Thrombotic thrombocytopenic purpura - haemolytic uraemic syndrome

Thrombotic thrombocytopenic purpura - haemolytic uraemic syndrome

Definition

Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are probably two separate entities, but have such similar clinical presentations and findings that they are usefully considered together. When acute renal failure is predominant it is called HUS, and when neurological problems are predominant it is called TTP. Often both ends of the spectrum are present in the same patient. The characteristic features of TTP–HUS are microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia, with variable renal and neurological abnormalities.

Incidence/prevalence

HUS is one of the commonest causes of ARF in children.

Age

More common in children and young adults.

Geography

Clusters and epidemic foci suggest an infective trigger.

Aetiology

There appear to be inherited and acquired forms of HUS and TTP.

The epidemic form of HUS has been associated with a variety of bacterial and viral agents, including a verotoxin (also called Shiga toxin) produced by Escherichia coli(O157:H7).

Many cases of TTP are idiopathic.

There is an association of TTP–HUS with later stages of pregnancy, SLE and certain drugs.

Pathophysiology

There are several postulated mechanisms.

It has been suggested that an initial toxic insult to the vascular endothelium may induce platelet activation. This results in intravascular coagulation and haemolysis of red blood cells. Certain individuals appear to be more susceptible, perhaps due to inherited or acquired abnormalities of their coagulation/platelet activation systems.

In E. coli O157 associated HUS, the verotoxin ap-pears to act by several mechanisms, including a direct platelet-aggregating effect, a toxic effect on the endothelium and neutrophil activation.

In familial TTP patients have a hereditary deficiency of von Willebrand Factor (vWF) cleaving protease, and many patients with non-familial TTP have an anti-body directed against this enzyme. vWF is produced by endothelial cells and forms Ultra Large (ULvWF) multimers which circulate in the plasma and promote aggregation of activated platelets. VWF cleaving protease breaks these multimers down rapidly; however, if there is a deficiency of this enzyme, ULvWF multimers accumulate and cause platelet aggregation.

Lack of other inhibitors or antibodies against them have also been postulated.

Clinical features

Patients may present with some or all of the following.

·        Haemolytic anaemia with mild jaundice, lethargy.

·        Thrombocytopenia which may result in purpuric rash or bleeding.

·        Acute renal failure (usually oligo-/anuric).

·        Neurological abnormalities including headache and confusion, seizures and coma.

·        Fever.

Microscopy

Thrombi mainly composed of platelets are found in arterioles and fibrin deposits are seen in the endothelium of glomerular capillaries. This causes a focal segmental glomerulonephritis. Widespread hyaline thrombi are seen in TTP.

Investigations

TTP-HUS should be suspected in any case of throm-bocytopenia and microangiopathic haemolytic anaemia (without another clinically apparent cause)

·        FBC and peripheral blood film: Anaemia, thrombo-cytopenia, film shows schistocytes and ‘helmet cells’ (fragments of red blood cells) and increased reticu-locytes. Direct antiglobulin test must be negative (to exclude an immune cause). Clotting profile should be normal.

·        U&Es to look for renal failure and hyperkalaemia.

·        Dipstick may show some proteinuria and be positive for blood because of haemoglobinuria, but urine microscopy usually shows few red cells.

·        Serum bilirubin and LDH are raised and haptoglobins are very low due to the haemolysis.

Management

Early diagnosis and treatment is needed to prevent irreversible renal failure and to reduce mortality. The treatment of choice is plasma exchange with fresh frozen plasma. Without this, TTP-HUS in adults had a âˆ¼90% mortality. In contrast, HUS in children due to O157 of-ten resolves spontaneously with supportive therapy, e.g. for the renal failure, and plasma exchange is used for persistent or severe cases.

Plasma exchange appears to correct the coagulation/platelet abnormalities, either by replacing the lost vWF cleaving protease or removing the antibodies, or both.

Platelet transfusions should be avoided unless there is severe bleeding, as they may exacerbate the condition.

Prognosis

This has markedly improved with the advent of plasma exchange. Chronic renal failure occurs in a substantial number of patients.