Platelet Function Disorders (Thrombocytopathy)

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Thrombocytopathy is an abnormality of platelets. It may be congenital or acquired. It may cause a thrombotic or a bleeding tendency or may be part of a wider disorder such as myelodysplasia. Under normal circumstances, when the endothelial cells lining blood vessels are breached, platelets interact with von Willebrand factor (vWF) via the membrane glycoprotein 1b complex to help seal the breach. Glycoprotein IIb/Ia complex attracts other platelets, which combine to form aggregates.[1] The platelets contain granules which break down to release fibrinogen, vWF, platelet-derived growth factor adenosine 5'-diphosphate (ADP), calcium and 5-hydroxytryptamine (5-HT) - serotonin. All this helps to promote the formation of a haemostatic plug (primary haemostasis).

Activated platelets also synthesise thromboxane A2 from arachidonic acid as well as presenting negatively charged phospholipids on the outer leaflet of the platelet membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system. The total effect is therefore to stimulate the coagulation system to form a clot (secondary haemostasis).

Defects of the platelet system thus manifest themselves as primary haemostatic phenomena - eg, increased bleeding times, petechiae, purpura, rather than secondary haemostatic phenomena - eg, haemarthrosis, muscle haematomas.[2]

Causes of inherited platelet function disorders[3]

  • Severe disorders of platelet function: Wiskott-Aldrich syndrome (WAS), Glanzmann's thrombasthenia (GT), Bernard-Soulier syndrome (BSS).
  • Disorders of receptors and signal transduction: platelet cyclo-oxygenase deficiency, thromboxane synthase deficiency, thromboxane A2 receptor defect, ADP receptor defect.
  • Disorders of platelet adhesion: von Willebrand's disease (vWD).
  • Disorders of the platelet granules: idiopathic dense-granule disorder (d-storage pool disease), Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, grey platelet syndrome (GPS), Paris-Trousseau/Jacobsen syndrome.
  • Idiopathic alpha- and dense-granule storage pool disease.
  • Disorders of phospholipid exposure; Scott syndrome.

Von Willebrand's disease (vWD) - this is inherited as an autosomal dominant condition. There is deficient or defective production of vWF. This protein mediates platelet adhesion to the endothelium and protects factor VIII from degradation. There are a couple of well recognised variations. See separate article Von Willebrand's Disease.

Bernard-Soulier syndrome (BSS) - this is a deficiency of platelet glycoprotein Ib which mediates the early action of platelets on the subendothelial surface via the von Willebrand protein. It is a rare but severe bleeding disorder. The platelets are large. They may be as big as red blood cells and may be missed because most automatic counters do not count them as platelets.[4] See separate article Bernard-Soulier Syndrome.

Glanzmann's thrombasthenia (GT) - this results from a deficiency of the glycoprotein IIb/IIIa complex. Platelets fail to aggregate. The more severe type I results from a complete absence of the glycoprotein IIb/IIIa complex, while in the milder type II, some of the glycoprotein IIb/IIIa complex is retained. Both GT and BSS respond to platelet transfusion but this should be reserved for severe problems, as alloantibodies may form.[5]

Grey platelet syndrome (GPS) - this is a rare autosomal recessive disorder with large platelets that appear grey. It is also called platelet alpha granule deficiency.[6] See separate article Grey Platelet Syndrome.

Congenital disorders of thromboxane and ADP metabolism - thromboxane and ADP play an important role in haemostasis. It is this pathway that is impaired by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Congenital disorders of this pathway have been described.

Causes of acquired platelet function disorders[7] 

ITP is one of the most common autoimmune disorders. The acute self-limiting form is observed almost entirely in children (5 cases per 100,000 persons). The chronic form is seen mostly in adults (3-5 cases per 100,000 persons).[2]

History

Thrombocytopathy should be considered if there is a history of:

  • Epistaxis - particularly if excessive, frequent or prolonged.
  • Bleeding gums - spontaneous or associated with brushing or flossing.
  • Bleeding from tooth extractions.
  • Haemoptysis, haematemesis, haematuria, haematochezia (passage of bright red blood with bowel movements) and melaena - not usually seen in the initial stages, but a bleeding disorder can exacerbate them if there is any secondary pathology.
  • Metromenorrhagia - especially seen in vWD and is often made worse when an NSAID is given to treat dysmenorrhoea.
  • Postpartum haemorrhage.
  • Excessive bleeding during or after surgery - even minor (congenital bleeding disorder often presents as excessive bleeding after circumcision).
  • Bleeding after aspirin.
  • Spontaneous bruising.
  • A history of previous iron therapy for anaemia.

