Age-related variation in coagulation factors in non-valvular atrial fibrillation patients receiving direct oral anticoagulants.

Age is a significant risk factor for ischemic stroke. However, the influence of aging on coagulation parameters in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOACs) remains unclear. A total of 775 samples were collected from 224 NVAF patients receiving apixaban, edoxaban or rivaroxaban. The samples were categorized into three age groups: (i) ≤ 64 years, (ii) 65-74 years, and (iii) ≥ 75 years (apixaban: N = 48, 108, 119; edoxaban: N = 63, 68, 126; rivaroxaban: N = 115, 90, 38, respectively). Coagulation parameters including fibrinogen (Fbg), factor II, factor V, factor VII, factor X, and D-dimer, were compared between the three age groups for each drug. The slopes in the correlation between drug concentrations and modified diluted prothrombin time (mdPT) were also assessed. Fbg and factor V increased with age, while factor II and factor X decreased. Factor VII and D-dimer showed no significant differences across age categories. The slope in response to drug concentrations was similar between the age groups. In NVAF patients treated with apixaban, edoxaban and rivaroxaban, some coagulation parameters exhibited age-related variation. However, the response of mdPT to drug concentration was consistent across age categories.

Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

A multicenter, observational study to evaluate hemostasis following recombinant activated FVII treatment in patients in Japan with congenital factor VII deficiency.

Reports describing symptoms and treatment of patients with congenital factor VII (FVII) deficiency frequently relate to patients in Europe, while only a small number describe data from Asian countries.This multicenter, prospective observational study (NCT01312636) collected data from 30 sites for 55% of patients registered in 2011 in Japan with congenital FVII deficiency treated with activated recombinant FVII (rFVIIa) for bleeding episodes and/or during surgery.The mean follow-up in 20 eligible patients was 11 months (range 1-49 months). Of 348 bleeding episodes in seven patients, 170 (48.9%) were intra-articular bleeding and 62 (17.8%) were menorrhagia, of which 92.9% (158/170) and 100% (62/62) were in patients with baseline factor VII activity 20 IU/dl or less, respectively. The hemostatic effect after rFVIIa treatment was rated as excellent, effective or partially effective for 45.7, 33.6 and 18.4% of 348 bleeding episodes. Overall, hemostasis for bleeding events and surgery was achieved in nearly 2 days, with the majority of patients receiving two doses or less. The hemostatic effect after the recommended dose (15-30 µg/kg) of rFVIIa was rapid and effective treatment for all categories of bleeding and surgical procedure.On the basis of data from routine clinical practice, no new safety signals were identified. TRIAL REGISTRATION: NCT01312636.

The Pharmacokinetics and Pharmacodynamics of A Novel Recombinant Activated Human Factor VII, GEN-0828, in Hemophilia B Mice.

GEN-0828, a proposed clinical candidate for hemophilia and trauma hemorrhage treatment, is a novel recombinant activated human factor VII (rFVIIa). The purpose of this paper is to compare the pharmacokinetics and pharmacodynamics of GEN-0828 in hemophilia B mice with those of NovoSeven®, the only marketed rFVIIa product worldwide., GEN-0828 and NovoSeven® showed similar affinity bioactivity to recombinant tissue factor (rTF) in vitro. Pharmacodynamics data indicated a generally similar hemostatic efficacy (ED50) of GEN-0828 (10.91 KIU·kg-1) and NovoSeven® (18.91 KIU·kg-1) at the doses studied in hemophilia B mice, while GEN-0828 represented a lower initial effective dosage compared with that of NovoSeven® in terms of both blood loss and APTT. GEN-0828 exhibited linear pharmacokinetic profiles in hemophilia B mice at the 30-338 KIU·kg-1 dose range, the comparative pharmacokinetic study with NovoSeven® indicated better characteristics than NovoSeven® in terms of the appropriate higher maximal concentration (Cmax) and area under the plasma concentration-time curve (AUClast) and longer mean residence time (MRT). In conclusion, GEN-0828 was a promising new type of rFVIIa compound with favourable pharmacokinetic and pharmacodynamic profiles.

Patient with congenital factor VII deficiency undergoing brain tumor neurosurgery successfully treated with recombinant factor VIIa and fresh frozen plasma: A case report and literature review.

