Glanzmann thrombasthenia (GT) is a rare inherited platelet function disorder caused by a quantitative and/or qualitative defect of the αIIbβ3 integrin. Pregnancy and delivery are recognized risk ...periods for bleeding in women with GT. The newborn may also be affected by fetal and neonatal immune thrombocytopenia induced by the transplacental passage of maternal anti-αIIbβ3 antibodies, which can lead to severe hemorrhage and fetal loss. Pregnancy in women with GT thus requires a multidisciplinary approach, including prepregnancy counseling and a treatment plan for delivery for both the mother and child. In this article, we summarize the current knowledge on pregnancy in women with GT and describe how we manage this severe platelet disorder in our clinical practice.
Hemophilia A and B predominantly attracts clinical attention in males due to X‐linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is ...contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01–0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research.
Glanzmann thrombasthenia (GT) is a rare inherited autosomal recessive bleeding disorder of platelet function caused by a quantitative or qualitative defect of platelet membrane glycoprotein IIb/IIIa ...(integrin αIIbβ3), a fibrinogen receptor required for platelet aggregation. Bleeds in GT are variable and may be severe and unpredictable. Bleeding not responsive to local and adjunctive measures, as well as surgical procedures, is treated with platelets, recombinant activated factor VII (rFVIIa), or antifibrinolytics, alone or in combination. Although platelets are the standard treatment for GT, their use is associated with the risk of blood-borne infection transmission and may also cause the development of platelet antibodies (to human leukocyte antigens and/or αIIbβ3), potentially resulting in platelet refractoriness. Currently, where rFVIIa is approved for use in GT, this is mostly for patients with platelet antibodies and/or a history of platelet refractoriness. However, data from the prospective Glanzmann’s Thrombasthenia Registry (829 bleeds and 206 procedures in 218 GT patients) show that rFVIIa was frequently used in nonsurgical and surgical bleeds, with high efficacy rates, irrespective of platelet antibodies/refractoriness status. The mechanisms underpinning rFVIIa effectiveness in GT have been studied. At therapeutic concentrations, rFVIIa binds to activated platelets and directly activates FX to FXa, resulting in a burst of thrombin generation. Thrombin converts fibrinogen to fibrin and also enhances GT platelet adhesion and aggregation mediated by the newly converted (polymeric) fibrin, leading to primary hemostasis at the wound site. In addition, thrombin improves the final clot structure and activates thrombin-activatable fibrinolysis inhibitor to decrease clot lysis.
•Glanzmann thrombasthenia is a serious inherited platelet bleeding disorder.•Platelets for bleed treatment/prevention may result in antibodies/refractoriness.•rFVIIa is effective whether antibodies/refractoriness to platelets is present.•rFVIIa’s mechanisms of action in Glanzmann thrombasthenia are now well understood.•A few patients have been cured by transplant; gene therapy remains a prospect.
Around one third of boys with severe hemophilia A develop inhibitors (neutralizing antibodies) against their therapeutic factor VIII product. This adverse effect may result in more life-threatening ...bleeding, disability, impaired quality of life, and costly care. We compared the incidence of inhibitors in boys treated with the three factor VIII products most used in France: one plasma-derived (Factane) and two recombinant products (Advate and Kogenate Bayer). A previously untreated cohort of patients was created in 1994 to investigate risk factors for inhibitor development. We selected boys with severe hemophilia A (factor VIII <1 IU/dL) first treated with one of the three factor VIII products studied. Details of product infusions, inhibitor assays and main fixed and time-varying inhibitor risk factors were recorded for the first 75 exposure days. Three outcomes (all inhibitors, high-titer inhibitors and subsequently treated inhibitors) were analyzed by univariate and multivariate Cox models. We studied 395 boys first treated between 2001 and 2016 (131, 137, and 127 with Factane, Advate, and Kogenate Bayer, respectively). Clinically significant inhibitors were diagnosed in 121 patients (70 high-titer). The incidence of high-titer inhibitors was significantly associated with the factor VIII product received (
=0.005): the cumulative incidence at 75 exposure days was 12.7% (95% CI: 7.7-20.6) with Factane, 20.4% (95% CI: 14.0-29.1) with Advate, and 31.6% (95% CI: 23.5-41.7) with Kogenate Bayer. The low inhibitor incidence observed with Factane is concordant with recent findings from the SIPPET randomized trial. These consistent results from observational and experimental studies should lead to improved care for previously untreated patients and cost savings for healthcare systems worldwide.
