established for accurate clinical diagnoses.

COVID-19's long-lasting and complex impacts have become a global concern, with diverse clinical outcomes. This study evaluated 226 participants to understand the clinical spectrum of COVID-19/Long COVID (LC), exploring how disease severity correlates with sociodemographic factors and biomarkers. Determinants related to COVID-19 severity included age (P < 0.001), lower education (P < 0.001), ethnicity (P = 0.003), overweight (P < 0.001), MTHFR gene rs1801133 (P = 0.035), cardiovascular diseases (P = 0.002), diabetes mellitus (DM) (P = 0.006), Factor VIII (FVIII) (P = 0.046), von Willebrand factor (VWF) (P = 0.002), and dimer D (DD) (P < 0.001). Six months later, in a portion of the monitored participants, a significant reduction in FVIII (P < 0.001), VWF (P = 0.002), and DD (P < 0.001) levels was observed, with only DD returning to normal values. Different systemic sequelae were identified, with higher incidences of joint pain and myalgia in participants with a clinical history of DM, chronic lung disease (CLD) and sustained high interleukin 6 values in the convalescent phase. CLD, COVID-19 severity and high DD levels increased the risk of developing dyspnea and palpitations. Women were more likely to develop lower limb phlebitis long-term, while sustained elevated FVIII in the convalescent phase was associated with an increased risk of swelling. Regular physical activity had a protective effect against swelling. This study highlights factors contributing to COVID-19 severity/LC, emphasizing endothelial cell activation as a potential mechanism.

Background To date, there is an ongoing debate regarding the ability to predict PVT development using markers of FVIII or FVIII/PC ratio. This study presents evidence-based medical findings on the influence of FVIII activity levels and FVIII/PC values in the formation of PVT in cirrhosis. Methods The search for original studies on risk factors for portal vein thrombosis (PVT) associated with cirrhosis was conducted, which primarily focused on comparing circulating FVIII activity levels or FVIII/PC ratio in cirrhotic patients with and without PVT. The quality of evidence from each study was assessed using the Newcastle-Ottawa Scale. Results The meta-analysis included a total of 10 original studies. In total, 2250 cirrhotic patients were included, with 414 having PVT and 1836 without PVT. The pooled analysis using a random-effects model showed no significant difference in standardized mean difference (SMD) for FVIII activity levels in cirrhotic patients with or without PVT (SMD = 0.12, 95% CI=-0.46 to 0.70, P  = 0.68), but there was significant heterogeneity (I 2  = 95.52%, P  = 0.00). Meta-regression analysis indicated that differences in mean FVIII activity levels in the PVT group, the number of cases in the non-PVT group, and the study design methods partially contributed to the heterogeneity ( P  < 0.05). However, compared to the non-PVT group, the PVT group had higher FVIII/PC ratio with a statistically significant difference (SMD = 0.39, 95% CI: 0.15 to 0.63, P  = 0.00), and there was no significant heterogeneity (I 2  = 28.62%). Conclusion In conclusion, the FVIII/PC ratio not only reflects the severity of liver disease, but also can be used as one of the predictors of PVT development.

Human endothelial cells (ECs) synthesize, store, and secrete von Willebrand factor multimeric strings and coagulation factor (F) VIII. It is not currently known if ECs produce other coagulation factors for active participation in coagulation. We found that 3 different types of human ECs in primary culture produce clotting factors necessary for FX activation via the intrinsic (FVIII-FIX) and extrinsic (tissue factor [TF]-FVII) coagulation pathways, as well as prothrombin. Human dermal fibroblasts were used as comparator cells. TF, FVII, FIX, FX, and prothrombin were detected in ECs, and TF, FVII, FIX, and FX were detected in fibroblasts. In addition, FVII, FIX, FX, and prothrombin were detected by fluorescent microscopy in EC cytoplasm (associated with endoplasmic reticulum and Golgi proteins). FX activation occurred on human umbilical vein EC surfaces without the addition of external coagulation proteins, proteolytic enzymes, or phospholipids. Tumour necrosis factor, which suppresses the generation of activated protein C and increases TF, augmented FX activation. Fibroblasts also produced TF, but (in contrast to ECs) were incapable of activating FX without the exogenous addition of FX and had a marked increase in FX activation following the addition of both FX and FVII. We conclude that human ECs produce their own coagulation factors that can activate cell surface FX without the addition of exogenous proteins or phospholipids.

