Activated Factor VII Research Articles

Use of thromboelastography before the administration of hemostatic agents to safely taper recombinant activated factor VII in acquired hemophilia A: a report of three cases

BackgroundAcquired hemophilia A (AHA) is a rare autoimmune disease characterized by bleeding events. Recombinant activated factor VII (rFVIIa) is a first-line bypassing agent, which is effective against clinically significant bleeding. However, there is no standard way of tapering and discontinuing rFVIIa, mainly because there is no established method for monitoring rFVIIa therapy for AHA.Case presentationHere, we report three AHA cases, in which we adjusted the rFVIIa dosing interval based on the results of thromboelastography (TEG) performed just before the administration of the next dose of rFVIIa. The dosing interval of rFVIIa was prolonged based on the reaction rate time (R) according to TEG, which is correlated with coagulation factor activity. The R-value reference range reported by the manufacturer of the TEG system was used as a threshold for making decisions. In these three cases, there was no rebleeding, and the patients’ ability to perform activities of daily living did not decline.ConclusionOur cases suggest that conducting TEG-based monitoring just before the administration of the next dose of rFVIIa may be useful for guiding increases in the rFVIIa dosing interval without causing rebleeding events. Further investigations are warranted to examine how TEG could be used to determine the most appropriate rFVIIa dosing interval, e.g., through regular TEG-based monitoring, and the optimal TEG-derived threshold for indicating changes to the rFVIIa dosing interval.

Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII

AbstractThe most significant complication in hemophilia A treatment is the formation of inhibitors against factor VIII (FVIII) protein. Glycans and glycan-binding proteins are central to a properly functioning immune system. This study focuses on whether glycosylation of FVIII plays an important role in induction and regulation of anti-FVIII immune responses. We investigated the potential roles of 4 N-glycosylation sites, including N41 and N239 in the A1 domain, N1810 in the A3 domain, and N2118 in the C1 domain of FVIII, in moderating its immunogenicity. Glycomics analysis of plasma-derived FVIII revealed that sites N41, N239, and N1810 contain mostly sialylated complex glycoforms, while high mannose glycans dominate at site N2118. A missense variant that substitutes asparagine (N) to glutamine (Q) was introduced to eliminate glycosylation on each of these sites. Following gene transfer of plasmids encoding B domain deleted FVIII (BDD-FVIII) and each of these 4 FVIII variants, it was found that specific activity of FVIII in plasma remained similar among all treatment groups. Slightly increased or comparable immune responses in N41Q, N239Q, and N1810Q FVIII variant plasmid-treated mice and significantly decreased immune responses in N2118Q FVIII plasmid-treated mice were observed when compared with BDD-FVIII plasmid-treated mice. The reduction of inhibitor response by N2118Q FVIII variant was also demonstrated in AAV-mediated gene transfer experiments. Furthermore, a specific glycopeptide epitope surrounding the N2118 glycosylation site was identified and characterized to activate T cells in an FVIII-specific proliferation assay. These results indicate that N-glycosylation of FVIII can have significant impact on its immunogenicity.

Effects of a Treadmill Workstation on Coagulation Potential

IntroductionApproximately 2.7 million blood clot‐induced events occur each year, including most strokes and heart attacks. An upright, seated position reduces blood flow, promotes blood pooling, viscosity, and may active the coagulation system. Thus, occupational environments that include prolonged periods of seated work may contribute to the formation of a thrombus. Use of an active workstation may beneficially impact thrombolytic potential.PurposeTo observe the effects of low intensity walking at a treadmill workstation on changes in coagulation potential compared to use of a traditional, sedentary workstation.MethodsFive apparently healthy college‐aged students (n= 4 men, 1 woman; 22 ± 2 yrs; 27.3 ± 6.2 kg/m2) completed the same series of mental tasks at a sedentary workstation and while walking one mile‐per‐hour at a treadmill workstation. Blood samples were collected at baseline and immediately after completion of tasks and analyzed for the following: prothrombin time (PT), active partial thromboplastin time (APTT), factor VII (FVII), factor VIII (FVIII), and fibrinogen (FGN).ResultsThe walking condition elicited greater responses in FVII compared to the sedentary condition at baseline. Additionally, there was a non‐significant trend observed for FVIII. All data presented in Table 1.ConclusionLow intensity walking at a treadmill workstation can attenuate prothrombotic changes that are associated with completing tasks at a sedentary workstation.

