Thrombotic microangiopathy (TMA) is a rare, severe medical condition characterized by damage to the body’s smallest blood vessels. This damage leads to microscopic blood clots, obstructing blood flow, causing widespread organ damage. Prompt recognition and management are important due to its rapid progression and life-threatening complications.
Understanding Thrombotic Microangiopathy
Thrombotic microangiopathy involves injury to the walls of tiny blood vessels (arterioles, capillaries). This triggers uncontrolled activation of platelets, clotting cells. Microscopic blood clots (thrombi) form within these vessels, impeding blood flow, depriving organs of oxygen and nutrients.
Widespread clot formation has two main consequences. Red blood cells fragment in narrowed vessels, causing microangiopathic hemolytic anemia (MAHA). Additionally, excessive clot formation consumes platelets, leading to thrombocytopenia.
MAHA and thrombocytopenia combined damage various organs. Kidneys are frequently affected, leading to impaired function or failure. The brain can be impacted, causing neurological symptoms. Other organs, including the heart, lungs, and gastrointestinal tract, can be damaged depending on where microclots form.
Causes and Associated Conditions
TMA can arise from various underlying causes, categorized into primary and secondary forms. Primary TMAs are often genetic, from inherited predispositions. Examples include atypical hemolytic uremic syndrome (aHUS), linked to genetic defects in the complement system, and thrombotic thrombocytopenic purpura (TTP), involving deficiency of the ADAMTS13 enzyme. TTP can be inherited or, more commonly, acquired due to autoimmune antibodies.
Secondary TMAs are acquired, triggered by various external factors or medical conditions. A common cause is infection, particularly by Shiga toxin-producing Escherichia coli (STEC), leading to STEC-hemolytic uremic syndrome (STEC-HUS). Certain medications can induce TMA, including chemotherapy drugs like gemcitabine, calcineurin inhibitors, and anti-VEGF agents.
Autoimmune diseases, such as systemic lupus erythematosus (SLE) and scleroderma, trigger secondary TMA. Malignancies, particularly advanced cancers, can be associated with TMA. Pregnancy-related conditions, including severe preeclampsia, eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), are causes of TMA. Organ transplantation can sometimes lead to post-transplant TMA, often due to drug toxicity or immune dysregulation.
Recognizing the Signs
The clinical manifestations of TMA vary widely, depending on the cause and affected organs. However, a classic triad often points to TMA: microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. MAHA can manifest as fatigue, paleness, and jaundice.
Thrombocytopenia can lead to increased bruising, petechiae, or more significant bleeding. Organ damage symptoms are diverse. Kidney involvement often presents as reduced urine output, swelling, and elevated blood pressure.
Neurological symptoms include headaches, confusion, altered mental status, and seizures. Severe cases may involve stroke-like symptoms or coma. Gastrointestinal involvement can lead to abdominal pain, nausea, vomiting, and diarrhea. Other general symptoms like fever and generalized weakness may also be present.
Diagnosis and Treatment Approaches
Diagnosing TMA typically begins with blood tests. A complete blood count (CBC) often reveals anemia and thrombocytopenia. A peripheral blood smear visualizes fragmented red blood cells (schistocytes), a MAHA hallmark. Additional blood tests often show elevated lactate dehydrogenase (LDH) and low haptoglobin, indicators of red blood cell destruction, alongside a negative direct Coombs test to rule out autoimmune hemolytic anemia.
Kidney function tests (BUN, creatinine) assess kidney damage. Specific tests pinpoint cause. For suspected TTP, ADAMTS13 activity levels are measured; very low activity points to this diagnosis.
For suspected STEC-HUS, stool tests detect Shiga toxin. Complement pathway analysis may be performed for atypical HUS. Medication history review identifies drug-induced TMA. In some situations, an organ biopsy (e.g., kidney) may confirm diagnosis or evaluate tissue damage.
Treatment strategies for TMA depend on the underlying cause and must be initiated urgently due to rapid progression. Supportive care includes blood transfusions for severe anemia, dialysis for kidney failure, and management of high blood pressure. For TTP, plasma exchange (plasmapheresis) is a primary treatment, removing harmful antibodies and replacing it with donor plasma.
For atypical HUS, targeted therapies like complement inhibitors (e.g., eculizumab, ravulizumab) block uncontrolled complement system activation. If an autoimmune disease is the cause, immunosuppressive medications are administered. For drug-induced TMA, discontinuing the causative medication is the first step. Treating the underlying infection or malignancy is important when identified as a trigger.