Concomitant Platelet Glycoprotein II-b/III-a and IV Deficiencies: Management Challenge - a Case Illustration

Immune-mediated platelet (PLT) refractoriness constitutes 10-25% of PLT refractoriness cases. It is primarily driven by antibodies to Human Leucocyte Antigens (HLA) class I, human platelet antigens, ABO, and drug-dependent antibodies (Cohn CS. 2020). In patients requiring frequent PLT transfusions due to chronic thrombocytopenia or hereditary PLT disorders, immune-mediated PLT refractoriness presents a significant challenge.

Glanzmann thrombasthenia (GT), is a rare hereditary PLT disorder, characterized by absent/decreased clot retraction, prolonged bleeding time, with normal PLT count and size. Mutations in ITGA2B or ITGB3 genes (Sosnoski DM, et al. 1988), gives rise to quantitative or qualitative defects in PLT glycoprotein (GP) IIb/IIIa (also known as αIIbβ3 and CD41/61), impairing PLT aggregation (Patel D, et al. 2003). GT presents as frequent mucocutaneous bleeding and severe, particularly post-surgical hemorrhage (Botero JP, et al. 2020). PLT transfusion together with recombinant Factor (rF) VIIa are the mainstays of treatment; however, PLT alloimmunization remains a critical challenge. Among 498 GT patients from 6 patient series and one registry, 29.7% had PLT antibodies, 23.1% to αIIbβ3 (with/without HLA antibodies) and 6.6% to HLA alone or other antibodies (Poon MC, d'Oiron R. 2018).

Glycoprotein IV (CD36), expressed on various cells including platelets and monocytes, plays roles in lipid metabolism, PLT adhesion to collagen, thrombus formation, and uptake of pathogen/apoptotic cells (malaria-infected cells). GP IV deficiency is uncommon but more prevalent (1-7%) in Asian, sub-Saharan African and Arab ethnicities (Schmidt AE, et al. 2020). While GP IV deficiency is not associated with a bleeding diathesis, affected individuals are at risk of forming anti-CD36 antibodies, immune-mediated thrombocytopenia and PLT refractoriness (Bierling P, et al. 1995). The following case illustrates the diagnosis of GT in conjunction with CD36 deficiency, and the management of surgery in the presence of anti-CD36 antibodies.

A 62-year-old Egyptian male, with a lifelong mucocutaneous bleeding was evaluated at the center for Bleeding and Clotting Disorders in San Diego prior to extensive dental surgery. Historic records were scarce. He had an incompletely characterized bleeding disorder complicated by anemia requiring several transfusions, patient-reported thrombocytopenia, and a splenectomy in his early 20s. Laboratory workup revealed mild normocytic anemia and normal PLT count. PLT aggregometry was consistent with GT. Diagnosis of GT was confirmed by the absence of PLT GP IIb/IIIa expression and the detection of pathogenic variants (c.2148dupG and c.1234G>A) in ITGA2B gene. Antibody screening revealed no antibodies against GP IIb/IIIa or HLA antigens but surprisingly demonstrated anti-CD36 IgG antibodies, indicating GP IV deficiency. The diagnosis was confirmed by absent CD36-specific monoclonal antibody binding to platelets and monocytes, consistent with Type I GP IV deficiency. CD36 gene sequencing revealed the following mutations (c.660_664del, p.Asn220Lysfs*2 and c.1079T>G, p.Leu360*).

The proposed treatment plan included PLT transfusion, administration of rFVIIa and tranexamic acid. To prevent PLT transfusion refractoriness or rapid clearance of transfused PLTs expressing GP IV, the transfusion medicine service collaborated with the American Red Cross to identify CD36 negative blood donors. Three suitable donors were identified across the nation and only one donor provided 2 crossmatch-compatible PLT units. The patient had no bleeding complications.

There seems little awareness and knowledge regarding the ramifications of coexistent PLT disorders, mostly because these are stochastically rare (~1 in 5 million for the present case). However, recognizing GP IV deficiency's disproportionate impact on certain ethnicities is crucial in the context of PLT disorders. This case illustrates the importance of evaluating for PLT GP IV deficiency in life-threatening bleeding disorders, to prevent anti-CD36 antibody formation, bleeding secondary to pre-existing anti-CD36 antibodies, or complications to the fetus in pregnant patients. Routine extended phenotyping of PLT donors, although resource-intensive, would help identify rare phenotypes, enabling blood centers to readily provide the needed units, particularly in bleeding emergencies.

Curtis:Atheneum: Consultancy; Rallybio: Consultancy. von Drygalski:Hematherix LLC: Other: Co-founder; Genentech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sparx Therapeutics: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; CSL-Behring: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Regeneron: Consultancy, Honoraria; Biomarin: Consultancy, Honoraria.