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Journal of Veterinary Internal Medicine 2024Glanzmann's thrombasthenia (GT) is a congenital platelet disorder affecting approximately 1:1 000 000 people globally and characterized by impaired platelet...
BACKGROUND
Glanzmann's thrombasthenia (GT) is a congenital platelet disorder affecting approximately 1:1 000 000 people globally and characterized by impaired platelet aggregation and clot retraction. Autosomal recessive, loss-of-function, variants in ITGA2B or ITGB3 of the αIIbβ3 receptor cause the disease in humans. A cat affected by Glanzmann's and macrothrombocytopenia was presented to the UC Davis VMTH.
HYPOTHESIS/OBJECTIVES
Severe thrombopathia in this cat has an underlying genetic etiology.
ANIMALS
A single affected patient, 2 age-matched clinically healthy controls, and a geriatric population (n = 20) of normal cats.
METHODS
Physical examination and clinical pathology tests were performed on the patient. Flow cytometry and platelet aggregometry analyses for patient phenotyping were performed. Patient and validation cohort gDNA samples were extracted for Sanger sequencing of a previously identified ITGA2B (c.1986delC) variant. Reverse transcriptase PCR was performed on patient and healthy control PRP samples to verify ITGA2B variant consequence.
RESULTS
A novel c.1986_1987insCC autosomal recessive variant in ITGA2B was identified. This variant was absent in a population of 194 unrelated cats spanning 44 different breeds. Complete loss of ITGA2B transcript and protein expression was verified by RT-PCR and flow cytometry, explaining the underlying etiology of GT, and likely macrothrombocytopenia, in this cat.
CONCLUSIONS AND CLINICAL IMPORTANCE
This study emphasizes the role of precision medicine in cardiovascular disease of cats and identified yet another variant that may be of utility for screening in the feline population. This study provides a small-volume, standardized, successful protocol for adequate platelet RNA isolation and subsequent molecular assessment of gene expression in cats.
Topics: Animals; Cats; Thrombasthenia; Cat Diseases; Integrin alpha2; Frameshift Mutation; Male; Female
PubMed: 38426552
DOI: 10.1111/jvim.17030 -
JPMA. the Journal of the Pakistan... Feb 2024This study presents the clinical outcomes of using inhouse prepared fibrin glue for controlling gingival bleeding in patients with inherited bleeding disorders (IBD)....
This study presents the clinical outcomes of using inhouse prepared fibrin glue for controlling gingival bleeding in patients with inherited bleeding disorders (IBD). The objective of the study was to assess the reduction in transfusion days and improvement in compliance for dental evaluation over a one-year period in a low-to-middle-income country. The quasiexperimental pilot study included 40 IBD patients with gingival bleeding. These were divided into two groups: Group A received fibrin glue (n=20), while Group B did not (n=20). The study compared outcome metrics, including the number of treatment days and blood components transfused, using non-parametric tests with a significance threshold of p<0.05. Results showed that Group A required fewer blood components (n=154) as compared to Group B (n=204) (p<0.001). Patients in Group A with Glanzmann thrombasthenia (GT) had a shorter treatment duration (one day) than those in group B (three days) (p<0.01). In conclusion, the application of fibrin glue effectively managed intractable gingival bleeding in IBD patients.
Topics: Humans; Fibrin Tissue Adhesive; Pilot Projects
PubMed: 38419241
DOI: 10.47391/JPMA.9378 -
Oxford Medical Case Reports Feb 2024Glanzmann thrombasthenia (GT) is a rare platelet disorder characterized by qualitative/quantitative deficiencies of the platelets' fibrinogen receptor, glycoprotein (GP)...
Glanzmann thrombasthenia (GT) is a rare platelet disorder characterized by qualitative/quantitative deficiencies of the platelets' fibrinogen receptor, glycoprotein (GP) IIb/IIIa complex, resulting in impaired platelet aggregation and increased bleeding time. Most cases are hereditary with an autosomal recessive pattern of inheritance, but acquired GT also occurs. We report the surgical management of symptomatic chronic subdural hematoma (CSDH), a rare condition in young individuals, in a 37-year-old man who had GT and a history of mild head trauma approximately one month before admission. Despite hematologic consultation, normal bleeding time and clotting time, and platelet transfusion before surgery, massive hemorrhage during surgery, epidural hematoma, and anisocoria in the ICU occurred that led to craniectomy. This report highlights that CSDH management in patients with GT requires close monitoring of these patients as well as collaboration between neurosurgeons, intensive care physicians, hematologists, and anesthesiologists.