RATIONALE: Congenital factor VII deficiency is the most common among rare bleeding disorders, characterized by spontaneous or traumatic bleeding. The clinical manifestation is heterogeneous, ranging from asymptomatic phenotype to life-threatening hemorrhages. Intracranial hemorrhage is a common complication of brain tumor neurosurgery, which significantly challenges the perioperative management of patients with hemostatic defects. PATIENT CONCERNS: This report presented a 55-year-old man with congenital factor VII deficiency, who had no history of hemorrhage or family history. He underwent a craniotomy for the treatment of papillary craniopharyngioma. DIAGNOSES: The patient was diagnosed as papillary craniopharyngioma, factor VII deficiency, and atrial fibrillation. INTERVENTIONS: To prevent bleeding, a total of 8 doses of recombinant activated factor VII and 1 dose of fresh frozen plasma were administered as the perioperative replacement therapy. This scheme was guided by a pharmacodynamic evaluation, laboratory tests, and imaging examinations. OUTCOMES: No excessive surgical bleeding was observed during the 22-day treatment. The patient was found to have compound heterozygous mutations, Ala304Thr (c.910G > A) and IVS5-2A > G (c.572-2A > G), in the F7 gene. LESSONS: This is the first reported case in which surgical hemorrhage secondary to brain tumor resection was successfully controlled in the presence of congenital factor VII deficiency. Perioperative coagulation state, hemostasis, and thrombosis events should be closely observed, and the interval and dosage of recombinant factor VIIa should be adjusted accordingly.

Results of multicenter registry for patients with inherited factor VII deficiency in Turkey.

INTRODUCTION: Inherited factor VII (FVII) deficiency (FVIID) is the most common of inherited rare bleeding disorders. Other determinants of clinical severity apart from FVII level (FVIIL) include genetic and environmental factors. We aimed to identify the cut-off FVIILs for general and severe bleedings in patients with FVIID by using an online national registry system including clinical, laboratory, and demographic characteristics of patients. METHODS: Demographic, clinical, and laboratory data of patients with FVIID extracted from the national database, constituted by the Turkish Society of Hematology, were examined. Bleeding phenotypes, general characteristics, and laboratory features were assessed in terms of FVIILs. Bleeding rates and prophylaxis during special procedures/interventions were also recorded. RESULTS: Data from 197 patients showed that 46.2% of patients had FVIIL< 10%. Most bleeds were of mucosal origin (67.7%), and severe bleeds tended to occur in younger patients (median age: 15 (IQR:6-29)). Cut-off FVIILs for all and severe bleeds were 16.5% and 7.5%, respectively. The major reason for long-term prophylaxis was observed as central nervous system bleeding (80%). CONCLUSION: Our data are consistent with most of the published literature in terms of cut-off FVIIL for bleeding, as well as reasons for prophylaxis, showing both an increased severity of bleeding and younger age at diagnosis with decreasing FVIIL. However, in order to offer a classification similar to that in Hemophilia A or B, data of a larger cohort with information about environmental and genetic factors are required.

Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry.

Cardiovascular diseases (CVDs) are a major issue in aging patients with hemophilia (PWHs). Antithrombotic agents are widely used in the general population for CVD treatment, but this recommendation is not fully applicable to PWHs. To improve treatment strategies, a prospective case-control study (COCHE) that analyzed CVD management and follow-up (2 years/patient) in PWHs was performed in France from 2011 to 2018. In total, 68 PWHs (median age: 65 years [39-89]; 48 mild, 10 moderate, and 10 severe hemophilia) were included (n = 50 with acute coronary syndrome, n = 17 with atrial fibrillation, n = 1 with both). They were matched with 68 control PWHs without antithrombotic treatment. In our series, bleeding was significantly influenced by (1) hemophilia severity, with a mean annualized bleeding ratio significantly higher in COCHE patients than in controls with basal clotting factor level up to 20%, (2) antihemorrhagic regimen (on-demand vs. prophylaxis) in severe (hazard ratio [HR] = 16.69 [95% confidence interval, CI: 8.2-47.26]; p < 0.0001) and moderate hemophilia (HR = 42.43 [95% CI: 1.86-966.1]; p = 0.0028), (3) type of antithrombotic treatment in mild hemophilia, with a significantly higher risk of bleeding in COCHE patients than in controls for dual-pathway therapy (HR = 15.64 [95% CI: 1.57-115.8]; p = 0.019), anticoagulant drugs alone (HR = 9.91 [95% CI: 1.34-73.47]; p = 0.0248), dual antiplatelet therapy (HR = 5.31 [95% CI: 1.23-22.92]; p = 0.0252), and single antiplatelet therapy (HR = 3.76 [95% CI: 1.13-12.55]; p = 0.0313); and (4) HAS-BLED score ≥3 (odds ratio [OR] = 33 [95% CI: 1.43-761.2]; p = 0.0065). Gastrointestinal bleeding was also significantly higher in COCHE patients than in controls (OR = 15 [95% CI: 1.84-268]; p = 0.0141). The COCHE study confirmed that antithrombotic treatments in PWHs are associated with increased bleeding rates in function of hemophilia-specific factors and also of known factors in the general population.

