Shiga toxin, von Willebrand factor, TTP and HUS

on 17.6.09 with 0 comments

In 1985, Karmali discovered a link between in haemolytic-uremic syndrome (HUS) and enteric infections with Escherichia coli that produce Shiga toxin. Such infections are very common in the tropics. HUS is mainly a disease of children. A combination of thrombocytopenia with an increased number of megakaryocytes in the bone marrow, microangiopathic haemolytic anemia with schistocytes and elevated LDH, renal failure with hypertension and fever is suggestive of HUS. The clinical distinction between thrombotic thrombocytopenic purpura (TTP, Moschcowitz's disease) and HUS is not always clear-cut, but neurological abnormalities are more common in TTP.

Shiga toxin is a 70-kD protein exotoxin encoded by Shigella dysenteriae DNA. Shiga toxins 1 and 2 (syn. Shiga-like toxin 1 and 2; also known as verotoxins) are encoded by bacteriophage DNA, which can be present in several E. coli serotypes. Verotoxins were first described in 1977. Their name refers to the cytopathogenic effect on Vero cells (in vitro cultivated monkey kidney cells). All these toxins have similar structures. They are so-called binary AB toxins. This group includes cholera, diphtheria and pertussis toxins. As their name suggests, AB toxins consist of two sub-units, A and B. The sub-unit B is a pentamer with five-fold symmetry. Each of the five sub-unit B monomers has three binding sites, which explains why Shiga toxin is so efficient. With these 15 sites it binds like Velcro to receptors on endothelial cells. Sub-unit B of Shiga toxin binds with high affinity to a certain glycolipid (globotriaosylceramide, Gb3) present on glomerular, colonic and microvascular endothelial cells. This action stimulates glomerular endothelial cells to secrete unusually large von Willebrand factor multimers, which promote local platelet aggregation. The predominance of renal injury in HUS may be caused by differential expression of Gb3 on glomerular capillaries versus other endothelial cells. After it has been taken up into the cell, sub-unit A migrates through the cytoplasm and binds to ribosomes. Cell death follows. Antibiotics used in cases of diarrhoea might increase the risk of the haemolytic–uremic syndrome by causing the release of Shiga toxin from injured bacteria in the intestine, making the toxin more available for absorption. Oral administered porous particles which are coated with synthetic oligosaccharide receptors for verotoxin (Syncorb-PK) can be given.

HUS often resembles TTP. Von Willebrand Factor (vWF) is a heterogeneous multimeric glycoprotein which is produced by endothelial cells and megakaryocytes. The molecular weight varies from 400 kD to 20,000 kD. In platelets, vWF is stored in the alpha-granules. In endothelial cells vWF is stored in so-called Weibel-Palade bodies. The normal function of vWF is to stabilize factor VIII, as well as to be a carrier protein of factor VIII. Large vWF multimers also stabilise platelet adhesion to the subendothelial matrix in case of tissue injury. Secreted uncleaved unusually large multimers induce adhesion and aggregation of platelets in the circulation itself and have therefore considerable prothrombotic properties, especially in situations of high shear stress (arterioles and capillaries). Normally, these multimers are cleaved within seconds to a few minutes by the circulating plasma metalloprotease ADAMTS 13 (acronym for "a disintegrin-like and metalloprotease with thrombospondin type I repeats"). The function of ADAMTS 13 is therefore to cleave secreted vWF to limit the size of the multimers and to prevent platelet aggregation in the circulation. This enzyme is produced by the liver. Endothelial cells have a receptor for this enzym. When the unusually large multimers are cleaved so quickly, no thrombosis will occur. Platelets do not adhere to the smaller von Willebrand factor forms. In most types of TTP, plasma ADAMTS 13 activity is less than 5% of normal. The unusually large multimers are not cleaved on the surface of endothelial cells during more than 10 minutes in patients with TTP, leading to thrombosis. Acquired idiopathic TTP can occur when neutralising IgG auto-antibodies inhibit ADAMTS 13 activity. Multiple loss-of-function mutations in ADAMTS 13 are associated with congenital TTP. Testing for the activity of this enzyme could thus allow differentiation of HUS and TTP. Patients with idiopathic thrombocytopenic purpura (ITP), liver cirrhosis, chronic uraemia, new born babies and pregnant women tend to have low ADAMTS 13 in their plasma, but in these people, the activity is not less than 5%.

Category: Medical Subject Notes , Medicine Notes



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