Diagnostic utility of bleeding assessment tools in congenital fibrinogen deficiencies.

BACKGROUND: The assessment of clinical history is crucial before referring a patient for further laboratory testing. Bleeding assessment tools (BAT) are developed to standardize clinical evaluation. A small number of patients with congenital fibrinogen deficiencies (CFDs) have been evaluated with these tools without definitive results. AIMS: We compared the adequacy of the ISTH-BAT and the European network of rare bleeding disorders bleeding score system (EN-RBD-BSS) to identify patients with CFDs. The correlation between the two BATs and fibrinogen levels and patient clinical grade severity was further analyzed. METHODS: We included 100 Iranian patients with CFDs. Routine coagulation and fibrinogen-specific tests (fibrinogen antigen [Fg:Ag] and activity [Fg:C]) were performed. The ISTH-BAT and EN-RBD-BSS were used to assess the bleeding score (BS) of all patients. RESULTS: The ISTH-BAT and EN-RBD-BSS median (range) were 4 (0-16) and 2.21 (-1.49 to 6.71), with a statistically significant moderate correlation between the two systems (r = .597, P < .001). In patients with quantitative deficiencies (afibrinogenemia and hypofibrinogenemia), the correlation between Fg:C and the ISTH-BAT was moderately negative (r = -.4, P < .001), while the correlation between Fg:C and the EN-RBD-BSS was weakly negative (r = -.38, P < .001). Overall, 70% and 72% of patients with fibrinogen deficiencies were correctly identified by both the ISTH-BAT and EN-RBD-BSS, respectively. CONCLUSION: These results suggest that in addition to the ISTH-BAT, the EN-RBD-BSS may also be useful in identifying CFD patients. We found a significant level of sensitivity for detecting fibrinogen deficiency in the two BATs, and bleeding severity classification correctly identified severity grades in almost two-thirds of patients.

von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

BACKGROUND: Type 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions. OBJECTIVE: The objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS. METHODS: An indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay. RESULTS: In total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14). CONCLUSIONS: Anti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used.

Von Willebrand factor propeptide and pathophysiological mechanisms in European and Iranian patients with type 3 von Willebrand disease enrolled in the 3WINTERS-IPS study.

BACKGROUND: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. OBJECTIVE: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. METHODS: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients' diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman's rank correlation. RESULTS: Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2-2.7; P = .016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0-4.2; P = .054]). FVIII: C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r = .024; P = .778). CONCLUSIONS: An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.

Congenital Combined Bleeding Disorders, a Comprehensive Study of a Large Number of Iranian Patients.

Congenital combined bleeding disorders (CBDs) are extremely rare disorders which mainly occur in regions with a high rate of consanguineous marriage. These disorders can present with a variety of symptoms ranging from mucocutaneous bleeding to life-threatening episodes. This study aims to evaluate the prevalence and clinical course of Iranian patients with congenital CBDs. This study is conducted on 450 patients with CBDs who were referred to the Iranian Comprehensive Hemophilia Care Center (ICHCC) between 2010 and 2020. All these patients were diagnosed through evaluation of past medical history and coagulation laboratory investigation. Out of 450 patients, 33 were entered in this study. Having excluded cases with factor (F) V and FVIII deficiency, as well as those with hereditary combined Vitamin K dependent clotting factor deficiency (VKCFD), We found the most common CBDs to be FV-FVII deficiency (n: 6, 18.1%), together with FVII and FX deficiency (n: 6, 18.1%). The most common reason for referral of these patients to ICHCC was postoperative bleeding (14.3%). The mean of The International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) and condensed MCMDM-1VWD bleeding assessment tool were 9.6 ± 4.79 and 9.1 ± 4.87, respectively (P < 0.005). In 10 females of reproductive age, the mean of Pictorial Bleeding Assessment Chart (PBAC) score was 649.3 ± 554. Among all patients, 23 (69.7%) received on-demand replacement therapy, whereas 5 patients (15.1%) received prophylaxis. In Iran, the coinheritance of bleeding disorders is surprisingly higher than expected. Moreover, patients with congenital CBDs may experience serious bleeding manifestations.

Challenges and concerns of patients with congenital bleeding disorders affected by coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) is a new medical challenge for all individuals, especially for those with underlying disorders, such as congenital bleeding disorders (CBDs). Therefore, the pandemic might significantly change the behaviour of patients with CBDs and results in some challenges. In the present study, we assessed the main challenges of COVID-19 infection to patients with CBDs. Data were collected from medical files and interviews of patients with CBDs who had COVID-19 infection. Follow-ups were performed on patients who had active severe acute respiratory syndrome coronavirus 2 infection between April and October 2020. All patients were interviewed by an expert in order to collect the pertinent data. Some questions were about patients' preventive behaviors and feelings prior to infection, and some were about the consequences of infection on patients' replacement therapy and bleeding management. Among 25 patients, infection and death of loved ones (n: 7, 28%), and their own (n: 5, 20%) or family members' (n: 1, 4%) infection, and the resulting economic burden (n: 2, 8%) were main concerns. Six patients experienced depression during the pandemic. The pandemic caused all severely affected patients but one (n: 11, 92%) to abandon replacement therapy. However, two received on-demand therapy after exacerbation of their bleeding. Only one (25%) of four patients on prophylaxis received in-home therapy, whereas the others (75%) abandoned prophylaxis. It seems that COVID-19 infection has great consequences on the lives of patients with CBDs, causing some to take dangerous actions, such as abandonment of their treatment. Healthcare systems, and healthcare providers, should have an appropriate strategy for management of patients with CBDs that prevents infection and provides timely replacement therapy.

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease: Results from 3WINTERS-IPS, an international and collaborative cross-sectional study.

BACKGROUND: Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. AIMS: To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. METHODS: We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. RESULTS: In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels < 20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. CONCLUSIONS: In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.

Strategies for inhibitor treatment and costs in the short and long term: a critical evaluation of recent clinical studies.

One important complication of patients with severe haemophilia A is the formation of inhibitory antibodies to factor VIII (FVIII). Immune tolerance induction (ITI) is the treatment of choice for patients with inhibitors, but this approach is successful in about 60% of patients. Treatment of acute bleeding in patients with inhibitors is one of the greatest challenges in haemophilia management and is costly. Bypassing agents are the mainstay of treatment in these patients. The aims of this study were to review the most recent publications concerning the costs of inhibitor treatment. We conducted a literature review using PubMed which yielded 63 papers analysing the costs of inhibitor management of which 12 were suitable for our study. Four of eight studies supported the use of activated prothrombin complex concentrate (aPCC) with lower costs, but the remaining four studies showed that recombinant factor VIIa (rFVIIa) had a lower average treatment cost. Of four ITI studies, two supported lifelong cost-effectiveness of ITI vs. bypassing agents and the remaining two papers showed a high cost of inhibitor treatment. Dosages, time between onset of bleeding and treatment, patient characteristics and the price of drugs are some of the important issues that should be considered for further studies.