Articles & Papers

Inherited platelet disorders cumulatively affect roughly 1:20,000 people worldwide. Glanzmann Thrombasthenia (GT) is among these due to defects in genes encoding integrin αIIbβ3 subunits that prevent platelet aggregation, leading to recurrent mucocutaneous bleeding episodes and increased risk of morbidity and mortality from gastrointestinal or intercranial hemorrhage. GT is commonly treated with platelet transfusion, although patients often experience immune-mediated destruction of donor platelets. Antifibrinolytic agents and rFVIIa are also used to treat uncontrolled bleeding but require frequent administration. Allogeneic bone marrow transplant (BMT) has been shown to correct the GT phenotype; however, BMT can cause graft vs host disease and excludes patients without a BMT match. Thus, an effective long-term treatment to control bleeding in human GT is essential.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by a deficiency of the platelet integrin alpha IIb beta3, which is essential for platelet aggregation and hemostasis. This deficiency disrupts normal clot formation, leading to recurrent mucocutaneous bleeding episodes. The condition is associated with mutations in the ITGA2B or ITGB3 genes on chromosome 17, with these genetic changes altering the function or expression of the integrin. GT’s prevalence is approximately 1 in 1,000,000, but it is significantly higher in populations with high rates of consanguinity.

Diagnosing GT involves ruling out more common bleeding disorders through a comprehensive approach, including a complete blood count, coagulation studies, and von Willebrand factor assays. Definitive diagnosis requires advanced platelet function tests and genetic analysis. Treatment follows a tiered strategy: mild bleeding episodes are managed with local hemostatic measures, whereas severe bleeding may require platelet transfusions or recombinant activated clotting factor VIIa (rFVIIa).

Consanguineous marriages increase the risk of autosomal recessive disorders like GT because related couples are more likely to share and transmit the same gene variants. Research indicates that congenital anomalies are nearly twice as common among offspring of consanguineous unions. In populations with prevalent inbreeding, ancestral gene variants significantly influence the occurrence of these disorders. This case illustrates the impact of consanguinity, given that our patient exhibited symptoms such as bruising and gum bleeding shortly after birth rather than the typical presentation within the first year.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder affecting the megakaryocyte lineage and is associated mainly with mucocutaneous bleeding. We herein report a woman in her early 40s, with no known comorbidities, who presented with severe gingival bleeding and severe fatigue. Past history revealed recurrent gingival bleeding, bruising, and heavy menstrual bleeding. Platelet aggregation studies revealed normal aggregation. Finally, a diagnosis of GT with microcytic hypochromic anemia was established after ruling out all the other differential diagnoses. The patient was transfused with multiple units of packed cells (PCs), random donor platelets (RDPs), and single donor platelets (SDPs) and treated with intravenous (IV) and topical tranexamic acid. Our patient presented with a rare bleeding disorder very late in life. GT can be potentially life-threatening and is difficult to diagnose in the early stages. Therefore, it is imperative to highlight the importance of early diagnosis of this rare condition to provide supportive care for a good prognosis.

Glanzmann thrombasthenia (GT) is an uncommon bleeding disorder that causes bleeding under the skin. Issues with platelet membrane glycoprotein IIb/IIIa are the cause of it, which makes it simpler for platelets to adhere to one another and form a thrombus. Symptoms can range from mild bruising to severe hemorrhages. Dental management of children with GT was complex, necessitating a multi-disciplinary approach in a hospital setting. The case report aimed to document a GT case involving a seven-year-old Saudi girl under general anesthesia treatment.

Glanzmann thrombasthenia (GT) is a rare inherited platelet bleeding disorder caused by a quantitative and/or qualitative defect of the αIIbβ3 integrin. Pregnancy and delivery pose special challenges as they entail increased risks of both maternal and foetal bleeding that may be life-threatening. Multidisciplinary management throughout the preconception, intrapartum and peripartum periods is vital to optimize pregnancy outcomes. This Nutshell review focuses on the challenging management of pregnancy and childbirth in patients with GT.

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.