Haemolytic uraemic syndrome (HUS)

The answer can be inferred from…

• Thrombocytopenia: (low PLT-I and PLT-F)
• Increased thrombopoiesis: (high IPF# and IPF%)
• Increased erythropoiesis: (high RET#, RET% and IRF)
• Presence of fragmented red cells: (high FRC# and FRC%)
• Presence of immature granulocytes: (high IG# and IG%)

Case history

A 12-year old boy was brought to the emergency room with bloody diarrhoea, abdominal cramps, fever, nausea and bruising. Blood analysis showed thrombocytopenia (23,000/μL), an increased immature platelet fraction, reticulocytosis, as well as the presence of fragmented red blood cells and immature granulocytes. The platelet count dropped to 14,000/μL within the next hour and a platelet transfusion had to be considered. It was important to rule out thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) as the cause of thrombocytopenia, as platelet transfusions are contraindicated in these conditions when no active bleeding is observed.

Case results

The presence of red blood cell fragments (FRC#, FRC%) and high reticulocyte counts (RET#, RET%, IRF) are signs of a haemolytic anaemia. This was confirmed by the presence of fragmented red blood cells in the peripheral blood smear (visible as tapered and hornlike ‘helmet’ cells) and elevated LDH and bilirubin levels. Together with a low platelet count (PLT-F) and a high platelet turnover, indicated by a high immature platelet fraction (IPF%), this is highly suggestive of microangiopathic haemolytic anaemia (MAHA). MAHA can be caused by a number of underlying conditions such as TTP, HUS, disseminated intravascular coagulation (DIC), HELLP syndrome and eclampsia.

The presence of atypical lymphocytes (probably reactive lymphocytes), and immature granulocytes in the peripheral blood, as well as the patient’s fever indicated an infection. Enzyme immunoassay analysis of a stool sample showed the presence of enterohaemorrhagic Escherichia coli (EHEC) endotoxins. Hence, HUS due to an EHEC infection was diagnosed.

Differential diagnosis

 The following answers are incorrect for the described reasons.

Thrombotic thrombocytopenic purpura (TTP)

TTP is usually caused by a lack or deficiency of the enzyme ADAMTS13, which cleaves multimers of von Willebrand factor in the peripheral vasculature. Accumulation of the uncleaved multimers leads to spontaneous aggregation of platelets, activation of coagulation and clot formation. When red blood cells pass areas with blood clots, they are sheared by the accumulated fibrin mesh or damaged by the turbulences in the circulation, producing cell remnants that appear as helmets or other odd shapes when viewed under the microscope. The diagnosis is based on clinical symptoms and blood tests, e.g. the presence of typical ’helmet cells‘ in the blood film, thrombocytopenia, haemolytic anaemia, reticulocytosis, fragmented red cells and increased LDH. Other thrombocytopenic conditions must be excluded. In this case the young age of the patient and the observed diarrhoea make a HUS diagnosis more likely.

Idiopathic thrombocytopenic purpura (ITP)

ITP is an autoimmune haematological disorder in which accelerated platelet destruction leads to a reduction in peripheral blood platelets. It causes a characteristic purpuric rash and a tendency to bleed. The diagnosis of ITP is a process of exclusion. Megakaryopoietic activity of the bone marrow may be enhanced, which is also indicated by the high IPF%. However, ITP is not associated with haemolysis and fragmentocytes and can therefore be excluded in this case.

Sickle cell anaemia crisis

Sickle cell anaemia (SCA) or drepanocytosis is a hereditary blood disorder. The sickling of red blood cells occurs because of a mutation in the haemoglobin gene (HbS). Deoxygenated sickle haemoglobin polymerizes into long insoluble fibres, leading to a change in the cellular shape. Sickle-shaped rigid erythrocytes may block areas of microcirculation and cause local infarcts. Reticulocytosis and red blood fragments are associated with haemolytic crises in sickle cell disease. However, another feature is a low haemoglobin level (usually 60-90 g/L), which was not observed in this patient. Thrombocytopenia is also not associated with sickle cell disease.

Microangiopathic haemolytic anaemia (MAHA)

Microangiopathic haemolytic anaemia (MAHA) is a subgroup of haemolytic anaemias caused by factors in the small blood vessels. In diseases such as haemolytic uraemic syndrome (HUS), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), as well as malignant hypertension (pre-eclampsia/HELLP), the endothelial layer of small vessels is damaged with resulting fibrin deposition and platelet aggregation. As red blood cells travel through these damaged vessels, they are shredded. The result is red cell fragmentation and intravascular haemolysis. Microscopically, damaged red cells have the appearance of schistocytes. The most important causes are:

• Thrombotic thrombocytopenic purpura (TTP)
• Haemolytic uraemic syndrome (HUS)
• Disseminated intravascular coagulation (DIC)
• HELLP syndrome and eclampsia
• Several other rare causes
  
  

In all causes, the mechanism of MAHA is the formation of a fibrin mesh due to increased activity of the coagulation system. The red blood cells are physically cut by these protein networks, and the fragments are identical to schistocytes.

Haemolytic uraemic syndrome (HUS)

Haemolytic uraemic syndrome combines microangiopathic haemolytic anaemia and thrombocytopenia, and is recognized as the most common cause of acute renal failure in the paediatric population. Haemolytic uraemic syndrome shares many features with thrombotic thrombocytopenic purpura (TTP). Both diseases include multiorgan dysfunction due to thrombotic microangiopathy, with active haemolysis and thrombocytopenia. TTP and HUS differ mainly in the relative degree of kidney failure. Typically, disorders in adults are described as TTP and are less likely to involve kidney failure. HUS is used to describe the disorder in children, which typically involves kidney failure.

In children HUS is usually preceded by a colitis (inflammation of the colon) caused by Shiga toxin–producing Escherichia coli (STEC). The toxins bind to a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and occasionally other organs. Differential expression of receptor on glomerular capillaries compared with other endothelial cells may explain the predominance of renal injury. Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances. The endothelial cells swell, and fibrin is deposited on the injured vessel walls. The swelling of endothelial cells and the formation of small blood clots (microthrombi) within the glomerular capillaries produce a localized intravascular coagulopathy. The glomerular filtration rate is reduced, and renal insufficiency ensues. Red blood cells are damaged and fragmented as they traverse the narrowed glomerular capillaries. This leads to the characteristic microangiopathic haemolytic anaemia.

Thrombocytopenia is believed to result from a combination of platelet destruction, increased consumption, sequestration in the liver and spleen, and intrarenal aggregation. Platelets are damaged as they pass through the affected glomerular capillaries. Remaining platelets circulate in a degranulated form and show impaired aggregation.

White blood cell counts are usually elevated in the blood of patients with haemolytic uraemic syndrome. Activated neutrophils are believed to damage endothelial cells by releasing elastase and by producing free radicals. Monocytes may be stimulated to release cytokines that also damage endothelial cells.

Typical diarrhoea-associated HUS in children caused by enterohemorrhagic infection usually spontaneously remits and is treated with supportive care; over half of patients require renal dialysis.

Literature HUS and TTP

1. Medscape: Pediatric Hemolytic Uremic Syndrome. Robert S Gillespie, MD, MPH; Chief Editor: Craig B Langman, MD.
http://emedicine.medscape.com/article/982025-overview

2. Thrombocytopenia. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011: chap 175.

3. Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome. The Merck Manuals: The Merck Manual for Healthcare Professionals. http://www.merck.com/mmpe/print/sec11/ch133/ch133g.html