Thrombotic Microangiopathies

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent a spectrum of thrombotic microangiopathies.

TTP and HUS share the general features of idiopathic thrombocytopenic purpura, hemolytic anemia, fever, renal failure, and neurologic disturbances. When patients have more evidence of renal injury, their condition tends to be called HUS, and when there is more neurologic disease, it is considered to be TTP. In adults there is often a mixture of both, which is why they are often called TTP/HUS.

On examination of kidney tissue there is evidence of glomerular capillary endotheliosis associated with platelet thrombi, damage to the capillary wall, and formation of fibrin material in and around glomeruli . These tissue findings are similar to what is seen in preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), malignant hypertension, and the antiphospholipid syndrome. TTP/HUS is also seen in pregnancy; with the use of oral contraceptives or quinine; in renal transplant patients given OKT3 for rejection; in patients taking the calcineurin inhibitors cyclosporine and tacrolimus or in patients taking the antiplatelet agents ticlopidine and clopidogrel; or following HIV infection.

Although there is no agreement on how much they share a final common pathophysiology, two general groups of patients are recognized:
a) childhood HUS associated with enterohemorrhagic diarrhea and
b) TTP-HUS in adults.

Childhood HUS is caused by a toxin released by Escherichia coli O157:H7 and occasionally by Shigella dysenteriae. This shiga toxin (veratoxin) directly injures endothelia, enterocytes, and renal cells, causing apoptosis, platelet clumping, and intravascular hemolysis by binding to the glycolipid receptors (Gb3). These receptors are more abundant along endothelia in children compared to adults.

In familial cases of adult TTP/HUS, there is a genetic deficiency of the ADAMTS13 metalloprotease that cleaves large multimers of von Willebrand's factor. Absent ADAMTS13, these large multimers cause platelet clumping and intravascular hemolysis. An antibody to ADAMTS13 is found in many sporadic cases of adult TTP/HUS, but not all; many patients also have antibodies to the thrombospondin receptor on selected endothelial cells in small vessels or increased levels of plasminogen-activator inhibitor 1 (PAI-1).

The treatment of childhood HUS or adult TTP/HUS is daily plasmapheresis, which can be lifesaving. Plasmapheresis is given until the platelet count rises, but in relapsing patients it may need to be continued well after the platelet count improves, and in resistant patients twice-daily exchange may be helpful. Most patients respond within 2 weeks of daily plasmapheresis. Since TTP/HUS often has an autoimmune basis, there is an anecdotal role in relapsing patients for using splenectomy, steroids, immunosuppressive drugs, or anti-CD20 antibody. Patients with childhood HUS from infectious diarrhea are not given antibiotics, as antibiotics are thought to accelerate the release of the toxin and the diarrhea is usually self-limited.