PubMed: 38370496
DOI: 10.1093/omcr/omae004 -
Blood Coagulation & Fibrinolysis : An... Apr 2024As bleeding disorders are a worldwide health concern, Saudi Arabia is experiencing a notable prevalence of such disorders. Studying the frequency and cause of hemostatic... (Review)
Review
As bleeding disorders are a worldwide health concern, Saudi Arabia is experiencing a notable prevalence of such disorders. Studying the frequency and cause of hemostatic disorders is the key to successful clinical interventions and instigating effective public policies that limit the spread of such disorders. The current review aims to highlight the major findings of the body of literature that has investigated the causes, prevalence, and major challenges associated with bleeding disorders in the country. The current review summarizes the major findings of different studies that have been conducted in Saudi Arabia regarding different bleeding disorders. Multiple causes and symptoms of bleeding disorders have been reported by different studies. Some studies investigated the genetic aspect of bleeding disorders and revealed specific mutations in coagulation factor genes influencing the symptoms of different bleeding disorders. Moreover, rare bleeding disorders such as Glanzmann thrombasthenia and Henoch-Schönlein purpura, have been reported in different regions of Saudi Arabia. Combining clinical presentations, genetic factors, and epidemiological data, the current review of the literature provides a comprehensive insight into bleeding disorders in the kingdom. This will help in advancing the diagnostic capabilities and genetic counseling enhancing management strategies and therapeutic interventions benefiting bleeding disorder patients and the kingdom.
Topics: Humans; Saudi Arabia; Blood Coagulation Disorders; Thrombasthenia; Hemorrhage; Hemostatic Disorders; Prevalence; Rare Diseases
PubMed: 38358894
DOI: 10.1097/MBC.0000000000001286 -
Alternative Therapies in Health and... Jan 2024The objective of this study was to investigate the clinical phenotype and genetic etiology of Glanzmann's thrombasthenia in a consanguineous pedigree.
OBJECTIVE
The objective of this study was to investigate the clinical phenotype and genetic etiology of Glanzmann's thrombasthenia in a consanguineous pedigree.
METHODS
Clinical data and ancillary test results were collected from pedigrees with Glanzmann's thrombasthenia. High-throughput sequencing was used to detect variants in the proband. Candidate variants were verified by Sanger sequencing.
RESULTS
Two patients in the pedigree were homozygous for the c.2248C>T (p. Arg750Ter) variant of the ITGB3 gene. The parents and maternal grandmother, who didn't have any recurrent haemorrhage, were found to carry a heterozygous c.2248C>T variant of the ITGB3 gene, which was absent in the aunt and paternal grandmother.
CONCLUSION
The homozygous variant c.2248C>T (p. Arg750Ter) in the ITGB3 gene underlies the disease in this pedigree. This diagnosis will facilitate genetic counselling in this pedigree for better patient management and life guidance.
PubMed: 38294750
DOI: No ID Found -
Research and Practice in Thrombosis and... Jan 2024In hemophilia and von Willebrand disease, the degree of alteration of laboratory assays correlates with bleeding manifestations. Few studies have assessed the predictive...
Association of laboratory test results with the bleeding history in patients with inherited platelet function disorders (the Bleeding Assesment Tool - LABoratory tests substudy): communication from the Platelet Physiology ISTH-SSC.
BACKGROUND
In hemophilia and von Willebrand disease, the degree of alteration of laboratory assays correlates with bleeding manifestations. Few studies have assessed the predictive value for bleeding of laboratory assays in patients with inherited platelet function disorders (IPFDs).
OBJECTIVES
To assess whether there is an association between platelet function assay results and bleeding history, as evaluated by the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT).
METHODS
Centers participating in the international ISTH-BAT validation study were asked to provide results of the diagnostic assays employed for the patients they enrolled, and the association with the individual patients' bleeding score (BS) was assessed.
RESULTS
Sixty-eight patients with 14 different IPFDs were included. Maximal amplitude of platelet aggregation was significantly lower in patients with a pathologic BS and correlated inversely with the BS, a finding largely driven by the subgroup of patients with Glanzmann thrombasthenia and CalDAG-GEFI deficiency; after their exclusion, TRAP-induced aggregation remained significantly lower in patients with a pathologic BS. Bleeding time was significantly more prolonged in patients with a high BS than in those with a normal BS (27.1 ± 6.2 minutes vs 15.1 ± 10.6 minutes; < .01). Reduced α-granule content was significantly more common among patients with a pathologic BS than among those with a normal BS (80% vs 20%; < .05). Receiver operating characteristic curve analysis revealed a significant discriminative ability of all the aforementioned tests for pathologic BS ( < .001), also after exclusion of patients with Glanzmann thrombasthenia and CalDAG-GEFI deficiency.
CONCLUSION
This study shows that altered platelet laboratory assay results are associated with an abnormal ISTH-BAT BS in IPFD.
PubMed: 38292347
DOI: 10.1016/j.rpth.2023.102305 -
Research and Practice in Thrombosis and... Jan 2024Glanzmann thrombasthenia (GT) is a rare bleeding disorder caused by inherited defects of the platelet αβ integrin. Platelet transfusions can be followed by an immune...
characterization of rare anti-αβ isoantibodies produced by patients with Glanzmann thrombasthenia that severely block fibrinogen binding and generate procoagulant platelets via complement activation.
BACKGROUND
Glanzmann thrombasthenia (GT) is a rare bleeding disorder caused by inherited defects of the platelet αβ integrin. Platelet transfusions can be followed by an immune response that can block integrin function by interfering with fibrinogen binding.