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Examination

  • This may reveal petechiae (<2 mm), purpura (0.2-1 cm) and ecchymoses on the skin.
  • Other abnormalities on examination may provide an indication of an underlying cause.
  • Careful and thorough history and examination, including any features associated with platelet dysfunction and any indication of the underlying cause.
  • Initial laboratory test should include FBC with differential and a blood film, prothrombin time, activated partial thromboplastin time (aPTT), renal function and TFTs.
  • In patients with a normal platelet count and no clear aetiology for the dysfunction, further evaluation for a paraprotein and acquired vWD should be performed.
  • Bleeding time, PFA-100® closure time and platelet aggregation studies are of limited value in diagnosis or assessment of treatment:
    • Bleeding time:
      • Measures the time required for bleeding to stop from a fresh superficial cut (1 mm deep and 1 cm long) made on the volar surface of the forearm, using a template under standard conditions.
      • If platelet count is normal but bleeding time prolonged this suggests a problem of platelet function.
      • The bleeding time is very dependent on operator technique, is influenced by patient variables unrelated to haemostasis, such as age, gender, haematocrit, vascular pattern, skin thickness and skin temperature, and therefore has poor reproducibility, sensitivity and specificity.[8]
    • Platelet function analyzer-100 (PFA-100®):
      • There are some automated machines like the PFA-100® that assesses platelet function under stress of shear.[8]
      • The PFA-100® may be used as a screening test, but must be interpreted with caution and in the context of the clinical background, as the test is not diagnostic or sensitive for mild platelet disorders.[8]
    • Platelet aggregation - the ability of platelets to aggregate may be assessed by exposing them to ristocetin. This induces von Willebrand protein binding to the platelet glycoprotein Ib complex, thus stimulating aggregation.
  • Specific assays of inherited platelet dysfunction include:[8] 
    • Light transmission aggregometry: evaluates the aggregation or clumping of platelets in response to aggregating stimuli.
    • Flow cytometry: should be used in the investigation or confirmation of Glanzmann's thrombasthenia (GT), Bernard-Soulier syndrome (BSS) (1B) and Scott syndrome, and may also be used to investigate abnormalities in the collagen and thrombin receptors.
    • Measurement of total and released nucleotides: provides an important additional diagnostic tool usually in conjunction with aggregometry for determining whether there is any specific deficiency in dense granule numbers or their content (eg, storage pool disease), or specific defect(s) in degranulation (eg, release defects).
    • Platelet alpha granule proteins and beta-thromboglobulin can be measured by ELISA, radioimmunoassay or Western blotting and may be helpful for the diagnosis of Quebec platelet disorder.
    • Electron microscopy is very useful for defining ultrastructural abnormalities associated with a variety of platelet defects.
    • Molecular genetic diagnosis of heritable platelet disorders may offer valuable confirmation of diagnosis in affected individuals, in family members where phenotypic testing of platelets is impractical and for antenatal diagnosis.
  • Bone marrow examination is not usually required except in those with an atypical course, a large spleen or if splenectomy is contemplated.
  • Testing for drug-dependent platelet antibodies - this is not widely available but may be useful in severe disease where the diagnosis is in doubt.[9]

Other causes of abnormal bleeding. See also separate articles Bleeding Disorders and Thrombocytopenia.

Management depends on the underlying disease of the platelet dysfunction.

