Disorders of platelet function and vascular purpuras

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

Print this page

This article have been viewed 1247 times

Disorders of platelet function and vascular purpuras

Platelet dysfunction should be considered wherever there are the clinical symptoms and signs of thrombocytopenia (p. 14) in the presence of a normal or only moderately reduced platelet count. Disorders of platelet function can be divided into inherited disorders which are rare but well characterised in the laboratory, and acquired disorders which are much more common but often of obscure aetiology. Bleeding problems may also arise in a number of inherited and acquired disorders of the vasculature and its supporting connective tissue – the vascular purpuras.

Laboratory testing of platelet function

Ideally, blood samples for testing of platelet function should be taken from fasting and resting subjects who have not smoked, ingested caffeine or drugs known to affect platelet function. A blood count and blood film are routinely performed. The bleeding time, where a small incision is made in the forearm skin and the time to cessation of bleeding recorded, is now less used as it is subjective and has poor reproducibility. A number of dedicated platelet function instruments (e.g. PFA-100) allow screening tests but the results must be interpreted with caution as they are not diagnostic or sensitive for mild platelet disorders.

Platelet aggregation studies assess the ability of platelets to aggregate in response to the addition of a variety of agonists (e.g. ADP, adrenaline (epinephrine), collagen, arachidonic acid, ristocetin). The tracings produced (Fig 35.1) require expert interpretation. The methodology remains the gold standard with the response to agonists giving characteristic patterns in inherited disorders. Other tests of platelet function include flow cytometry for the quantitation of glycoprotein receptor density, and the measurement of total and/or released adenine nucleotides. The latter tests may confirm the findings from platelet aggregation studies (e.g. in Bernard–Soulier syndrome) or reveal abnormalities where aggregation studies are normal or equivocal (e.g. in a storage pool disease or release defect).

Fig 35.1 Platelet aggregation studies.
When compared with the normal control it can be seen that in Glanzmann’s thrombasthenia there is loss of aggregation with all the agonists used.

Inherited disorders of platelet function

The commonest inherited platelet function and coagulation disorder, von Willebrand disease, is described on page 74.

Bernard–Soulier syndrome

This is a rare autosomal recessive bleeding disorder. There is a combination of platelet dysfunction, thrombocytopenia and abnormal platelet morphology. The mild thrombocytopenia is probably caused by reduced platelet survival. The functional platelet defect arises from mutation in the polypeptides of the glycoprotein (GP) Ib/IX/V complex. This complex is crucial for the initial adhesion of platelets to exposed subendothelium at high shear flow and for binding of platelets to von Willebrand factor. In platelet aggregation studies there is failure to aggregate with ristocetin. Bleeding can be severe and particularly complicates other predisposing events such as peptic ulcers and pregnancy. Patients require platelet transfusion for severe bleeding and prior to surgery. Antifibrinolytic agents and DDAVP (see p. 73) are useful in some cases.

Glanzmann’s thrombasthenia

This rare autosomal recessive disease is also caused by loss or dysfunction of a platelet glycoprotein complex – GP IIb/IIIa. This normally acts as a receptor for adhesive proteins such as fibrinogen and von Willebrand factor. Platelet numbers and morphology are normal but the platelets fail to aggregate with all agonists except ristocetin (see Fig 35.1). Clinical manifestations are variable but there is typically onset in the neonatal period and subsequent cutaneous and gastrointestinal bleeding, and menorrhagia. Platelet transfusions are indicated where local haemostatic measures fail. If there is platelet refractoriness, recombinant factor VIIa can be used.

Other disorders

Hereditary diseases of platelet function may also result from deficiency of platelet storage organelles (storage pool disorders) or release defects where there is failure to successfully release granule contents upon platelet activation. These disorders usually cause only mild bleeding problems.

Acquired disorders of platelet function

These disorders are common. Causes include foods, drugs, systemic disorders and diseases of the blood (Table 35.1).

Table 35.1

Causes of abnormal platelet function

Inherited	Bernard–Soulier syndrome
	Glanzmann’s thrombasthenia
	Storage pool disorders
	Release defects
	Other (e.g. von Willebrand disease)
Acquired	Drugs (e.g. aspirin)
	Foods (e.g. garlic)
	Chronic renal failure
	Cirrhosis
	Cardiopulmonary bypass surgery
	Blood diseases: acute myeloid leukaemia, myelodysplastic syndromes, myeloproliferative disorders, myeloma
	Various systemic disorders¹

¹ These include disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP).

