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Grey platelet syndrome (GPS) is a rare congenital genetic disease that affect the blood platelets as an autosomal recessive disorder and affect males and females equally. GPS is caused by the lack of alpha granules and the proteins stored inside the granules. The platelets are descended from the megakaryocyte lineage, which means platelets are formed by fragmentation of the megakaryocyte into a thousand platelets upon maturation. In GPS, proteins from alpha granules are released into the bone marrow before megakaryocyte maturation and causes bone marrow fibrosis. Without alpha granule, the haemostatic proteins are not released at the site of injury and platelets cannot stick to the blood vessel wall to clump together and repair the injured vessel. This contribute to the bleeding tendency that GPS patients experience. Overall, the prognosis is good and although few cases of patients have severe hemorrhage, no fatal cases have been reported. Most patients have a mild reticular fibrosis in the bone marrow, but it does not appear to be progressive or to induce anaemia.

Alpha granules

Alpha granules are the most abundant vesicles in platelets, and store proteins that promote platelet adhesiveness and wound healing when secreted during platelet activation. The basic defect in gray platelet syndrome is thought to be the inability of megakaryocytes to pack endogenously synthesized secretory proteins into developing α-granules. The number of megakaryocytes in the bone marrow is normal, but platelet survival is reduced. The shortened survival of α-granule-deficient platelets and the inability of defective megakaryocytes to mature normally to make healthy platelets are thought to contribute to the thrombocytopenia of GPS.

Symptoms

Gray platelet syndrome exhibit heterogeneity and have variable bleeding severity and varying response to platelet function testing. Typically patients have mild thrombocytopenia, which may cause easy bruising or slow clotting time, reduced platelet count, and myelofibrosis. Myelofibrosis progresses in GPS, and severity increased with age. Premature release of platelet-derived growth factor and other profibrotic substances from the megakaryocytes into the bone marrow is thought to cause the myelofibrosis in GPS.

Diagnosis

In Gray platelet syndrome there is a deficiency of α-granules. In contrast to other known platelet granule abnormalities, such as Hermansky-Pudlak syndrome and Chédiak-Higashi syndrome, the dense granules in patients with gray platelet syndrome remained unaffected. The diagnosis can be confirmed by analysis of alpha-granule proteins, using Western blot or immunological methods. Using electron microscopy to show the absence of alpha-granules is considered the gold standard of GPS diagnosis, but it’s not widely available.

Management

Due to the bleeding tendencies, patients should anticipate risks and prevent bleeding by avoiding drugs which impair platelet function, especially aspirin. Desmopressin is a drug option- it is a synthetic analogue of vasopressin, which improves bleeding time and clotting.

Genetics

After haplotype and pedigree analysis, gray platelet syndrome is categorized as an autosomal recessive conditionGPS is primarily inherited in an autosomal recessive manner, and the gene that is mutated in GPS has recently been mapped to chromosome 3p[3] and identified as NBEAL2.[4] NBEAL2 encodes a protein containing a BEACH domain that is predicted to be involved in vesicular trafficking.. Consanguineous families have a higher chance of having affected individuals than the general population.

The genetic cause of gray platelet syndrome have been mapped to the NBEAL2 gene at the chromosome location 3p21.31 . NBEAL2 is a protein coding gene that plays a role in megakaryocyte alpha-granule biogenesis, and belongs to a family of proteins involved in membrane dynamics and intracellular vesicle trafficking . Biallelic mutations in the NBEAL2 gene is the cause of GPS, and the mutations can be missense, nonsense, frameshift, or splice site mutations.