OBJECTIVES
In this study, we aimed to determine the prevalence of such isoantibodies and better characterize their pathogenic properties.
METHODS
Twelve patients with GT were evaluated for anti-αβ isoantibodies. Sera from patients with GT with or without anti-αβ isoantibodies were then used to study their effect on platelets from healthy donors. We used several approaches (IgG purification, immunofluorescence staining, and inhibition of signaling pathways) to characterize the pathogenic properties of the anti-αβ isoantibodies.
RESULTS
Only 2 samples were able to severely block integrin function. We observed that these 2 sera caused a reduction in platelet size similar to that observed when platelets become procoagulant. Mixing healthy donor platelets with patients' sera or purified IgGs led to microvesiculation, phosphatidylserine exposure, and induction of calcium influx. This was associated with an increase in procoagulant platelets. Pore formation and calcium entry were associated with complement activation, leading to the constitution of a membrane attack complex (MAC) with enhanced complement protein C5b-9 formation. This process was inhibited by the complement 5 inhibitor eculizumab and reduced by polyvalent human immunoglobulins.
CONCLUSION
Our data suggest that complement activation induced by rare blocking anti-αβ isoantibodies may lead to the formation of a MAC with subsequent pore formation, resulting in calcium influx and procoagulant platelet phenotype.
PubMed: 38268518
DOI: 10.1016/j.rpth.2023.102253 -
Biomedicines Dec 2023Platelet lipid rafts are critical membrane domains for adhesion, aggregation, and clot retraction. Lipid rafts are isolated as a detergent-resistant membrane fraction...
Platelet lipid rafts are critical membrane domains for adhesion, aggregation, and clot retraction. Lipid rafts are isolated as a detergent-resistant membrane fraction via sucrose density gradient centrifugation. The platelet detergent-resistant membrane shifted to a higher density on the sucrose density gradient upon thrombin stimulation. The shift peaked at 1 min and returned to the control level at 60 min. During this time, platelets underwent clot retraction and spreading on a fibronectin-coated glass strip. Thrombin induced the transient tyrosine phosphorylation of several proteins in the detergent-resistant membrane raft fraction and the transient translocation of fibrin and myosin to the detergent-resistant membrane raft fraction. The level of phosphatidylserine (36:1) was increased and the level of phosphatidylserine (38:4) was decreased in the detergent-resistant membrane raft fraction via the thrombin stimulation. Furthermore, Glanzmann's thrombasthenia integrin αIIbβ3-deficient platelets underwent no detergent-resistant membrane shift to a higher density upon thrombin stimulation. As the phosphorylation of the myosin regulatory light chain on Ser19 was at a high level in Glanzmann's thrombasthenia resting platelets, thrombin caused no further phosphorylation of the myosin regulatory light chain on Ser19 or clot retraction. These observations suggest that the fibrin-integrin αIIbβ3-myosin axis and compositional change of phosphatidylserine species may be required for the platelet detergent-resistant membrane shift to a higher density upon stimulation with thrombin.
PubMed: 38255176
DOI: 10.3390/biomedicines12010069 -
Surgical Neurology International 2023Glanzmann's thrombasthenia (GT) is a rare autosomal recessive disorder characterized by impaired platelet function. Symptoms range from mild to life-threatening...
BACKGROUND
Glanzmann's thrombasthenia (GT) is a rare autosomal recessive disorder characterized by impaired platelet function. Symptoms range from mild to life-threatening bleeding. However, it is extremely rare for a patient to have intracranial bleeding. This study presents two cases of GT: one with a spontaneous epidural hematoma (EDH) and the other with a subarachnoid hemorrhage due to traumatic causes. The discussion that follows then derives relevant supporting insights through a review of the literature.
CASE DESCRIPTION
Case Report 1: A 9-year-old girl with a known case of GT presented to an emergency department with a severe headache but no other complaints or history of trauma. The physical examination was normal. Computed tomography (CT) head without contrast revealed multiple EDHs with no midline shift. She received factor VII, tranexamic acid, and platelets transfusion and was admitted to the intensive care unit to be managed conservatively. After a month, a CT head follow-up showed complete resolution of all hematomas. Case Report 2: A 20-year-old male with a known case of GT was brought to the hospital with a history of loss of consciousness for several minutes after a road traffic accident. He suffered from a headache on regaining consciousness and received analgesia. CT head showed diffuse subarachnoid hemorrhage. He was managed with factor VII, tranexamic acid, and platelets transfusion and was admitted to an intermediate care unit for close observation.
CONCLUSION
In a GT patient with intracranial hemorrhage, conservative management with close clinical observation and platelet transfusion in combination with recombinant activated factor VII and/or antifibrinolytics can be safely conducted.
PubMed: 38213436
DOI: 10.25259/SNI_680_2023 -
World Journal of Emergency Medicine 2024
PubMed: 38188552
DOI: 10.5847/wjem.j.1920-8642.2024.012