Effect of PCSK9 Inhibitors on Hemostasis in Patients with Isolated Hypercholesterolemia.

Background: In addition to reducing plasma lipids, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may produce numerous nonlipid-related pleiotropic effects. The purpose of this trial was to determine the efficacy of PCSK9 inhibitors alone in patients with isolated hypercholesterolemia. Methods: The trial enrolled 21 individuals with isolated hypercholesterolemia and atherosclerosis who received alirocumab for 90 days (150 mg every two weeks). Lipids, glucose homeostasis factors, and hemostatic markers were measured in the plasma at baseline and after treatment. Results: The PCSK9 inhibitor administered to these patients reduced plasma levels/activity of fibrinogen (from 3.6 ± 0.5 to 2.9 ± 0.4 g/L, p < 0.01), factor VII (from 143.8 ± 16.7 to 114.5 ± 14.1%, p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) (from 74.9 ± 13.9 to 52.8 ± 9.1 ng/mL, p < 0.001) without a significant reduction in von Willebrand factor levels, and it tended to prolong the partial thromboplastin and prothrombin times. Conclusion: Our findings indicate that treatment with PCSK9 inhibitors has a multipotential effect on fibrinolysis and coagulation in patients with isolated hypercholesterolemia and that this medication may have some future benefits in patients who are statin-intolerant or contraindicated to statin use.

Inhibitors: Diagnostic challenges, unknowns of inhibitor development, treatment of bleeding and surgery, and insights into diagnosis and treatment in China.

Factor (F) VIII inhibitors develop in around 30% of previously untreated patients (PUPs) with severe haemophilia, to a lesser extend in moderate and mild haemophilia A and in up to 10% in severe haemophilia B. Diagnostic challenges and questions remain including access to high quality testing, the role for functional inhibitor testing and binding antibody testing, and the adaptations needed in the presence of non-factor replacement therapy. Despite significant gains in knowledge there are still many unanswered questions underlying the immunologic mechanisms of inhibitor development and tolerance. Therapeutic options include eradication of inhibitors using immune tolerance induction therapy (ITI), prophylaxis with bypassing agents (i.e., recombinant activated factor VII /rFVIIa or activated prothrombin complex concentrate/aPCC) or non-factor replacement therapies (e.g., emicizumab) and treatment of bleeds or coverage of surgeries/invasive procedure. Recently a haemophilia centre capacity building program was launched in China to further develop the infrastructure and support needed to improve the diagnosis of haemophilia, detection of inhibitors, and continue to improve the care of patients with haemophilia and inhibitors.

Managing invasive procedures in haemophilia patients with limited resources, extended half-life concentrates or non-replacement therapies in 2022.

New treatment possibilities and modalities are now available globally for patients with haemophilia requiring surgery or invasive procedures. The first is the appropriate application of low-dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resources constraint environments. The increasing availability of CFC through humanitarian aid programs allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half-life CFC that are increasingly available in many countries represent valuable alternatives to standard half-life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half-life factor IX. Third, in the era of recently introduced nonfactor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low-dose administrations of CFC or bypassing agents. Additional factor VIII/IX or recombinant activated factor VII has proven to be safe and effective in association with emicizumab for major surgeries and it was effectively given at low doses in association with fitusiran (including activated prothrombin complex concentrate). No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents.

Iron deficiency anemia and bleeding management in pediatric patients with Bernard-Soulier syndrome and Glanzmann Thrombasthenia: A single-institution analysis.

