Pathogenetic mechanisms

Thrombotic thrombocytopenic purpura

• Multimers of von Willebrand factor (vWF) are synthesized in megakaryocytes and endothelial cells (stored in alpha-granules and Weibel-Palade bodies respectively)
• Unusually large  multimers can bind strongly to glycoprotein Iba component of platelet glycoprotein Ib/IX/V receptor together with subsequent ADP-activated platelet glycoprotein IIb/IIIa complexes induce platelet aggregration
• These unusually large  multimers are normally prevented from entering the circulation by a von Willebrand factor-cleaving metalloprotease (ADAMTS 13), which is produced by hepatocytes
• ADAMTS 13 may actually bind to receptors and function on surface of endothelial cells
• With deficient ADAMTS 13, unusually large multimers of vWF  are not cleaved and are attached to the endothelial surfaces in long strings
• Platelets can further adhere to the multimers to form platelet thrombi with systemic multiorgan vascular occlusion
• Plasma ADAMTS 13 activity can be low in liver disease, disseminated malignancy, chronic inflammatory conditions, pregnancy and newborn
• Autoantibodies against ADAMTS 13 have been described in patients after use of ticlopidine or clopidogrel

Haemolytic uraemic syndrome

2 types - Shiga-like toxin related and non-Shiga-like toxin related

The first type is  associated with infection of Shiga-like toxin producing E coli  O157:H7 with bloody diarrhoea and renal failure. In developing countries (Asia and Africa) Shiga toxin producing Shigella dysenteriae serotype 1 has been associated with HUS.

2 types of Shiga-like toxins

Shiga-like toxin 1: almost identical to Shiga toxin produced by Shigella dysenteriae type 1 except for 1 amino acid

Shiga-like toxin 2: 50% homologous with Shiga toxin by Shigella dysenteriae

Recent study shows that Shiga-like toxin 2 is most commonly associated with haemolytic uraemic syndrome

• Oral ingestion of Shiga-like toxin producing E coli
• 40-60% will have bloody diarrhoea
• 3-9% develop HUS in sporadic infection
• Up to 20% develop HUS in epidemic infection
• Colonization of bacteria at large intestine with firm adherence to epithelial cells
• Translocation of Shiga-like toxin into circulation and facilitated by transmigration of neutrophils
• Binding of toxin to neutrophil surface
• Transfer of the toxin to glomerular endothelial and tubular epithelial cells (higher receptor affinity to toxin than neutrophils)
• Dissociation of A and B subunit of Shiga-like toxin once internalized into cells
• Binding of toxin to target cells depends on B subunits
• Increase in production of interleukin-8, monocyte chemoattractant protein-1 and cell adhesion molecules
• Changes in endothelial cell adhesion properties and metabolism encourage leukocyte dependent inflammation with loss of thromboresistance resulting in microvascular thrombosis

The second type can be sporadic or familial and has poor prognosis with 50% progressing to end stage renal failure and 25% death in acute phase. It is much less common than the first type (only 5 to 10% of all cases of haemolytic uraemic syndrome). It is related to genetic abnormalities of complement regulatory proteins.

• No preceding diarrhoea
• Sporadic cases may be related to nonenteric infections (especially Streptococcus pneumoniae infection*, accounting for 40% of non-Shiga like toxin related HUS), viral infection, autoimmune diseases (systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome), transplantation, pregnancy and postpartum, drugs (antineoplastics- cisplatin, gemcitabine, mitomycin, bleomycin; immunosuppressants- cyclosporin, tacrolimus,OKT3 , interferon; antiplatelet agents- ticlopidine and clopidogrel). No triggering conditions in 50% of cases
• Familial cases - can be autosomal dominant or recessive of inheritance, accounting for fewer than 3% of all HUS
• For example mutation in complement regulatory protein factor H, membrane cofactor protein, complement factor I

*Streptococcus pneumonia produces neuroaminidase, removes sialic acids from surface of cell membranes and exposes Thomsen-Friedenreich antigen to antibodies in circulation. The binding of antibodies to this antigen on platelets and endothelial cells can cause platelet aggregation and endothelial injury leading to HUS

Diagnosis

Thrombotic thrombocytopenic purpura

• adult
• microangiopathic haemolytic anemia and thrombocytopenia without apparent alternative cause
• regardless of the presence of neurological or renal abnormalities, cause or associated condition

Haemolytic uraemic syndrome

• children
• microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure (50-70%)
• prodromal diarrhoea(25% cases of Shiga-like toxin producing E coli associated HUS have been reported to have no diarrhoea)
• In adult, it is indistinguishable from TTP except for severity of acute renal failure
  •

Clinical manifestations of TTP

• Symptoms are often non-specific including abdominal pain, nausea, vomiting and weakness
• 50% of patients have severe neurological abnormalities including seizures or fluctuating neurological deficits
• Some may only have mild transient confusion
• Some may have symptoms for a few weeks before diagnosis

Clinical categories of acquired TTP

1. Familial (rare)
2. Idiopathic
3. Pregnancy (usually in last trimester or postpartum period)
4. Autoimmune disorders
5. With prodrome of bloody diarrhoea
6. Acute drug related (immune mediated) - quinine
7. Cumulative dose dependent drug toxicity
8. After haematopoietic stem cell transplant

Laboratory findings

• Microangiopathic haemolytic anaemia ( schistocytes and reticulocytes on blood smear)
• Thrombocytopenia
• ­ Lactic dehydrogenase and unconjugated bilirubin
• Negative direct Coomb's test
• Unclear value of measurement of ADAMTS 13 activity and inhibitors

Consider other possibilities:

• Sepsis
• Disseminated intravascular coagulation (low circulating level of fibrinogen, prolonged PT or APTT)
• Disseminated malignancy
• Malignant hypertension
• Catastrophic antiphospholipid syndrome (lupus anticoagulant and prolonged APTT)
• Severe preeclampsia
• Eclampsia
• HELLP syndrome

Clinical manifestations of haemolytic uraemic syndrome

Shiga-like toxin related HUS

• Prodromal diarrhoea typically develops 3 (range: 1-8) days after exposure to contaminated food
• 70% cases have bloody diarrhoea
• 30%-70% have vomiting
• 30% have fever
• Usually have leukocytosis
• Shedding of Shiga-like toxin producing E coli  in stool can occur for several weeks after resolution of symptoms
• 70% of Shiga-like toxin related HUS require red cell transfusion
• 50% require renal replacement therapy during acute phase
• 5% die during acute phase
• usually stormy disease course complicated by bacteraemia, septic shock, DIC in Shigella dysenteriae related HUS

Non-Shiga-like toxin related HUS

• Sporadic form usually has heterogeneous clinical manifestations depending of triggering conditions
• Usually more severe with respiratory distress, neurological involvement
• Familial form can be autosomal dominant or recessive.
• Autosomal recessive form usually occurs in early childhood
• Autosomal dominant form usually occurs in adult