Management of inherited platelet disorders[10] 

  • Platelet transfusions:
    • Frequently needed for patients with severe inherited platelet dysfunctions - eg, Glanzmann's thrombasthenia (GT) or Bernard-Soulier syndrome (BSS).
    • Usually unnecessary for mild to moderate bleeding entities - eg, storage pool disease, thromboxane A2 receptor defect, platelet transfusion.
    • Should be used selectively and sparingly because of the risk of alloimmunisation against HLA antigens and/or platelet glycoproteins. To reduce the risk, HLA-matched single donors of platelets should be used.
    • If such donors are unavailable, leukocyte-depleted blood components should be used.
  • Topical measures (compression with gauze soaked with tranexamic acid, fibrin sealants, splints for dental extractions and packing for nosebleeds).
  • Antifibrinolytic agents are useful for minor surgery and as adjuncts for other treatment modalities.
  • Desmopressin increases plasma levels of vWF and factor VIII giving rise to increased platelet adhesiveness and aggregation associated with shortened bleeding time.
  • Recombinant factor VIIa (rFVIIa). GT patients have been treated for bleeding episodes by rFVIIa with partial success.
  • Stem cell or bone marrow transplantation has been successful for several diseases and gene therapy has shown promise in treating Wiskott-Aldrich syndrome (WAS).[11]
  • Female hormones:
    • Excessive bleeding during menarche in patients with GT or BSS can be controlled by high doses of oestrogen followed by high doses of oral oestrogen-progestogen.
    • Menorrhagia later in life can be managed by continuous oral contraceptives.
    • Depo-medroxyprogesterone acetate administered every three months is an alternative when combined oral contraceptives are contra-indicated.
  • Measures to prevent bleeding include vaccination against hepatitis B, avoidance of NSAIDs, preservation of dental hygiene and correction of iron deficiency.

Management of acquired platelet disorders[7] 

  • Treatment of patients with suspected platelet dysfunction is generally specific to the underlying cause but may include desmopressin and platelet transfusion.
  • Antifibrinolytic therapy (epsilon aminocaproic acid or tranexamic acid) may be useful, especially for mucosal bleeding, but should not be used in patients with haematuria or disseminated intravascular coagulation.
  • rFVIIa has been used to treat bleeding in patients with acquired and inherited platelet disorders, but is associated with an increased risk of thrombosis.

Further reading & references

  1. Rozman P; Platelet antigens. The role of human platelet alloantigens (HPA) in blood transfusion and transplantation. Transpl Immunol. 2002 Aug;10(2-3):165-81.
  2. Thiagarajan P; Overview of Platelet Disorders, Medscape, May 2011
  3. Bolton-Maggs PH, Chalmers EA, Collins PW, et al; A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol. 2006 Dec;135(5):603-33.
  4. Bernard-Soulier Syndrome; Online Mendelian Inheritance in Man (OMIM)
  5. Glanzmann Thrombasthenia (Thrombasthenia of Glanzmann and Naegeli), Online Mendelian Inheritance in Man (OMIM)
  6. Gray Platelet Syndrome, GPS; Online Mendelian Inheritance in Man (OMIM)
  7. Konkle BA; Acquired disorders of platelet function. Hematology Am Soc Hematol Educ Program. 2011;2011:391-6.
  8. Harrison P, Mackie I, Mumford A, et al; Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol. 2011 Oct;155(1):30-44. doi: 10.1111/j.1365-2141.2011.08793.x. Epub 2011 Jul 26.
  9. Kenney B, Stack G; Drug-induced thrombocytopenia. Arch Pathol Lab Med. 2009 Feb;133(2):309-14.
  10. Seligsohn U; Treatment of inherited platelet disorders. Haemophilia. 2012 Jul;18 Suppl 4:161-5. doi: 10.1111/j.1365-2516.2012.02842.x.
  11. Nurden AT, Freson K, Seligsohn U; Inherited platelet disorders. Haemophilia. 2012 Jul;18 Suppl 4:154-60. doi: 10.1111/j.1365-2516.2012.02856.x.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Laurence Knott
Current Version:
Peer Reviewer:
Dr John Cox
Document ID:
2863 (v22)
Last Checked:
13/12/2012
Next Review:
12/12/2017