Management of pregnancy in women with factor VII deficiency: A case series.

INTRODUCTION: Inherited factor VII deficiency is the most common autosomal recessive inherited bleeding disorder, with an estimated incidence of one per 500 000 cases in the general population. Bleeding manifestations correlate poorly with circulating FVII levels. During pregnancy, increases in FVII levels can occur in women with mild-moderate FVII deficiencies but not in those with severe deficiency. AIM: We present five pregnant patients with FVII deficiency and describe the management during their pregnancies and peripartum periods. METHODS: Retrospective analysis of six pregnancies in five women with FVII deficiency followed during pregnancy and delivery at an academic medical centre between January 2013 and December 2019. RESULTS: Of the five patients, two had severe, one with moderate and two with mild FVII deficiency. Early postpartum haemorrhage (PPH) occurred in two patients. One of the two severe FVII-deficient patients had PPH with a laceration at delivery despite replacement therapy with recombinant factor VII. The other PPH occurred in a patient with mild FVII deficiency who delivered twins by caesarean section under general anaesthesia. Neuraxial anaesthesia was utilized in only one woman with mild deficiency whose FVII level normalized at the end of the pregnancy. CONCLUSIONS: Management of delivery for women with FVII deficiency should be addressed on a case-by-case basis at centres with expertise in rare bleeding disorders, maternal foetal medicine and obstetric anaesthesiology. These management discussions should factor the patient's bleeding history, third trimester PT, FVII level, multiple gestation and mode of delivery.

Spontaneous hepatic rupture due to primary amyloidosis.

Spontaneous hepatic rupture is an uncommon cause of haemorrhagic shock and very rarely happens due to amyloidosis. This report describes one such case in which a middle-aged man presented in extremis. He was managed initially with massive transfusion, interventional radiology embolisation and decompressive laparotomy for abdominal compartment syndrome. Subsequent coagulopathy was treated with activated factor VII due to deficient native activity. Serum protein electrophoresis and liver biopsy during his hospital course yielded a diagnosis of amyloidosis, which was treated palliatively with steroids and bortezomib. Despite supportive care, he died 10 days after presentation. This case illustrates the importance of considering an uncommon pathology when a patient presents with a condition in an uncommon way.

An overview of inherited factor VII deficiency.

Factor VII (FVII) deficiency is the most common of the Rare Inherited Coagulation Disorders. The inheritance is autosomal recessive but there is variable penetrance. Overall there is poor correlation between the FVII level and the bleeding phenotype. Heterozygotes may have significant bleeding and severe homozygotes, or compound heterozygotes can be asymptomatic. Typically, homozygotes have FVII levels <10% and heterozygotes have levels above that. In most cases bleeding is uncommon with FVII levels>10-20%. A personal and family history is essential to determine the bleeding risk and to plan for surgical and obstetrical prophylaxis. Severe bleeding complications including central nervous system bleeding, gastrointestinal system bleeding and bleeding into the joints occurs in 10-15% of FVII deficient patients. Mucocutaneous bleeding is a common symptom but 30% of patients are asymptomatic. Fifty to 69% of women have heavy menstrual bleeding. Due to the limited number of publications regarding this rare disorder there are no consensus guidelines. There is registry data which has led to the best recommendations for treatment of bleeding episodes, initiation of long-term prophylaxis in addition to surgical plus ante and peripartum prophylaxis. Recombinant FVII concentrate is the best replacement therapy and a review of treatment and prophylaxis dosing is discussed.

Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal: Does One Dose Fit All?

Four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown. Although several studies have attempted to determine the optimal dose of 4F-PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Many of these studies have evaluated a low, fixed dose of 4F-PCC rather than individualized dosing as recommended in product labeling. The purpose of this review was to evaluate the efficacy and safety of various fixed-dose strategies of 4F-PCC for emergent VKA reversal and to assess limitations of the existing literature. A search of the PubMed database was performed from the earliest available date through 2018 for relevant articles describing fixed-dose 4F-PCC for VKA reversal. Reference lists of relevant articles were also manually reviewed. Most currently available studies are primarily observational and heterogeneous in design. A very low fixed dose of 500 IU is likely inadequate for successful VKA reversal, but increased fixed doses of 1000-1500 IU have found some degree of success and may be considered for VKA reversal. However, many of these studies consistently identified a trend toward international normalized ratio (INR) reversal failure in patients presenting with high baseline INR values or intracranial hemorrhage, suggesting that higher 4F-PCC doses are needed in these patients. Available studies are underpowered to determine whether a dose-dependent association with thrombotic risk exists. Additional large, randomized studies are needed to determine the optimal dosing strategy and ascertain the role for fixed-dose 4F-PCC.