von Willebrand disease (VWD) is a hereditary bleeding disorder, caused by a deficiency in the levels and/or function of von Willebrand factor (VWF). Women with VWD appear to be at increased risk of experiencing postpartum hemorrhage (PPH), though the levels of VWF increase during pregnancy. There is limited knowledge of how PPH is associated with the subtype of VWD, plasma levels of other coagulations factors than VWF and given hemostatic treatment. The aims were to investigate the incidence of PPH in women with VWD and to analyse the correlation between PPH and: (1) type of VWD, (2) laboratory monitoring of VWF and FVIII and (3) hemostatic drug treatment. This was a retrospective observational study. The study participants (n = 34) were recruited from the Coagulation Unit, Karolinska University hospital. Fifty-nine deliveries, which occurred in 14 different obstetrics units (years 1995-2012) were included in the study. The incidence of primary PPH was 44%, severe primary PPH 20% and secondary PPH 12%. VWD type 3 was associated with a higher risk of experiencing severe primary PPH compared to other subtypes. FVIII:C in pregnancy was inversely correlated to blood loss during delivery. There was a significantly higher incidence of secondary PPH when the VWD diagnosis was unknown at time of delivery. The women with VWD are at higher risk of PPH, especially those with type 3 VWD or when diagnosis is unknown prior to delivery. Identification of pregnant women with undiagnosed VWD may be of importance in order to prevent PPH.

Objective To investigate the association between periodontitis and cardiometabolic and haemostatic parameters. Materials and methods Between 2014 and 2019, 54 individuals needing full mouth extraction, and 50 control individuals, were recruited for a combined cross-sectional (individuals versus controls) and longitudinal (individuals before and after extraction) study. Periodontitis severity was measured using the periodontal inflamed surface area (PISA). Blood was drawn to measure the haemostatic (Factor VIII, von Willebrand factor [VWF], endogenous thrombin potential, d-dimer, clot lysis time) and cardiovascular risk (C-reactive protein [CRP], lipid profile) parameters, prior to and 12 weeks post-extraction. The results were analysed group-wise. Results The mean VWF and CRP levels were higher and the high-density lipoprotein levels were lower in the individuals prior to extraction compared to the controls. The VWF was significantly correlated with the PISA (a 21% unit increase in VWF per 1000 mm 2 increase in PISA, 95%CI: 6–36%, p  = 0.01). The other analyses were comparable between the individuals and controls, and did not change in the individuals after the extraction. Conclusion VWF levels are associated with periodontitis severity; they do not improve after full-mouth extraction. Severe periodontitis in control individuals does not induce substantial changes in their haemostatic or inflammatory systems. Clinical relevance Treatment of periodontitis has been shown to improve the cardiometabolic blood profile of patients with established cardiometabolic disease. However, whether periodontitis treatment improves cardiometabolic and haemostatic profiles in people without cardiometabolic disease is uncertain.

Portal vein thrombosis seems to be dependent on local hypercoagulation and venous stasis; data regarding endothelial damage are lacking. von Willebrad factor, a marker of endothelial damage/perturbation, factor VIII, and lipopolysaccharides (LPS) were studied in the portal and systemic circulation of 20 cirrhotic patients undergoing transjugular intrahepatic portosystemic procedure. von Willebrad factor, factor VIII, and LPS were higher in the portal compared with systemic circulation, with a significant correlation between LPS and the other 2 variables. Endothelial damage and hypercoagulation coexist in the portal tree of patients with cirrhosis, and both could contribute to portal vein thrombosis. LPS may be a potential trigger of endothelial damage.