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P. Nurden et al.
threatening infections. There is mild bleeding with a partial to severe reduction of dense granules.67,69,74 It is a rare but fatal autosomal recessive disorder with multiple clinical features, including hypopigmentation of skin and hair, reduction of leukocytes, giant organelles in circulating granulated cells, and neurological dysfunction. Recurrent infections are associated with defective function of natural killer cells. Immune dysregulation often leads to lympho- proliferative histiocytosis with an accelerated phase that determines the prognosis.73 Platelet function defects resem- ble those seen in HPS. The LYST gene (also called CHS1) alone is responsible for this disease and a wide variety of mutations have been described.67,69,74 Chediak-Higashi syn- drome is particularly prevalent in Puerto Rico.67,69 LYST is a member of the BEACH protein family and is required for sorting resident endosomal proteins into late multivesicu- lar endosomes (Figure 4B).71,74
Other defects involving platelet granules
As well as the above disorders, qualitative defects can lead to decreased dense granule content, inability to secrete their contents or combined dense- and α-granule
deficiency.71,75,76 An absent second wave of aggregation in response to ADP and collagen is characteristic. This can be secondary to mutations of genes for membrane recep- tors: P2RY12, GP6, TBXA2R, EPHB2, G6b-B; or genetic defects often accompanied by thrombocytopenia (Online Supplementary Table S1).11 Applying next-generation sequencing procedures targeting 329 preselected genes, Leo et al. analyzed 18 patients including six with secretion defects, highlighting 49 genes not previously known to be causal of IPD.77 Gorski et al. performed a similar study using whole exome sequencing of 14 patients with bleed- ing caused by primary platelet secretion defects.78 Both studies exposed the complications of whole exome sequencing and next-generation sequencing when isolat- ed gene variants are identified as potentially causal with- out statistical validation or comprehensive biological studies or usage of mouse models.
A specific condition with defective granule secretion from platelets is familial hemophagocytic lymphohistio- cytosis, a rare primary immunodeficiency syndrome in which autosomal recessively inherited variants of UNC13D, STX11 and STYXBP2 can result in defects in the secretory machinery of dense bodies and α-granules as well as lysosomes.79-82
Figure 5. Schema with management options for patients with inherited defects of platelet function. It is important to limit risks in daily life. It is also important to provide each patient with a card detailing the type of disorder and proposing the medication to be used according to the bleeding risk, in particular when platelet expert medical centers are unavailable to take charge of the patient’s needs. While the main therapeutic approaches for all disorders, including those patients with Glanzmann thrombasthenia (GT), RASGRP2 (CalDAG-GEFI)-related disease, and leukocyte adhesion deficiency III (LAD-III) syndrome for whom bleeding can be severe, are similar, some situations (e.g., isoantibody formation in GT) or infections in LAD-III syndrome need special care. Surgery requires a multidisciplinary consensus to evaluate the risk of bleeding, the benefit-risk ratio of prophylaxis, and to assess therapeutic efficiency. Pregnancy is always a challenge, from women with mild bleed- ing risks for whom minimal measures are needed to those with a severe bleeding history and for whom maximal prophylactic care is required. Here again, the man- agement must be planned between obstetricians, anesthetists and hematologists. The contraindication of epidural or spinal anesthesia for those with mild risk remains a difficult problem, as is the choice of vaginal delivery or Cesarean section for the most severe forms. In the figure, it is noted that for mild bleeding risk, an antifibrinolytic medication or desmopressin is preferred as the first line of bleeding prevention and that platelet transfusions should be considered only when these approaches are insufficient. There is a risk of allo- or iso-immunization which, if it occurs, can be a lifelong handicap, and recombinant activated factor VII is increas- ingly recommended. Finally, stem cell transplantation is reserved for young patients with recurrent, severe bleeding that fails to respond to standard treatments and when the survival of the patient is at risk. Gene therapy is not yet an option for the disorders covered in this review but will probably become available in the future.
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haematologica | 2021; 106(2)