Acquired Hemophilia A After Hepatic Yttrium-90 Radioembolization: A Case Report.

Acquired hemophilia is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors, most frequently factor VIII. We report a case of a 65-year-old man with hepatocellular carcinoma who bled massively after a hepatic Yttrium-90 radioembolization procedure (Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres [SIRTex]). An acquired deficiency of factor VIII was diagnosed and successfully treated with recombinant activated factor VII and immunosuppression.

[Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance]. / Hereditärer heterozygoter Faktor VII-Mangel beim chirurgischen Patienten : Klinische Relevanz.

BACKGROUND: A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. METHODS: In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. RESULTS: We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. DISCUSSION: Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.

Inhibitor development after liver transplantation in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement.

Rare coagulation disorders: fibrinogen, factor VII and factor XIII.

Rare coagulation disorders (RCDs) include the inherited deficiencies of fibrinogen, factor (F) II, FV, combined FV and VIII, FVII, FX, combined FVII and X, FXI, FXIII and combined congenital deficiency of vitamin K-dependent factors (VKCFDs). Despite their rarity, a deep comprehension of all these disorders is essential to really understand haemostasis. Indeed, even if they share some common features each RCD has some particularity which makes it unique. In this review, we focus on three disorders: fibrinogen, FVII and FXIII.

The safety of pharmacologic options for the treatment of persons with hemophilia.

INTRODUCTION: The mainstay of treatment of hemophilia A and B is the replacement of the congenitally deficient coagulation factor through the intravenous infusion of specific concentrates (factor VIII, FVIII, in hemophilia A; factor IX, FIX, in hemophilia B). Several commercial brands of FVIII or FIX products extracted from human plasma or engineered using recombinant DNA technology are available. AREAS COVERED: We analyze the safety aspects of plasma-derived and recombinant FVIII and FIX products licensed in Europe, focusing on their pathogen safety and inhibitor and thrombosis risks. The safety aspects of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII) used for treatment of bleeding episodes in inhibitor patients will be also briefly discussed. EXPERT OPINION: The analysis of the published literature documents the high degree of safety from pathogen risk for both plasma-derived and recombinant products available for hemophilia treatment. The main threat to factor concentrate safety is represented by the development of neutralizing alloantibodies against the infused coagulation factor, which in hemophilia A seem to occur more frequently following the administration of recombinant than plasma-derived FVIII products. Great expectations are placed on newer products, particularly on those based upon mechanisms of action other than FVIII replacement.

Emergent reversal of vitamin K antagonists: addressing all the factors.

BACKGROUND: Reversal of warfarin-induced coagulopathy after traumatic injury may be done exclusively with prothrombin complex concentrates (PCCs). No direct comparisons between different PCC regimens exist to guide clinical decision-making. Our institution has used 2 distinct PCC strategies for warfarin reversal; a 3-Factor PCC (Profilnine) combined with activated Factor VII (3F-PCC+rVIIa), and a 4-Factor PCC (Kcentra) given without additional factor supplementation. METHODS: Retrospective review of all PCC administrations to trauma patients with acute bleeding who were taking warfarin before injury. Primary endpoints were international normalized ratio (INR) reduction, in-hospital mortality, and diagnosis of deep venous thrombosis (DVT). RESULTS: Eighty-seven patients were identified from 2011 to 2015. Fifty-three were treated with 3F-PCC+rVIIa and 34 with 4F-PCC. Patient demographics, injury severity, and presenting laboratory data were similar. The 3F-PCC+rVIIa produced a lower median (IQR) INR postreversal compared with 4F-PCC (.75 (.69, 1.00) vs 1.28 (1.13, 1.36), P<.001). Both regimens were able to obtain an INR lower than 1.5 immediately after administration (3F+rVIIA 93.9% vs 4F 97.1%, P =.51). In the 4F-PCC group, there was a significant decrease in the incidence of DVT (2.9% vs 22.6%), P < .01), and a nonsignificant reduction in mortality (2.9% vs 17.0%, P = .08). CONCLUSIONS: Use of 4F-PCC for warfarin reversal after traumatic hemorrhage is associated with a less severe decrease in INR, a significant reduction in DVT rates and a trend toward reduced mortality when compared with similar patients treated with 3F-PCC+rVIIa.