Gray Platelet Syndrome

Synonyms: GPS, grey platelet syndrome, platelet alpha-granule deficiency.

Gray platelet syndrome (GPS) is a rare congenital disorder, in which the platelets are large and have a grey appearance on light microscopy.¹ It is one of the macrothrombocytopaenias, which are inherited thrombocytopaenias with increased platelet size.²

GPS is extremely rare. About 50 cases so far have been reported.²
It seems to be an inherited disorder; the pattern of known cases so far suggests that autosomal dominant inheritance is usual. However, autosomal recessive patterns of inheritance or sporadic cases also occur in some families.^1,3

The underlying defect is the inability of megakaryocytes to pack secretory proteins into alpha-granules on the platelets. These abnormal alpha-granules appear grey on blood films stained by the May-Grünwald-Giesma stain, hence the syndrome's name. The platelets' haemostatic proteins are not released at the site of vascular injury, which may contribute to the bleeding tendency. The platelet count is also reduced - it is not clear why.

The secretory proteins designated for alpha-granules are eventually secreted instead into the extracellular space of the bone marrow. These proteins include growth factors, which cause myelofibrosis in the marrow. In some families, neutrophils are also affected, with a reduction in their secretory vesicles.

Symptoms are: easy bruising, nosebleeds, menorrhagia and prolonged bleeding. Often there is a family history of mild bleeding tendency, particularly following surgery or injury.¹ The bleeding tendency in GPS ranges from mild to severe.²

• Any cause of mild thrombocytopenia, particularly ITP.
• There are other rare thrombocytopathies with large platelets, for example:³
  • May-Hegglin anomaly (thrombocytopenia, giant platelets and neutrophil inclusions)
  • Bernard-Soulier syndrome
  • Montreal platelet syndrome (abnormality in platelet aggregation)
  • Fechtner syndrome (macrothrombocytopathy, nephritis, deafness)
  • Epstein syndrome (Alport's syndrome with macrothrombocytopathy)
  • Sebastian syndrome (macrothrombocytopathy and leukocyte inclusions)
  • DiGeorge syndrome
• One case of "pseudo grey platelet syndrome" was reported, in which the typical abnormalities of the syndrome were seen when blood was collected in EDTA containers, but not when citrate or heparin tubes were used.⁴

• Clotting screen - The bleeding time is prolonged.
• Blood films: platelets look pale and can be hard to detect. There is variation in platelet size (anisocytosis), even though GPS is classified under large platelet syndromes. GPS is usually suspected by the characteristic grey appearance of the platelets seen with the May-Grünwald-Giesma stained blood film.
• The diagnosis can be confirmed by analysis of alpha-granule proteins, using Western blot or immunological methods.²
• A diagnostic algorithm for inherited thrombocytopaenias has been devised, which is suitable for use in non-specialised centres.⁵

In one family, GPS was associated with Marfan syndrome.⁶

There is no specific treatment for GPS, but management of the inherited thrombocytopaenias as a group involves:

• Anticipating risks and preventing bleeding:
  • Avoid drugs which impair platelet function, especially aspirin.
  • Regular dental care to prevent gingival bleeding.
  • Oral contraceptives to reduce menorrhagia.
  • If bleeding occurs, use local measures where possible, such as nasal packing for epistaxis. Platelet transfusions may be used if necessary (but see below).
• Preparation for surgery or invasive procedures:
  • Platelet count alone is not useful; risk of bleeding is assessed by clinical history and results of platelet function testing.
  • Platelet transfusions and desmopressin may be used.
• Platelet transfusions:
  • Generally, the risk of platelet transfusion is greater than the benefit. In GPS the bleeding tendency is often mild; whereas the risks from transfusion are relatively high, especially the risk of alloimmunization.
  • Platelet transfusion may be useful preoperatively or to treat active haemorrhage.
  • If possible, HLA-matched donor platelets should be used in order to reduce alloimmunization.
• Desmopressin, a synthetic analogue of vasopressin, improves bleeding time.and clotting (its mechanism of action is unknown). Individual responses to desmopressin vary, so a test dose is advised. It should be used with caution in elderly patients with heart disease.
• Splenectomy does not seem to be helpful in GPS.

The overall prognosis is good. No fatal bleeds 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. In some families there are also neutrophil defects.¹