Articles & Papers

This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbβ3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report β3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sβ3 substitution within the βI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153β3. F153 is completely conserved among β3 of several species and all human β-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sβ3 also displays reduced levels of a constitutively activated αIIb-S153β3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153β3 is critical for maintaining the resting conformation of α2- and α1-helices of the βI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the βI-domain toward the constitutively active αIIbβ3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbβ3 activation. The data collectively demonstrate that disruption of F153β3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153β3 may be compensated by a hyperactive conformation that promotes viable hemostasis.

While selective serotonin reuptake inhibitors (SSRIs) remain the most commonly prescribed class of antidepressants, many physicians and patients express concerns about the risks of bleeding associated with these medications. It is thought that this risk is due to reduction in platelets’ serotonin, which impairs their role in clotting (Anglin et al. 2014). There is also evidence that SSRI use increases gastric acidity, promoting gastritis and peptic ulcers and associated gastrointestinal (GI) bleeding (Andrade and Sharma 2016).

Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are widely used for the treatment of depression and anxious disorders. The observation that depression is an independent risk factor for cardiovascular mortality and morbidity in patients with ischemic heart disease, the assessment of the central role of serotonin in pathophysiological mechanisms of depression, and reports of cases of abnormal bleeding associated with antidepressant therapy have led to investigations of the influence of antidepressants on hemostasis markers. In this review, we summarize data regarding modifications of these markers, drawn from clinical studies and case reports. We observed an association between the type of antidepressant drug and the number of abnormal bleeding case reports, with or without modifications of hemostasis markers. Drugs with the highest degree of serotonin reuptake inhibition – fluoxetine, paroxetine, and sertraline – are more frequently associated with abnormal bleeding and modifications of hemostasis markers. The most frequent hemostatic abnormalities are decreased platelet aggregability and activity, and prolongation of bleeding time. Patients with a history of coagulation disorders, especially suspected or documented thrombocytopenia or platelet disorder, should be monitored in case of prescription of any serotonin reuptake inhibitor (SRI). Platelet dysfunction, coagulation disorder, and von Willebrand disease should be sought in any case of abnormal bleeding occurring during treatment with an SRI. Also, a non-SSRI antidepressant should be favored over an SSRI or an SRI in such a context. Considering the difficulty in performing platelet aggregation tests, which are the most sensitive in SRI-associated bleeding, and the low sensitivity of hemostasis tests when performed in case of uncomplicated bleeding in the general population, establishing guidelines for the assessment of SRI-associated bleeding complications remains a challenge.

Eduard Glanzmann was a Swiss pediatrician who in 1918 reported an inherited platelet functional disorder associated with a defective clot retraction. The clinical phenotype of this autosomal recessive bleeding disorder, later known as Glanzmann thrombasthenia (GT), was largely defined in the 1960s with major contributions from Jacques Caen in Paris and Marjorie Zucker in New York. My involvement in platelet research began in Oxford in 1968. Our project at that time was to define the components of the platelet “glycocalyx”, a carbohydrate-rich layer first highlighted on platelets by an electron microscopes, Olaf Behnke, in Copenhagen. I applied cytochemical techniques to identify negatively charged elements digested from this surface layer and separated by polyacrylamide gel electrophoresis (PAGE). Use of the detergent sodium dodecyl sulfate (SDS) and SDS-PAGE soon enabled the separation of the major intrinsic membrane glycoproteins (GP). Teams led by Ralph Nachman (New York) and David Phillips (Memphis) highlighted three major bands termed GPI (a sialic acid rich GP), GPII and GPIII. I continued my research in London and identified these GP in a range of mammals. However, I quickly realized that inherited platelet disorders held the key to identifying their function.

