Thrombotic microangiopathies: Similar presentations, different therapies
ABSTRACT
Thrombotic thrombocytopenic purpura, Shiga toxin hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome are thrombotic microangiopathies that present similarly but arise from different causes. Management depends on distinguishing them promptly and providing targeted therapy.
KEY POINTS
- Thrombotic thrombocytopenic purpura is diagnosed with the ADAMTS13 assay. As soon as it is suspected, it should be treated with daily plasma exchange, steroids (at least until the diagnosis is certain), and, if additional treatment is needed, rituximab.
- Hemolytic uremic syndrome is seen in children who handle farm animals and in children and adults in food outbreaks. It is managed supportively with transfusion of packed red blood cells and dialysis.
- Atypical hemolytic uremic syndrome should be suspected in patients with normal ADAMTS13 and without diarrhea or evidence of Shiga toxin-producing Escherichia coli. It often responds well to eculizumab, a blocker of C5 (the fifth component of complement).
- Antiphospholipid syndrome should be investigated in women who have multiple miscarriages or thrombotic events. Symptomatic disease requires long-term anticoagulation therapy.
HEMOLYTIC UREMIC SYNDROME
A child with sudden onset of bloody diarrhea and kidney failure
A 4-year-old girl plays with baby animals at a petting zoo and does not wash her hands immediately afterwards. Three days later, she develops fever, abdominal cramps, nausea, vomiting, and bloody diarrhea. Her pediatrician gives her antibiotics. On day 6, she develops ecchymoses on the extremities and lips, thrombocytopenia, low urine output, and seizures. Her stool tests positive for Escherichia coli O157:H7
Classic presentation: Young patient with bloody diarrhea
The classic presentation of hemolytic uremic syndrome is of a young patient with bloody diarrhea typically lasting 5 to 10 days. Kidney failure may follow, requiring dialysis in about 60% of patients for a mean of 10 days. About one-fourth of patients develop neurologic symptoms, and about the same fraction are left with long-term morbidity, eg, hypertension, proteinuria, and reduced glomerular filtration rate. The mortality rate is typically 4%10,11 but varies with the outbreak.
Histologically, the kidneys look identical to those in thrombotic thrombocytopenic purpura, with thrombi in glomeruli and small vessels.
E coli is the most common culprit, but other bacteria, including Shigella dysenteriae, and viruses are sometimes the cause. Fewer than 10% of children infected with Shiga toxin-positive E coli, also known as enterohemorrhagic E coli (O157:H7, O104:H4), develop hemolytic uremic syndrome.
Lessons from outbreaks
Petting zoos are a common source of transmission of pathogenic bacteria. Disease can be extremely serious: in 15 cases linked to a Florida petting zoo, 3 children died.
Other outbreaks involving pathogenic E coli have been tied to fresh vegetables and to undercooked hamburger at fast-food chains.
In Germany in 2011, more than 3,000 people acquired Shiga toxin nonhemolytic uremic syndrome due to E coli, and 16 of them died. In addition, 845 acquired hemolytic uremic syndrome, and 36 died. This outbreak was associated with the more virulent and less common O104:H4 strain, which has acquired a Shiga toxin-encoding phage. Patients were treated with quinolone antibiotics, which actually increase toxin production in this strain.12
Unusual in the German epidemic was that more adults were affected (88%), especially women (68% of cases).13 The source of infection was eventually found to be alfalfa sprouts, the seeds of which had been contaminated by E coli. Women did not harbor any intrinsic factor making them more susceptible; rather, they were more likely to eat salads.13
Supportive management
Supportive care is most important. Transfusion with packed red blood cells is indicated for hemoglobin below 6 g/dL. Hypertension should be controlled and dialysis provided. For central nervous system involvement or severe disease, plasma exchange is sometimes used.
Eculizumab was tried for a time as therapy but did not prove to be of benefit. Shiga toxin-binding agents have been developed, but by the time they are given it is too late in the disease process to help.
