Synonyms: GPS, gray platelet syndrome, platelet alpha-granule deficiency

Grey platelet syndrome (GPS) is a rare, congenital disorder which causes a bleeding disorder. The platelets are large and have a grey appearance on light microscopy.¹ It is one of the macrothrombocytopenias, which are inherited thrombocytopenias with increased platelet size.²

Epidemiology and inheritance

• Grey platelet syndrome (GPS) is extremely rare. About 50 cases so far have been reported.²
• The pattern of inheritance may be autosomal dominant or recessive. A possible X-linked inheritance pattern has also been reported. ³

Pathology^2,3,4

• Grey platelet syndrome (GPS) is probably a heterogeneous disorder with more than one molecular cause.
• The underlying defect is the inability of platelets to store alpha-granule proteins. The 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.
• There may also be a neutrophil secretory defect,⁵ although the involvement of neutrophils is controversial.⁶

Presentation

• 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 grey platelet syndrome (GPS) ranges from mild to severe.²
• Spontaneous bleeding is usually mucocutaneous when there is an inherited platelet disorder.⁷

Differential diagnosis⁸

• Any cause of mild thrombocytopenia, particularly idiopathic thrombocytopenic purpura (ITP).
• There are other rare thrombocytopathies with large platelets, for example:⁹
  • 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's 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.¹⁰

Investigations

• 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 grey platelet syndrome (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
• Electron microscopy of the platelets shows absent alpha-granules, which is diagnostic of GPS.¹¹
• A diagnostic algorithm for inherited thrombocytopenias has been devised, which is suitable for use in nonspecialised centres.¹²

Management²

There is no specific treatment for grey platelet syndrome (GPS), but management of the inherited thrombocytopenias as a group involves:

• Anticipating risks and preventing bleeding:
  • Avoiding drugs which impair platelet function, especially aspirin.
  • Regular dental care to prevent gingival bleeding.
  • Oral contraceptives to reduce menorrhagia.
  • If bleeding occurs, using 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 (see below) 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 alloimmunisation.
  • Platelet transfusion may be useful preoperatively or to treat active haemorrhage.
  • If possible, HLA-matched donor platelets should be used in order to reduce alloimmunisation.
• Desmopressin:
  • This is a synthetic analogue of vasopressin, which 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.
• Newer therapies such as recombinant activated factor VIIa (rFVIIa) may have a role in some platelet disorders.¹³

Prognosis²

• 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

Document references

1. OMIM - Gray Platelet Syndrome; GPS
2. Balduini CL, Iolascon A, Savoia A; Inherited thrombocytopenias: from genes to therapy. Haematologica. 2002 Aug;87(8):860-80. [abstract]
3. Nurden AT, Nurden P; Inherited thrombocytopenias. Haematologica. 2007 Sep;92(9):1158-64.
4. Nurden AT, Nurden P; The gray platelet syndrome: clinical spectrum of the disease. Blood Rev. 2007 Jan;21(1):21-36. Epub 2006 Jan 25. [abstract]
5. Chedani H, Dupuy E, Masse JM, et al; Neutrophil secretory defect in the gray platelet syndrome: a new case. Platelets. 2006 Feb;17(1):14-9. [abstract]
6. White JG, Brunning RD; Neutrophils in the gray platelet syndrome. Platelets. 2004 Aug;15(5):333-40. [abstract]
7. Nurden P, Nurden AT; Congenital disorders associated with platelet dysfunctions. Thromb Haemost. 2008 Feb;99(2):253-63. [abstract]
8. Salles II, Feys HB, Iserbyt BF, et al; Inherited traits affecting platelet function. Blood Rev. 2008 May;22(3):155-72. Epub 2008 Jan 3. [abstract]
9. Drachman JG; Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood. 2004 Jan 15;103(2):390-8. Epub 2003 Sep 22. [abstract]
10. Cockbill SR, Burmester HB, Heptinstall S; Pseudo grey platelet syndrome--grey platelets due to degranulation in blood collected into EDTA. Eur J Haematol. 1988 Oct;41(4):326-33. [abstract]
11. Laskey AL, Tobias JD; Anesthetic implications of the grey platelet syndrome. Can J Anaesth. 2000 Dec;47(12):1224-9. [abstract]
12. Noris P, Pecci A, Di Bari F, et al; Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients. Haematologica. 2004 Oct;89(10):1219-25. [abstract]
13. Mannucci PM; Prophylaxis in congenital coagulation disorders: past, present and future. Blood Transfus. 2008 Sep;6 Suppl 2:s1-3.

Internet and further reading

• Clauser S, Cramer-Borde E; Role of platelet electron microscopy in the diagnosis of platelet disorders. Semin Thromb Hemost. 2009 Mar;35(2):213-23. Epub 2009 Apr 30. [abstract]
• Nurden AT, Fiore M, Pillois X, et al; Genetic testing in the diagnostic evaluation of inherited platelet disorders. Semin Thromb Hemost. 2009 Mar;35(2):204-12. Epub 2009 Apr 30. [abstract]

Acknowledgements