Frequent and severe bleeding events (SBE) in patients with inherited qualitative platelet disorders Bernard-Soulier Syndrome (BSS) and Glanzmann Thrombasthenia (GT) can lead to secondary iron deficiency anemia (IDA). SBE are primarily treated with platelet transfusions or recombinant activated factor VII (rFVIIa) infusions. The impact of IDA on bleeding management and disease outcomes is understudied. To evaluate bleeding management, outcomes, and any association with IDA in pediatric patients with BSS and GT. Retrospective chart-review of pediatric patients with BSS or GT followed at a single hemophilia treatment center between 2007 and 2019. We identified 14 patients with BSS (n = 2) or GT (n = 12). Patients received rFVIIa (7%), platelet transfusions (7%), or a combination of both (57%) for SBE. Eleven patients (79%) had IDA requiring oral and/or intravenous iron replacement and 50% required red blood cell transfusions. Due to recurrent SBE and refractory IDA, three patients (21%) received rFVIIa prophylaxis at 90μg/kilogram 2-3times/week for ≥15months. Patients initiated on rFVIIa prophylaxis had a median baseline hemoglobin of 9.8 g/dL (min-max: 8.0-10.7 g/dL) compared to 11.7 g/dL (8.4-13.8 g/dL) for patients treated on-demand. Following initiation of rFVIIa prophylaxis, median hemoglobin and ferritin increased by 1.3 g/dL (0.7-2.5 g/dL) and 14.6 ng/mL (0.2-42.9ng/mL), respectively, and bleeding rates were reduced by 7-78%. IDA is a known complication of recurrent bleeding events in individuals with inherited bleeding disorders. Routine monitoring for IDA may help improve bleeding management and reduce bleed burden in BSS/GT.

Haematuria: A Rare Manifestation of Glanzmann Thrombasthenia

Summary: Glanzmann Thrombasthenia (GT) is a congenital thrombopathy characterised by bleeding manifestations that are sometimes severe. Treatment is based on platelet transfusions during bleeding. We report a case of TG revealed by haematuria and which presented a severe bleeding syndrome refractory to transfusions. Treatment with injections of recombinant activated factor VII was necessary. This case illustrates the value of using recombinant activated factor VII in TG in case of antiplatelet alloimmunisation or in case of lack of response to platelet transfusions.

Recombinant porcine factor VIII corrects thrombin generation in vitro in plasma from patients with congenital hemophilia A and inhibitors

BackgroundNeutralizing factor VIII (FVIII) antibodies are a major complication in hemophilia A. Antihemophilic factor VIII (recombinant), porcine sequence (rpFVIII; susoctocog alfa; Baxalta US Inc., a Takeda company) has low cross‐reactivity to anti‐human FVIII antibodies and can provide functional FVIII activity in the presence of FVIII inhibitors. ObjectivesEvaluate in vitro thrombin generation and clot formation responses to rpFVIII in blood from patients with congenital hemophilia A. MethodsIn this multicenter study, blood was obtained for in vitro analyses that included human and porcine FVIII inhibitors, low <5 Bethesda units (BU)/ml or high ≥5 BU/ml titer (Nijmegen‐modified Bethesda assay); thrombin generation assay (TGA), clot viscoelasticity (thromboelastography), fibrin clot structure analysis (scanning electron microscopy), and epitope mapping. ResultsBlood samples were from 20 patients with congenital hemophilia A (FVIII activity <1%, mean [range] inhibitor titers: anti‐human FVIII, 14 [1–427] BU/ml [n = 13 high, n = 6 low, n = 1 data unavailable]); anti‐porcine FVIII, 12 (0–886) BU/ml (n = 11 high, n = 8 low, n = 1 data unavailable). Porcine inhibitor titer and TGA response measured by endogenous thrombin potential showed an inverse correlation (2.7–10.8 U/ml rpFVIII Spearman correlation coefficient: −0.594 to −0.773; p< 0.01). Clot structures in low anti‐porcine inhibitor titer plasmas were similar to those in noninhibitor plasma. ConclusionsRecombinant porcine factor VIII demonstrated a dose‐dependent correction of thrombin generation and clot formation in vitro, dependent on the anti‐porcine FVIII inhibitor titer. Procoagulant responses to rpFVIII occurred in plasma containing FVIII inhibitors.

