Thrombocytopathy

Thrombocytopathy is an abnormality of platelets. It may be congenital or acquired. It may result in 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/IIa 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 (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

Causes of low of or defective platelets are many and the following is by no means exhaustive:

Idiopathic Thrombocytopenia Purpura (ITP)

This is one of the commonest 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. 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.

Alloimmune Thrombocytopenia

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

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.

Drug Induced Thrombocytopenia Purpura³

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:

• Quinidine
• Amiodarone
• Gold
• Captopril
• Sulphonamides
• Glibenclamide
• Carbamazepine
• Ibuprofen
• Cimetidine
• Tamoxifen
• Ranitidine
• Phenytoin
• Vancomycin
• Interferon
• Thiazides
• Cytotoxic drugs
• Heparin⁴

Alcohol can also inhibit the marrow from producing platelets.

Thrombotic Thrombocytopenia 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 von Willebrand factor (a multimer is a term used to describe a group of linked polypeptide chains).

Haemolytic Uraemic Syndrome

This usually follow infection with E.coli O157. Toxins lead to destruction of erythrocytes and platelets with thrombosis in the microcirculation leading to acute renal failure.

von Willebrand's Disease

This is inherited as an autosomal dominant condition. There is deficient or defective production of von Willebrand factor. 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

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.⁵

Glanzmann's Thrombasthenia

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 Glanzmann's thrombasthenia and Bernard-Soulier disease respond to platelet transfusion but this should be reserved for severe problems as alloantibodies may form.⁶

Gray Platelet Syndrome

This is a rare autosomal recessive disorder with large platelets that appear grey. It is also called platelet alpha granule deficiency.⁷

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 von Willebrand disease and is often made worse when a non-steroidal anti-inflammatory is given to treat dysmenorrhea
• Post-partum 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 idiopathic thrombocytopenia purpura and in Bernard-Soulier disease they may be as large as erythrocytes. In thrombotic thrombocytopenia purpura platelet 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 (1mm deep and 1cm 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.

This depends on the underlying disease. A few examples are given here.

Acute ITP in Children

This does not normally require treatment as it is usually mild and self-limiting. If the platelet count falls below 20,000/μl however, treatment may be required to prevent intracranial or other internal bleeding. Treatment options include intravenous immunoglobulin G (IgG) and oral or intravenous prednisolone. If imminent haemorrhage is suspected, IgG and prednisolone may be given simultaneously.

Chronic ITP in Adults

There is no consensus, but most haematologists treat this condition when the platelet count falls below 50,000μL or bleeding manifestations are present. Treatment options include intravenous IgG, oral or intravenous steroids, and high-dose dexamethasone. Resistant cases may require splenectomy.Post-splenectomy resistant cases sometimes respond to chemotherapeutic agents such as cyclophosphamide, or immune modulators such as rituximab.

TTP

This is a medical emergency which requires immediate plasma exchange. Milder cases may respond to steroids, but antiplatelet drugs have not been found to be helpful.

von Willebrand Disease

The usual treatment of type I disease is to prime the patient with desmopressin acetate (DDVAP) which stimulates the release of vWf from endothelial cells prior to minor or dental surgery. It is infused 30 minutes before the procedure. A nasal spray is also becoming available. For type II and type III disease, and for more extensive surgery, the treatment is vWf concentrates.