Standard treatment for Glanzmann thrombasthenia, a severe inherited bleeding disorder, is platelet transfusion. Recombinant factor VIIa is reported to be effective in Glanzmann thrombasthenia with ...platelet antibodies and/or refractoriness to platelet transfusions. We aimed to evaluate recombinant factor VIIa effectiveness and safety for the treatment and prevention of surgical bleeding in patients, with or without platelet antibodies and/or refractoriness, using data from the Glanzmann Thrombasthenia Registry, an international, multicenter, observational, post-marketing study of rFVIIa. Between 2007 and 2011, 96 patients were treated for 206 surgical procedures (minor 169, major 37). History of platelet antibodies was present in 43 patients, refractoriness in 23, antibodies+refractoriness in 17, while 47 had no confirmed antibodies/refractoriness. Treatments analyzed included antifibrinolytics, recombinant factor VIIa, recombinant factor VIIa+antifibrinolytics, platelets±antifibrinolytics and recombinant factor VIIa+platelets±antifibrinolytics. The most frequent treatment for minor procedures was recombinant factor VIIa+antifibrinolytics (n=65), and for major procedures, recombinant factor VIIa+platelets±antifibrinolytics (n=13). In patients without antibodies/refractoriness, recombinant factor VIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for minor and major procedures. The effectiveness of treatment for minor procedures in patients with antibodies and refractoriness was 88.9% for recombinant factor VIIa, 100% for recombinant factor VIIa+antifibrinolytics, 66.7% for platelets±antifibrinolytics and 100% for recombinant factor VIIa+platelets±antifibrinolytics. One of four adverse events reported for surgery was considered recombinant factor VIIa-treatment-related (non-fatal thromboembolic event in an adult female receiving recombinant factor VIIa+platelets+antifibrinolytics). For all patients, regardless of platelet antibody or refractoriness status, recombinant factor VIIa, administered with or without platelets (±antifibrinolytics), provided effective hemostasis with a low frequency of adverse events in surgical procedures in Glanzmann thrombasthenia patients. This trial was registered at clinicaltrials.gov identifier: 01476423.
Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of ...inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio aHR, 1.55; 95% confidence interval CI, 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA.
•A currently marketed rFVIII product is associated with a higher risk of inhibitor development in boys with severe hemophilia A.•This result, validated by extensive sensitivity analyses, confirms a recently published study and cannot be explained by identified biases.
Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet ...antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423.
Glanzmann thrombasthenia (GT) is a genetic bleeding disorder characterised by severely reduced/absent platelet aggregation in response to multiple physiological agonists. The severity of bleeding in ...GT varies markedly, as does the emergency situations and complications encountered in patients. A number of emergency situations may occur in the context of GT, including spontaneous or provoked bleeding, such as surgery or childbirth. While general management principles apply in each of these settings, specific considerations are essential for the management of GT to avoid escalating minor bleeding events. These recommendations have been developed from a literature review and consensus from experts of the French Network for Inherited Platelet Disorders, the French Society of Emergency Medicine, representatives of patients' associations, and Orphanet to aid decision making and optimise clinical care by non-GT expert health professionals who encounter emergency situations in patients with GT.
Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). ...Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown.
To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding.
A survey was sent to the 30 centers of the French-network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan-Meier analysis the recurrence-free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small-bowel localizations on VCE exploration.
GI bleeding source localization was significantly improved when including VCE exploration (P < .01), even in patients without history of angiodysplasia (P < .05). Patients with angiodysplasia had more GI bleeding recurrences (P < .01). A lower recurrence-free survival was observed in patients with angiodysplasia (log-rank test, P = .02), and especially when lesions were located in the small bowel (log-rank test, P < .01), even after endoscopic treatment with argon plasma coagulation (log-rank test, P < .01).
VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse.
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