Recombinant Activated Factor VII in Aortic Surgery for Patients Under Hypothermic Circulatory Arrest.

PurposeWe aimed to identify the risk factors of critical bleeding and investigate the safety of recombinant activated factor VII (rFVIIa) in aortic surgery under hypothermic circulatory arrest (HCA).Patients and MethodsThe present single-center retrospective study compared the baseline characteristics of 144 patients who underwent aortic surgery under HCA at our institute. Among the total cohort of 144 patients, 42 received rFVIIa (rFVIIa group), while the remaining 102 patients did not (non-rFVIIa group). Perioperative bleeding and transfusions, postoperative 30-day mortality, and adverse events (AEs) were analyzed in 29 propensity score-matched pairs.ResultsBefore surgery, the rFVIIa group demonstrated a greater number of shocks (p=0.019), higher JapanSCORE II mortality rate (p=0.033), low platelet count (p=0.015) and fibrinogen (p<0.001) level, prolonged activated partial thromboplastin time (aPTT) (p=0.005) and prothrombin time international normalized ratio (PT-INR) (p=0.006), and longer aortic cross clamp time (p=0.049). Postoperative bleeding, transfusion, 30-day mortality, and AEs were comparable between the groups both in the entire-unmatched cohort and propensity score matching cohort.ConclusionPreoperative shock, higher JapanSCORE II mortality rates, low platelet and fibrinogen levels, prolonged aPTT and PT-INR, and longer aortic clamping time might be risk factors for excessive bleeding and indicate the need for rFVIIa treatment. The present study suggests that rFVIIa can be safely used to address critical and continuous bleeding in spite of adequate transfusion and supplementation of other coagulation factors in aortic surgery under HCA, without an increase in 30-day mortality and AEs.

Acquired hemophilia A secondary to rheumatoid arthritis

Acquired hemophilia A (AHA) is a rare plasma diathesis. Unlike congenital hemophilia A, AHA occurs in both sexes and the incidence of the disease increases with age. It is caused by the production of autoantibodies against the coagulation factor VIII. AHA can be primary or secondary. The clinical course is characterized by a rapid development of symptoms, massive bleeding and high mortality. In the described case, a 69-year-old female was successfully treated for severe AHA with bypass-concentrate — recombinant activated factor VII and immunosuppressive therapy.

Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

AbstractAdvances in the development of novel treatment options for hemophilia A are prevalent. However, the anti–factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy–based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.

Multicenter performance evaluation and reference range determination of a new one-stage factor VIII assay.

IntroductionWe conducted a multicenter evaluation of a new one‐stage factor VIII (FVIII) assay (Roche Diagnostics), intended for the quantitative assessment of FVIII activity. We evaluated the analytical performance of the FVIII assay on the cobas t 711 analyzer.MethodsExperiments performed at three laboratories used 3.2% citrated residual or commercially purchased plasma samples. Five human plasma pools and two controls were used to determine assay within‐run and within‐laboratory precision, and total reproducibility; coefficients of variation (CVs) and/or standard deviations (SDs) were calculated. Lot‐to‐lot variability and method comparison (vs Coagulation FVIII Deficient Plasma/Dade Actin FS Activated PTT reagent/Standard Human Plasma Calibrator on the Sysmex CS‐5100 analyzer; Siemens Healthineers) were evaluated by Passing–Bablok and Deming regression, respectively, and Pearson's r calculated. Assay‐specific reference range was determined using 199 fresh plasma samples from healthy adults, not receiving anticoagulants.ResultsAcross sites, SDs for repeatability were 0.016–0.046 for samples with ≤1.0 international units (IU)/dL FVIII activity; CVs were 0.9%–3.8% for samples with >1.0 IU/dl activity. Among samples with mean FVIII activity 0.344–133 IU/dl, good intermediate precision (SD 0.020 for samples with 0.344 IU/dl activity; CV 1.8%–4.7%) and good total reproducibility (CV 2.0%–13.3%) were observed. The FVIII assay showed excellent lot‐to‐lot variability (Pearson's r = .999) and good correlation with the comparator assay (Pearson's r = .993–.996). The reference range for FVIII activity was 82.2−218.0 IU/dl.ConclusionThe one‐stage FVIII assay demonstrated robust analytical performance on the cobas t 711 analyzer, supporting its use in routine laboratory practice.

