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Thrombotic Microangiopathy

What is it?

Thrombotic microangiopathies (TMA) are clinical syndromes defined by the presence of hemolytic anemia (destruction of red blood cells), low platelets, and organ damage due to the formation of microscopic blood clots in capillaries and small arteries.  The kidneys are commonly affected, although virtually any organ may be involved.  Smoldering TMA will sometimes result in kidney damage without significant anemia or low platelets.  Under the microscope, the blood demonstrates injured red blood cells known as schistocytes or fragments.  Kidney disease can be severe, with over 50% of individuals requiring dialysis with a cause of TMA known as atypical hemolytic uremic syndrome (aHUS).  Historically, TMA were often referred to as TTP/HUS, or thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.  It is now recognized that a large number of different diseases can result in TMA.

What causes it?

TMA are associated with a large number of diseases.  A common cause is thrombotic thrombocytopenic purpura (TTP) which is due to low activity of a protein called ADAMTS13.  Some individuals are born with a mutation in the gene for ADAMTS13, although most affected patients have an acquired auto-antibody (a form of autoimmune disease) that blocks the activity of ADAMTS13.  Another major cause for TMA is atypical hemolytic uremic syndrome (aHUS), a disorder caused by dysregulation of a part of the immune system known as complement.  Approximately 50% of aHUS patients are found to have either a genetic mutation in the complement system or an auto-antibody that interferes with the regulation of complement.  Other notable causes for TMA include infection (e.g., bloody diarrhea associated with E. coli infection), medications (e.g., quinine, bevacizumab), connective tissue diseases (e.g., systemic lupus erythematosus, antiphospholipid antibody syndrome, scleroderma), cancer, vasculitis, pregnancy, malignant hypertension, organ transplant, and metabolic disorders.

How is it diagnosed?

TMA often present very suddenly and result in severe illness in many patients.  Patients are often hospitalized at the time of diagnosis.  Diagnosis requires blood tests to confirm red blood cell destruction, the presence of schistocytes on blood smears, and organ damage that can be attributed to the TMA.  Typical organ damage includes very high blood pressure (malignant hypertension), kidney injury, abdominal pain, diarrhea, stroke, confusion, heart injury, and eye damage.  Identifying the specific cause for TMA requires specialized blood and genetic testing to evaluate for the different causative diseases.  Some of this testing can take weeks to months to return.  Since treatment must be initiated immediately, it is important to have a team of doctors experienced in the diagnosis and management of TMA.  A team at Johns Hopkins has developed a research test that may be capable of diagnosing TMA due to problems in the complement system (aHUS) within several hours.

How is it treated?

Many patients are treated with therapeutic plasma exchange, a procedure in which plasma (water and protein portion of blood) is removed from the body and replaced with fresh donor plasma.  This is effective therapy for TTP, and patients are usually treated with a combination of plasma exchange and immune suppression including corticosteroids.  For aHUS, patients are treated with an intravenous medication that blocks the complement system.  For other diseases that cause TMA, the treatment focuses on managing the underlying disease.  For example, infectious causes of TMA might be treated with antibiotics and supportive care.  At times, plasma exchange, immune suppression, and/or complement blocking therapies may be used to treat other causes of TMA.  Individuals with severe kidney injury may require dialysis.  Some causes of TMA (e.g., aHUS and TTP) may be chronic, relapsing conditions that require ongoing therapy.

Johns Hopkins has assembled a team of physicians and researchers dedicated to the care and management of patients diagnosed with TMA.  This multidisciplinary team draws from Nephrology, Hematology, Transfusion Medicine, Pathology, and Laboratory Medicine.

What type of research into TMA is being conducted at Johns Hopkins?

At present, the Johns Hopkins Complement Associated Disease Registry is currently enrolling individuals with TMA, TMA-predisposing conditions, and complement associated diseases.  This is a clinical registry that collects information, blood, urine, and tissue specimens for ongoing research into mechanisms, diagnosis, and therapy of TMA.

Johns Hopkins is also an enrolling site for the Global aHUS Registry, an international observational registry of individuals diagnosed with aHUS.  This is an anonymous registry designed to help researchers better understand the disease, and it does not involve the administration of any specific treatment.

I have been diagnosed with TMA or a TMA related disease and would like to be seen at Johns Hopkins.

Patients interested in being evaluated at Johns Hopkins should call 410-955-5268 (option #4) to request an evaluation with Dr. C. John Sperati.

Dr. C. John Sperati, MD, MHS
Johns Hopkins University School of Medicine
Division of Nephrology
1830 E Monument St, Rm 416
Baltimore, MD 21287
410-955-5268 (office)
410-367-2258 (fax)

jsperati@jhmi.edu

Selected References:

1. Sperati CJ and Moliterno AR. Thrombotic microangiopathy: Focus on atypical hemolytic uremic syndrome. Hematol Oncol Clin North Am. 2015;29:541-59.

2. Gavriilaki E et al. Modified Ham test for atypical hemolytic uremic syndrome. Blood. 2015;125:3637-46.

3. Licht C et al. The global aHUS registry: methodology and initial patient characteristics. BMC Nephrol. 2015;16:207.

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