Case#: 40 yo, Female, W. Turkey

DiseaseAssertion: Glanzmann Thrombasthenia

FamilyInfo: Consanguineous (cousins).

ParentalGenotype: Both carriers.

CasePresentingHPOs: (HP:0007420) Spontaneous hematomas, (HP:0001892) Abnormal bleeding, (HP:0100608) Metrorrhagia, (HP:0001935) Microcytic anemia, (HP:0034263) Abnormal vaginal bleeding, (HP:0004944) Cerebral aneurysm,

PlateletAggregation: Hypochromic anemia and a platelet count of 198 × 109/L (normal range 150–400 × 109/L). Platelet aggregometry showed no aggregation after stimulation with collagen (2 and 10 µg/mL), ADP (4 and 10 µmol/L), and epinephrine (8 µmol/L) (norm > 70%), and reduced (42%, Norm > 70%) agglutination after stimulation with ristocetin (1.2 mg/mL).

CaseHPOFreeText: Received platelet concentrates multiple times as a young adult before dental surgery. Pregnancy, alloantibodies to glycoprotein αIIbβ3 were detected in the patient’s blood. emergency caesarean section was performed in another hospital. Because the patient developed severe bleeding problems, she received two red cell units, two pooled platelet concentrates, tranexamic acid, and desmopressin intraoperatively. Two drainages were placed. Three platelet concentrates were transfused in the following days, resulting in a first-time transfusion reaction. Emergency cesarean- endometrial coagulation, operative hysteroscopy.

ProteinExpression: Flow cytometry showed the absence of expression of CD41 (integrin αIIbβ3) and severely impaired fibrinogen binding after ADP activation

CasePreviousTesting: molecular genetic analysis was performed using a custom gene panel for inherited platelet disorders (Nextera Rapid Custom Enrichment, Illumina, San Diego, CA, USA) established in our department, followed by sequencing on a MiSeq (Illumina)

Gene: ITGA2B

HGVS: 6138

ClinVar: Unregistered

CAID: CA2261369696

gnomAD: Absent

Gene: ITGA2B

HGVS: 6138

ClinVar: Unregistered

CAID: CA2261369696

gnomAD: Absent

Case#: 13 yo, Female

DiseaseAssertion: GT

FamilyInfo:

CasePresentingHPOs: (HP:0002249) Melena; (HP:0002248) Hematemesis

PlateletAggregation: Prothrombin time: 20, Partial thromboplastin time: 28, Platelet function analyzer-100: >300

CaseHPOFreeText: gastric and jejunum angiodysplasia

ProteinExpression: Flow cytometry: CD41 and 61 <50%

CasePreviousTesting: Molecular sequencing, Patients’ information was obtained from the medical record system of the Madinah Hereditary Blood Disorders Center, Maternity and Children Hospital, King Fahd Hospital, Al Madinah, Saudi Arabia.

Gene: ITGB3

HGVS: NM_000212.3:c.2111_2112del

ClinVar:

CAID: CA3062865178

gnomAD:

Case#: 11 yo, Female

DiseaseAssertion: GT

FamilyInfo: No family hx. No pedigree.

CasePresentingHPOs: (HP:0002249) Melena; (HP:0000421) Epistaxis; (HP:0000225) Gingival bleeding; (HP:0100769) Synovitis; (HP:0005261) Joint hemorrhage, right ankle; (HP:0001891) Iron deficiency anemia;

PlateletAggregation: Prothrombin time: 11, Partial thromboplastin time: 26, Platelet function analyzer-100: >300

CaseHPOFreeText: stable intestinal angiodysplasia

ProteinExpression: Flow cytometry: CD41 and 61 <50%

CasePreviousTesting: Molecular sequencing, Patients’ information was obtained from the medical record system of the Madinah Hereditary Blood Disorders Center, Maternity and Children Hospital, King Fahd Hospital, Al Madinah, Saudi Arabia.

Gene: ITGB3

HGVS: NM_000212.3:c.2111_2112del

ClinVar:

CAID: CA3062865178

gnomAD:

Case#: 4 mo, Female

DiseaseAssertion: GT

CasePresentingHPOs: (HP:0001892) Abnormal bleeding; (HP:0000978) Bruising susceptibility

PlateletAggregation: Severe platelet refractoriness. Pretransplant evaluation revealed normal platelet count. Day +9, the patient had undetectable platelet count. Bleeding-control strategies included the use of thrombopoietin receptor agonist, romiplostim, and low-rate continuous platelet transfusion. Imlifidase was well tolerated with no side effects.

CaseHPOFreeText: Escherichia coli bacteremia.

ProteinExpression: Platelet GP expression testing confirmed the absence of platelet GPIIb/IIIa expression. Day +12 confirmed the presence of anti-GPIIb/IIIa antibodies among others.

Gene: ITGB3

HGVS: NM_000212.3:c.1788del

ClinVar:

CAID: CA2262611500

gnomAD: 0 https://gnomad.broadinstitute.org/variant/chr17-47299404-GC-G?dataset=gnomad_r4

Case#: Female, 29 yo

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Figure 2 Father and brother, unaffected carriers. Mother, unaffected negative. Sister, affected: Epistaxis, Cutaneous bleeding, Menorrhagia, Hematuria, Postpartum bleeding, Other bleeding symptoms (Ruptured corpus luteum bleeding)

ParentalGenotype: Father carrier, unaffected. Mother negative, unaffected.

CasePresentingHPOs: HP:0000421, Epistaxis. HP:0000132, Menorrhagia. HP:0000790, Hematuria. HP:0003540, Impaired platelet aggregation. HP:0001892, Abnormal bleeding. HP:0003010, Prolonged bleeding time. HP:0034263, Abnormal vaginal bleeding.

PlateletAggregation: Normal platelet morphology, count 159 (125-350), MPV 10.6 fL (6.5-12.0), and PDW 12% (19-17). Decreased platelet aggregation: ADP 29.7& (30-70), Collagen 14.5% (30-70), AA 14.5% (40-80). Normal response to ristocetin, 88.7% (40-80). Thromboelastography (TEG) examination: hypocoagulable.

CaseHPOFreeText: Cutaneous bleeding, Postpartum bleeding, Blood accumulation in the uterine cavity, Bleeding in ovaries, Vaginal bleeding during pregnancy,

CaseNotHPOs: HP:0011875, Abnormal platelet morphology. HP:0011873, Abnormal platelet count.

ProteinExpression: Protein structure model: destroyed local beta folding structure and molecular changes to structure of GPII beta helical region reduces the expression of GP IIb/IIIa. Proband refused further testing (flow cytometry).

Gene: ITGA2B

Variant: c.2822G>A, p. (Trp941Ter)

HGVS: NM_000419.5:c.2822G>A

ClinVar: absent

CAID: CA399791662

gnomAD: 0.00 https://gnomad.broadinstitute.org/variant/chr17-44375017-C-T?dataset=gnomad_r4