Antibiotics may harm; it is possible that they kill beneficial bacteria, allowing the Shiga toxin-producing E coli to better proliferate. Antimotility agents also are contraindicated. Other agents not recommended include urokinase, heparin, dipyridamole, and vincristine. Splenectomy is not advised.
The most important way to control hemolytic uremic syndrome is to prevent it by thoroughly cooking meat, cleaning fresh produce, and having children wash their hands after petting animals.
ATYPICAL HEMOLYTIC UREMIC SYNDROME
A young man in renal failure
A 28-year-old man has a history of “thrombotic thrombocytopenic purpura-hemolytic uremic syndrome” at age 12. He slowly progresses to end-stage renal disease and receives a renal transplant from his mother at age 20 that fails after 3 months. The renal transplant biopsy report at the time reads “thrombotic microangiopathy.” The patient’s brother also requires dialysis.
The patient’s complement values are low, especially C3. His father is offering him a kidney at this time, and the patient wants to know whether to proceed.
Normal ADAMTS13, no diarrhea
Hemolytic uremic syndrome without diarrhea is now called atypical hemolytic uremic syndrome. Patients have normal levels of ADAMTS13, do not have diarrhea, and have no evidence of Shiga toxin-producing E coli.
Continuous complement pathway activation
The complement system is part of the innate immune system, which provides immediate defense against infection and does not evolve as does the adaptive immune system. The classic complement pathway is activated by the C1 antibody-antigen complex. The alternative complement pathway leads to the same pathway via C3.14 Both pathways lead to the formation of C5 through C9 membrane attack complexes, which form channels across the membranes of target cells, leading to cell lysis and death.
The alternate pathway does not require an antibody trigger so is always active at a low level. Inhibitory factors (factor H, factor I, membrane cofactor protein, factor H-related proteins) are naturally present and slow it down at various steps. People who are born with an abnormal factor or, more commonly, develop antibodies against one of the factors, have uninhibited complement activation. If this happens in the blood vessels, massive coagulation and atypical hemolytic uremic syndrome ensues. The endothelial damage and clotting in the brain, kidney, and other organs are identical to that of hemolytic uremic syndrome caused by Shiga toxin.
Treat with eculizumab
Historically, atypical hemolytic uremic syndrome was treated with plasma exchange, which replaces defective complement regulatory proteins and removes inhibitory antibodies.
Understanding the complement pathways is key to developing drugs that target atypical hemolytic uremic syndrome, and about 60 are in the pipeline. The only one currently approved in the United States for atypical hemolytic uremic syndrome is eculizumab, a humanized monoclonal antibody that binds with high affinity to C5, blocking the end of the complement cascade and preventing formation of the membrane attack complex.15–18
The effects of eculizumab on atypical hemolytic uremic syndrome were studied in 2 prospective trials.19 Platelet counts rose rapidly within weeks of starting treatment, and kidney function improved. Benefits continued throughout the 64 weeks studied. There were no deaths among the 37 patients enrolled, and although these were single-arm trials, they provide evidence of dramatic benefit considering the high mortality risk of this disease.
Eculizumab is now considered the treatment of choice. It may be used empirically for patients with hemolytic uremic syndrome who test negative for Shiga toxin and antiphospholipid antibody, and who do not have a very low level of ADAMTS13. The big drawback of eculizumab is its high price,20–22 which varies by amount used, location, and pharmacy negotiation, but can be in the hundreds of thousands of dollars.
For a patient with atypical hemolytic uremic syndrome on dialysis, treatment with eculizumab should continue for 4 to 6 months if there are no extrarenal manifestations. But many patients continue to have the defect in the complement system, so the problem may recur.
Case revisited
For our patient considering a kidney transplant, many experts feel that a transplant can be done as long as platelet counts are monitored and treatment with eculizumab is restarted if needed. One can also make the case for waiting a few years for new oral drugs to become available before offering transplant.
