Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.

BACKGROUND: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). METHODS: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. FINDINGS: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. INTERPRETATION: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. FUNDING: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

The diagnostic accuracy of bleeding assessment tools for the identification of patients with mild bleeding disorders: A systematic review.

INTRODUCTION: The bleeding assessment tool (BAT) has been developed to standardize and interpret bleeding history for mild bleeding disorders. However, a critical appraisal addressing the quality and results of validation studies is lacking. AIM: We performed a systematic review of diagnostic studies assessing the performance of the BAT in patients referred for evaluation of bleeding symptoms. METHODS: The electronic database PubMed was searched from inception through July 27, 2017. Eligible publications were original studies that assessed and validated the diagnostic accuracy of bleeding questionnaires for identification of adults with mild bleeding disorders. For each study, sensitivity, specificity and diagnostic odds ratio (DOR) were calculated. Quality was assessed using the Quality Assessment of Diagnostic studies-2 tool. To assess the influence of specific study characteristics on DOR, univariate meta-regression analyses were performed. RESULTS: Nine studies were included. Five studies investigating the ISTH-BAT or other bleeding questionnaires had a moderate to low DOR. Four studies investigating Vicenza-based BATs had a high DOR, with high specificity (>90%) and sensitivity of 59%-85%. Study characteristics such as case-control design, retrospective data collection and differences in reference standard were associated with optimistic estimates of diagnostic performance. Three of four studies with a high DOR had these study characteristics. Studies with good methodological quality mainly had a low DOR. CONCLUSION: The main advantage of the BAT is that it offers a complete and structured interview. However, the BAT is of limited diagnostic value to the workup of patients referred for bleeding evaluation in clinical practice.

Hemorrhagic disorders of fibrinolysis: a clinical review.

Hyperfibrinolytic bleeding can be caused by a deficiency of one of the inhibitors of fibrinolysis (plasminogen activator inhibitor type 1 [PAI-1] or α2-antiplasmin [α2-AP]), or an excess of one of the activators of fibrinolysis: tissue-type plasminogen activator or urokinase-type plasminogen activator. This review focuses on the clinical implications of these disorders. The bleeding phenotype of fibrinolytic disorders is characterized by delayed bleeding after trauma, surgery and dental procedures. Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. Patients with α2-AP deficiency present with the most severe bleeding episodes. Recently, it was discovered that hyperfibrinolytic disorders are associated with a high rate of obstetric complications such as miscarriage and preterm birth, especially in PAI-1 deficient patients. Hyperfibrinolytic disorders are probably underdiagnosed because of lack of knowledge and lack of accurate diagnostic tests. A substantial part of the large group of patients diagnosed as 'bleeding of unknown origin' could actually have a hyperfibrinolytic disorder. In the case of a high index of suspicion (i.e. because of a positive family history, recurrent bleeding or uncommon type of bleeding such as an intramedullary hematoma), further testing should not be withheld because of normal results of standard hemostatic screening assays. Timely diagnosis is important because these disorders can generally be treated well with antifibrinolytic agents.

Perioperative dilutional coagulopathy treated with fresh frozen plasma and fibrinogen concentrate: a prospective randomized intervention trial.

BACKGROUND AND OBJECTIVES: Treatment of dilutional coagulopathy by transfusing fresh frozen plasma (FFP) remains sub-optimal. We hypothesized that partial replacement of transfused FFP by fibrinogen concentrate results in improved coagulant activity and haemostasis. This was tested in a controlled clinical intervention trial with patients experiencing massive bleeding during major surgery. METHODS: Patients undergoing major elective surgery were treated according to current protocols. When transfusion with FFP was required, patients were randomized as follows: group A received 4 units FFP and group B received 2 units FFP plus 2 g fibrinogen concentrate. Blood samples were taken before and after the intervention. Analysts were blinded to the treatment type. RESULTS: Group A (B) consisted of 21 (22) patients, in 16 (17) of whom bleeding stopped after intervention. Plasma fibrinogen increased significantly more in group B (0·57 g/l) than in group A (0·05 g/l). However, levels of prothrombin and factors VIII, IX and X increased more in group A than in group B. Rotational thromboelastometry (ROTEM) of whole blood and plasma revealed improved fibrin clot formation in group B but not in group A. Thrombin generation [calibrated automated thrombogram (CAT)] in plasma increased more in group A. Principal parameters determining whole-blood thromboelastometry were the fibrinogen level and platelet count. In vitro addition of fibrinogen and prothrombin complex concentrate to pre-intervention samples restored both ROTEM and CAT parameters. CONCLUSIONS: Partial replacement of transfused FFP by fibrinogen increases fibrin clot formation at the expense of less improved thrombin generation. Coagulation factors other than fibrinogen alone are required for full restoration of haemostasis.