Aspirin

Many drugs can affect platelet function but aspirin is the best documented and the most frequently prescribed. At lower doses aspirin selectively acetylates and irreversibly inactivates the enzyme cyclooxygenase-1 (COX-1), preventing the production of thromboxane A₂ from arachidonic acid and inhibiting aggregation for the remainder of the platelet’s lifespan. Responses are variable but aspirin can dramatically prolong the bleeding time and cause haemorrhage in patients with thrombocytopenia or other coexistent bleeding problems.

Chronic renal failure

Uraemia can lead to multiple platelet defects. Elevated levels of nitric oxide may inhibit platelet adhesion, activation and aggregation. Anaemia contributes to uraemic bleeding as fewer red cells mean that fewer platelets are displaced towards an injured vessel wall. Dialysis reduces haemorrhagic symptoms. This can be supplemented by correction of severe anaemia, DDAVP and platelet transfusions.

Cardiopulmonary bypass

Platelets are activated and degranulated in the extracorporeal circuit, impairing their effectiveness in vivo. This may be exacerbated by hypothermia and large doses of heparin. Excessive bleeding is uncommon but where this happens platelet transfusion is efficacious.

Haematological diseases

Platelet function is impaired in a number of blood diseases, including acute myeloid leukaemia, myelodysplastic syndromes, myeloproliferative disorders and myeloma.

Vascular purpuras

A bleeding tendency caused by a local or general vascular abnormality is referred to as a vascular purpura (Table 35.2). Diagnosis of these diseases is made mainly on clinical grounds with laboratory exclusion of other haemostatic defects.

Table 35.2

The vascular purpuras

Inherited	Hereditary haemorrhagic telangiectasia¹
	Connective tissue diseases
	Ehlers–Danlos syndrome
	Pseudoxanthoma elasticum
	Marfan syndrome
Acquired	Henoch–Schönlein purpura
	Various infections
	Drug reactions (allergic purpuras)
	Senility
	Prolonged corticosteroid treatment
	Scurvy
	Mechanical

¹ Sometimes known as Rendu–Osler–Weber disease.

Inherited disorders

Hereditary haemorrhagic telangiectasia (HHT)

The hallmark of this rare autosomal dominant disease is the development of multiple ateriovenous malformations (AVMs). Small AVMs are referred to as telangiectasia. Close to the surface of the skin and mucous membranes, they often rupture and bleed. Two mutated genes, endoglin and ALK1, have been implicated. Clinical problems include recurrent epistaxes (90% of cases), gastrointestinal haemorrhage, haematuria and larger pulmonary arteriovenous malformations (PAVMs). Chronic bleeding from the gut causes iron deficiency anaemia. On examination there are the characteristic telangiectasia (Fig 35.2). Management includes local control of bleeding (e.g. laser treatment of telangiectasia), iron supplements and embolisation of PAVMs.

Fig 35.2 Telangiectasia in hereditary haemorrhagic telangiectasia.

Inherited diseases of connective tissue

Several rare inherited disorders of connective tissue predispose to bleeding. The mechanism is either a general failure of support of blood vessels or defective interaction between platelets and abnormal collagen. Specific diseases include Ehlers–Danlos syndrome, pseudoxanthoma elasticum and Marfan syndrome.

Acquired disorders

This is a very heterogeneous group. Henoch–Schönlein purpura is a syndrome usually seen in childhood where an itchy purpuric rash typically follows an infection. Spontaneous remission is the rule but renal failure may result. Other causes of acquired purpuric rashes include infections, drug reactions, scurvy, trauma, prolonged steroid therapy and simple old age (senile purpura, Fig 35.3).

Fig 35.3 Senile purpura.

Disorders of platelet function and vascular purpuras

Platelet dysfunction should be considered where there are the clinical features of thrombocytopenia in the presence of a normal or only moderately reduced platelet count.

Laboratory testing of platelet function normally includes a blood count, a blood film and platelet aggregation studies. Careful collection of the sample is crucial.

Inherited disorders of platelet function are generally well characterised but rare (e.g. Bernard–Soulier syndrome), whereas acquired disorders are more frequent but often of obscure aetiology.

Aspirin is a common cause of acquired platelet dysfunction.

A ‘vascular purpura’ is a disorder with a bleeding tendency caused by a local or general vascular abnormality. Diseases may be inherited (e.g. hereditary haemorrhagic telangiectasia) or acquired (e.g. Henoch–Schönlein purpura).

Related

Haematology An Illustrated Colour Text