Glanzmann’s thrombasthenia (GT) and congenital factor VII deficiency (FVII CD) are rare autosomal recessive bleeding disorders: GT is the most frequent congenital platelet function disorder, and FVII CD is the most common factor-deficiency disease after haemophilia. The frequency of these disorders in the general population ranges from 1:500,000 to 1:2,000,000. Because GT and FVII CD are both rare, registries are the only approach possible to allow the collection and analysis of sufficient observational data. Recombinant activated factor VII (rFVIIa, eptacog alfa activated) is indicated for the treatment of acute bleeding episodes and for surgery coverage in patients with GT who are refractory to platelets and have antiplatelet or anti-human leukocyte antigen (HLA) antibodies, and for the prevention and treatment of bleeding in patients with FVII CD. This article summarises published data on the mechanism of action and use of rFVIIa in these disorders from two international, prospective, observational registries: the Glanzmann’s Thrombasthenia Registry (GTR) for GT; and the Seven Treatment Evaluation Registry (STER) for FVII CD. Haemostatic effectiveness rates with rFVIIa were high across all patients with GT and those with FVII CD, and treatment with rFVIIa in the GTR and STER registries was well tolerated. The GTR and the STER are the largest collections of data in GT and FVII CD, respectively, and have expanded our knowledge of the management of these two rare bleeding disorders.

Eptacog alfa (activated) is a recombinant activated factor VII (rFVIIa) used for the treatment and prevention of bleeding episodes in patients with congenital hemophilia with inhibitors. Frequent dosing requirements make the use of an automated bolus infusion pump a promising alternative to manual administration.

Glanzmann’s thrombasthenia is a rare clotting disorder caused by impaired platelet function. Lack of awareness of the appropriate management of rare medical conditions may lead to patient dissatisfaction and potentially poor treatment outcome. Case Report. A 78-year-old male with a history of Glanzmann’s thrombasthenia was admitted to the trauma service following a fall in which he sustained a facial laceration as well as maxillary sinus and nasal fractures. He received DDAVP 20 mcg and tranexamic acid upon presentation to the emergency department (ED). In the ED, the patient requested administration of platelet transfusion but was refused due to a normal platelet count. During the course of his hospital stay, he complained of epistaxis and was noted to have a downtrending hemoglobin from 11.0 g/dl to 9.0 g/dl. The patient and his family were not comfortable when the discharge plan was finalized and demanded platelet transfusion (due to history of needing platelets in association with injuries or procedures in the past) was refused by the primary team as they continued to state that his platelet count is normal. On hospital day 3, hematology was consulted as the patient and his family were extremely angry and hematology recommended platelet transfusion. Further clinical information was not available as the patient was transferred to another facility per family request as they wanted to be at a center which had the patient’s primary hematologist. Discussion. A delay in specialist consultation resulted in patient dissatisfaction and extended the length of stay. Patients with rare medical conditions and potential for major complications should be managed aggressively with appropriate specialist consultation to promote patient satisfaction and improve the overall quality of care. This case shows that as physicians it our duty to listen to our patient’s concerns and involve them in the medical decision-making to provide optimal patient-centered care.

Whether you are newly diagnosed with Glanzmann’s Thrombasthenia (GT) or have been diagnosed for some time, it is common to go through many ups and downs. We want to share information that you should know and some resources about this condition that can help you on your path to improved health and quality of life. When you are first given a new diagnosis, one as rare as GT, it is understandable to have many emotions or feel overwhelmed. The good thing is that you’re not alone. There are other people who have the same condition and lead full lives. They have had their lives enriched by becoming closer to other people who are traveling on a similar path. With the care of an experienced team, you will find support from your health care providers as well as from the vibrant and caring bleeding disorders community. You can be involved in this community and build meaningful relationships with your new extended family.

Glanzmann thrombasthenia (GT) is a rare bleeding disorder (~1:1,000,000) caused by impaired function of platelet glycoprotein IIb/IIIa responsible for aggregation. This novel survey was designed to identify the burden of GT through better understanding of the management of the disorder and its psychosocial impact on patients and caregivers.