Impaired thrombin generation and fibrin clot formation in patients with dilutional coagulopathy during major surgery.

Patients subjected to haemodilution during surgery are at increased risk of bleeding. We hypothesised that, in the acquired dilutional coagulopathy, insufficient haemostasis is due to either insufficient thrombin generation or insufficient fibrin clot formation. In tissue factor-activated plasmas from patients with coagulation deficiency, we measured time curves of thrombin generation and fibrin clot formation (thromboelastography). Investigated were in study A: 10 patients treated with vitamin K antagonist and five healthy subjects; in study B: 30 patients undergoing cardiopulmonary bypass (CPB) surgery and infused with on average 2,000 ml crystalloids and colloids (no major bleeding); in study C: 58 patients undergoing major general surgery, and transfused with >5,000 ml crystalloids, colloids and red cell concentrates, who experienced major bleeding and were post-transfused with fresh frozen plasma. The treatment with vitamin K antagonist led to a progressive reduction in thrombin generation but not fibrin clot formation. In CPB patients, plasma factor levels post-surgery were 53-60% of normal. This was accompanied by moderate reduction in both haemostatic processes. In plasmas from patients undergoing major surgery, factor levels were 38-41% of normal, and these levels increased after plasma transfusion. Taking preset thresholds for normal thrombin generation and fibrin clot formation, at least one of these processes was low in 88-93% of the patients with (persistent) bleeding, but only in 40-53% of the patients without bleeding. In conclusion, the ability of thrombin generation and fibrin clot formation is independently reduced in acquired dilutional coagulopathy, while minimal levels of both are required for adequate haemostasis.

Origin of the low-energy emission band in epitaxially grown para-sexiphenyl nanocrystallites.

A comparative study of steady-state and time-resolved photoluminescence of para-sexiphenyl (PSP) films grown by organic molecular beam epitaxy (OMBE) and hot wall epitaxy (HWE) under comparable conditions is presented. Using different template substrates [mica(001) and KCl(001) surfaces] as well as different OMBE growth conditions has enabled us to vary greatly the morphology of the PSP crystallites while keeping their chemical structure virtually untouched. We prove that the broad redshifted emission band has a structure-related origin rather than being due to monomolecular oxidative defects. We conclude that the growth conditions and type of template substrate impacts substantially on the film morphology (measured by atomic force microscopy) and emission properties of the PSP films. The relative intensity of the defect emission band observed in the delayed spectra was found to correlate with the structural quality of PSP crystallites. In particular, the defect emission has been found to be drastically suppressed when (i) a KCl template substrate was used instead of mica in HWE-grown films, and (ii) in the OMBE-grown films dominated by growth mounds composed of upright standing molecules as opposed to the films consisting of crystallites formed by molecules lying parallel to the substrate.

Spinocerebellar ataxia type 1: Clinical and neurophysiological characteristics in German kindreds.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of an unstable (CAG)n repeat on chromosome 6p. We investigated 36 German families suffering from hereditary ataxias for the SCA1 mutation and elaborated clinical and neurophysiological characteristics. SCA1 accounts for 10-15% of dominant cerebellar ataxias in German kindreds. The clinical presentation is characterized by broad, even intrafamilial variability and multiple system involvement already in early stages. Slowed saccades, ptosis and facial weakness are more prevalent in SCA1 but were unspecific differences compared to non-SCA1 ataxias. Two electrophysiological parameters characterize SCA1: markedly prolonged central motor conduction time in motor evoked potentials and predominantly demyelinating polyneuropathy. Molecular genetic analyses are indispensable to diagnose SCA patients precisely. Extensive neurophysiological studies are recommendable in the clinical approach as they are suitable to discover subclinical damage of the nervous system. In contrast to the enormous variability of clinical signs in SCA1 neurophysiological findings are rather constant.

Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients.

Autosomal dominant spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. A gene responsible for SCA type 3 has been mapped to human chromosome 14q, close to the Machado-Joseph disease (MJD) locus. The MJD1 gene has recently been cloned and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. As some clinical features of MJD overlap with those of SCA we investigated the MJD mutation in 38 German families with dominantly inherited SCA. The MJD1 (CAG)n expansion was identified in 19 families. In contrast, the trinucleotide expansion was not observed in 21 ataxia patients without family history of the disease. Analysis of the (CAG)n repeat length in 30 patients revealed an inverse correlation with the age of onset. The (CAG)n stretch of the affected allele varied between 67 and 78 trinucleotide units, the normal alleles carried between 12 and 28 simple repeats. These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patients in Germany.