Platelet Function Disorders (Thrombocytopathy)

See related Thrombocythaemia and Thrombocytopenia articles.

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, e.g. increased bleeding times, petechiae, purpura, rather than secondary haemostatic phenomena, e.g. haemarthrosis, muscle haematomas.²

The following list is by no means exhaustive:

• Idiopathic thrombocytopenic purpura (ITP) - see separate article Idiopathic Thrombocytopenic Purpura. This is one of the most common autoimmune diseases. For unknown reasons, the body produces antibodies against platelets, resulting in thrombocytopenia. It often follows infection in children. It may start in childhood or adulthood but become chronic. It is thought that both platelet production and survival may be implicated.³ The adult form is 3 times more common in females but the childhood form has equal sex distribution. As the antibodies are IgG, they cross the placenta and can produce the condition in the infant. If there is lymphadenopathy or splenomegaly this suggests a more sinister cause for the thrombocytopenia.
• Post-transfusion thrombocytopenic purpura (PTTP) - this follows blood transfusion. Antigens on transfused platelets can lead to destruction of not just the transfused platelets but the patient's own platelets too.¹ It starts about 10 days after transfusion but can last several weeks or even several months.
• Neonatal alloimmune thrombocytopenia (NAIT) - this occurs when the mother produces antibodies against fetal platelets with paternal antigens. It is the commonest cause of severe neonatal thrombocytopenia. It often follows an apparently uneventful pregnancy but the risk of intracranial haemorrhage is high and mortality is high too. Unlike haemolytic disease of the newborn, it commonly occurs in first pregnancies.⁴
• Drug-induced thrombocytopenic purpura^5,6 - this can result from a number of mechanisms, including suppression of the marrow and acting as a hapten to induce antiplatelet antibodies. Diagnosis is difficult and often empirical, especially when the patient is taking several drugs.
  The list of drugs that can be implicated includes:
  • Amiodarone
  • Gold
  • Captopril
  • Sulphonamides
  • Glibenclamide
  • Carbamazepine
  • Ibuprofen
  • Cimetidine
  • Tamoxifen
  • Ranitidine
  • Phenytoin
  • Vancomycin
  • Interferon
  • Thiazides
  • Cytotoxic drugs
  • Heparin⁷
  Alcohol can also inhibit the marrow from producing platelets.
• Thrombotic thrombocytopenic purpura (TTP) - see separate article Thrombotic Thrombocytopenic Purpura. This is a form of thrombotic microangiopathy combining microangiopathic haemolysis and thrombocytopenia causing arteriolar occlusion by microaggregates of platelets. There are large multimers of vWF (a multimer is a term used to describe a group of linked polypeptide chains).
• Haemolytic uraemic syndrome (HUA) - see separate article Haemolytic Uraemic Syndrome. This usually follows infection with Escherichia coli O157. Toxins lead to destruction of erythrocytes and platelets with thrombosis in the microcirculation leading to acute renal failure.
• Von Willebrand's disease (vWD) - see separate article Von Willebrand's Disease. 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.
• Bernard-Soulier syndrome (BSS) - see separate article Bernard-Soulier Syndrome. This is a deficiency of platelet glycoprotein protein 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.⁸
• 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.⁹
• Gray platelet syndrome (GPS) - see separate article Gray Platelet Syndrome. This is a rare autosomal recessive disorder with large platelets that appear grey. It is also called platelet alpha granule deficiency.¹⁰
• 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 NSAIDs. Congenital disorders of this pathway have been described.
• Uraemia - this may be associated with impaired platelet function. There are a number of mechanisms that make platelets less effective in chronic renal failure.
• Haematological malignancies - these are often associated with various platelet problems. In polycythaemia rubra vera, all components of the blood are increased and the high viscosity and high platelets predispose to thrombosis. Thrombocythaemia is characterised by excessive production of platelets and the risk of thrombosis. This should not be confused with thrombophilia where clotting factors are elevated. In most other haematological malignancies and tumours that invade the bone marrow, platelet production is suppressed as they are crowded out of the marrow.

The commonest disorder, 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

Examination

• This may reveal petechiae (<2 mm), purpura (0.2-1 cm) and ecchymoses on the skin.
• Splenomegaly, haemarthrosis and deep muscle haematomas are unusual in platelet disorders and suggest an alternative diagnosis should be sought , e.g. factor deficiencies.

• Full blood count- this should be accompanied by careful examination of a blood smear. Platelets often appear large in ITP and in BSS they may be as large as erythrocytes. In TTP numbers are low but red cell fragmentation is apparent.
• Bleeding time - this is a useful test. It 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 test requires experience to perform well. It should not be done if platelets are low.
• Shear test - there are some automated machines like the platelet function analyzer 100 (PFA-100®) that assesses platelet function under stress of shear.
• 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.
• Bone marrow examination - this 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.¹¹

This depends on the underlying disease.