Studies on activation and regulation of the coagulation cascade in chronic rhinosinusitis with nasal polyps

Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP. We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS. Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting. Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue. The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.

Perioperative management for patient with congenital factor VII deficiency who underwent laparoscopic cholecystectomy: Case report.

Introduction and importanceIn patients with congenital factor VII (FVII) deficiency, perioperative bleeding events are concern, so recombinant activated factor VII (rFVIIa) is favorably used, but the optimal dosage regimen has not clearly established. We report management of a patient with congenital FVII deficiency who underwent laparoscopic cholecystectomy.Case presentationA 70-year-male with congenital FVII deficiency was diagnosed as acute cholecystitis, so we planned laparoscopic cholecystectomy. FVII activity and prothrombin time international normalized ratio (PT-INR) were intraoperatively monitored as scheduled. At the start of surgery, FVII activity was 3.1% (75–130%) and PT-INR was 3.37 (0.8–1.2), so 1 mg of rFVIIa was administered. Both of these values then improved to 325.0% and 0.73, respectively. Laparoscopic cholecystectomy was successfully completed without unexpected bleeding or oozing. When FVII activity and PT-INR was re-checked 6 h after the first administration of rFVIIa, these values were 23.9% and 1.53, respectively. Additional 1 mg of rFVIIa was used only once after the operation. The patient was discharged on the sixth day after surgery without postoperative complication.Clinical discussionIn this case, rFVIIa was used just twice and there were no bleeding events during the perioperative period. Previous reports suggested using 15–30 μg/kg of rFVIIa before surgery and subsequent every 4–6 h in the first 24 h, then increasing the interval to 8–12 h. It is necessary to evaluate optimal dose of rFVIIa based on the risk and surgical invasiveness for each case.ConclusionOur patient with congenital FVII deficiency uneventfully underwent laparoscopic cholecystectomy.

Removal of single‐site N‐linked glycans on factor VIII alters binding of domain‐specific monoclonal antibodies

BackgroundA portion of individuals with hemophilia A develop neutralizing antibodies called inhibitors to glycoprotein factor VIII (FVIII). There are multiple risk factors that contribute to the risk of inhibitor formation. However, knowledge of the role of FVIII asparagine (N)‐linked glycosylation in FVIII immunity is limited. ObjectiveTo evaluate the effect of site‐specific N‐linked glycan removal on FVIII biochemical properties, endocytosis by murine bone marrow‐derived dendritic cells (BMDCs), and antibody responses. MethodsFour recombinant B domain‐deleted (BDD) FVIII variants with single‐site amino acid substitutions to remove N‐linked glycans were produced for experimental assays. ResultsBDD FVIII‐N41G, FVIII‐N239A, FVIII‐N1810A, and FVIII‐N2118A with confirmed removal of N‐linked glycans and similar glycosylation profiles to BDD FVIII were produced. There were no differences in thrombin activation or von Willebrand factor binding of FVIII variants compared with BDD FVIII; however, reduced FVIII expression, activity, and specific activity was observed with all variants. BDD FVIII‐N41G and FVIII‐N1810A had reduced uptake by BMDCs, but there were no differences in antibody development in immunized hemophilia A mice compared with BDD FVIII. Half of a repertoire of 12 domain‐specific FVIII MAbs had significantly reduced binding to ≥1 FVIII variant with a 50% decrease in A1 domain MAb 2‐116 binding to FVIII‐N239A. ConclusionsModifications of FVIII N‐linked glycans reduced FVIII endocytosis by BMDCs and binding of domain‐specific FVIII MAbs, but did not alter de novo antibody production in hemophilia A mice, suggesting that N‐glycans do not significantly contribute to inhibitor formation.

Therapeutic correction of hemophilia A using 2D endothelial cells and multicellular 3D organoids derived from CRISPR/Cas9-engineered patient iPSCs

The bleeding disorder hemophilia A (HA) is caused by a single-gene (F8) defect and its clinical symptom can be substantially improved by a small increase in the plasma coagulation factor VIII (FVIII) level. In this study, we used F8-defective human induced pluripotent stem cells from an HA patient (F8d-HA hiPSCs) and F8-corrected (F8c) HA hiPSCs produced by CRISPR/Cas9 genome engineering of F8d–HA hiPSCs. We obtained a highly enriched population of CD157+ cells from CRISPR/Cas9-edited F8c-HA hiPSCs. These cells exhibited multiple cellular and functional phenotypes of endothelial cells (ECs) with significant levels of FVIII activity, which was not observed in F8d-HA hiPSC-ECs. After transplantation, the engineered F8c–HA hiPSC-ECs dramatically changed bleeding episodes in HA animals and restored plasma FVIII activity. Notably, grafting a high dose of ECs substantially reduced the bleeding time during multiple consecutive bleeding challenges in HA mice, demonstrating a robust hemostatic effect (90% survival). Furthermore, the engrafted ECs survived more than 3 months in HA mice and reversed bleeding phenotypes against lethal wounding challenges. We also produced F8c-HA hiPSC-derived 3D liver organoids by assembling three different cell types in microwell devices and confirmed its therapeutic effect in HA animals. Our data demonstrate that the combination of genome-engineering and iPSC technologies represents a novel modality that allows autologous cell-mediated gene therapy for treating HA.

Acquired Factor VII Deficiency Presenting as Cardiac Tamponade: A Case Report

FVII (factor VII) is vitamin K-dependently synthesized in the liver. Hepatopathies, vitamin K deficiency, or use of vitamin K antagonists are the causes of acquired deficiency. Other types of acquired FVII deficiencies are rare. However, based on literature the incidence might be underestimated. The clinical manifestation of acquired FVII deficiency varies greatly in severity; asymptomatic course as well as severe life-threatening bleeding diathesis and fatal bleedings have been described. In this case report, we discuss a unique presentation of a 79-year-old male who was found to have cardiac tamponade revealing a severe acquired factor VII deficiency. A discordance between a prolonged PT and a normal aPTT was found in the biology lab report. And the diagnosis was confirmed by obtaining a factor VII activity assay. His management involved correction of his factor VII deficiency with fresh frozen plasma and pericardiocentesis.

Reference intervals for coagulation parameters in non-pregnant and pregnant women

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.

Examination of the effect of immunosuppressive therapy on acquired hemophilia A in elderly patients with bloodstream infections

Acquired hemophilia A (AHA) is an acquired autoantibody (inhibitor) against blood coagulation factor VIII (FVIII) that significantly reduces FVIII activity and causes a bleeding tendency. Immune acquired coagulation factor deficiency. The peak age of onset is in the 70s. In Japan, which has an aging society, the number of reports has recently been increasing, and it should be noted that AHA is a bleeding disease that can occur in the elderly. Examined 5 cases of AHA that were experienced in our hospital. The FVIII inhibitor level, APTT, underlying disease, treatment history, and outcome were retrospectively examined using medical records. The age of onset was 76-93 years. At the time of diagnosis, the Hb (mg/dL) value was 6.1-10.3, the APTT was 75.6-203.2 seconds, the FVIII inhibitor value (BU/mL) was 18-686, and the platelet count was within the normal range in all cases. Bleeding control was possible using a bypass hemostatic agent in 4 patients. All patients underwent immunosuppressive therapy. Two patients were discharged alive and 3 patients died. The cause of death was infectious disease in all cases. The total prednisolone-equivalent dose of the deceased patients was 1,240-3,206 mg; one patient was treated with cyclophosphamide and was treated with dexamethasone. Long-term immunosuppressive therapy is expected to increase the risk of infection in elderly patients. The risk assessment of AHA treatment-related bloodstream infections is insufficient, and it will be necessary to accumulate data and consider appropriate assessments and countermeasures.