Thrombotic Thrombocytopenic Purpura (TTP) is a severe blood disorder characterized by the widespread formation of small blood clots, called microthrombi, within the body’s smallest blood vessels. These clots consume platelets and damage red blood cells, leading to low platelet counts and anemia. If left untreated, TTP carries a very high mortality rate, making rapid diagnosis and immediate therapeutic intervention necessary. The diagnostic process is a time-sensitive sequence of clinical evaluation and specialized laboratory testing.
Recognizing the Clinical Suspicion
The diagnosis of TTP begins with a high index of clinical suspicion because the initial signs are often non-specific and can overlap with other conditions. The combination of unexplained microangiopathic hemolytic anemia and low platelet count in a patient without another clear cause is the primary trigger for suspicion.
The symptoms that prompt a physician to suspect TTP are varied, reflecting the multi-organ damage caused by the microthrombi. Neurological changes are common and can manifest as headaches, confusion, altered mental status, or seizures. Patients may also experience fatigue, weakness, or shortness of breath due to the severe anemia.
A physical examination may reveal petechiae or purpura, which are tiny spots on the skin caused by bleeding due to the low platelet count. Fever is sometimes present, and some patients may show signs of kidney problems. When these symptoms occur together, particularly with evidence of internal blood destruction, the diagnostic pathway for TTP must be initiated without delay.
Initial Laboratory Screening
The immediate next step involves rapid blood tests designed to identify the two core pathological features: thrombocytopenia and microangiopathic hemolytic anemia (MAHA). A complete blood count (CBC) will reveal a severely low platelet count, often less than 50,000 per microliter, which is a key finding in TTP. This low count results from the consumption of platelets as they form the widespread microthrombi.
The presence of MAHA is confirmed by markers indicating that red blood cells are being mechanically destroyed as they pass through the tiny clotted vessels. A peripheral blood smear is a defining test that will show fragmented red blood cells, known as schistocytes. Their presence strongly suggests mechanical damage to the red cells.
Other laboratory signs of MAHA include an elevated level of lactate dehydrogenase (LDH), an enzyme released when cells are damaged. Indirect bilirubin levels may also be elevated, sometimes leading to jaundice. Renal function must also be checked via serum creatinine levels. The results of these initial tests guide the immediate decision to begin treatment while awaiting the definitive diagnostic results.
Confirmatory Testing Using ADAMTS13
The definitive diagnosis of TTP relies on measuring the activity of the ADAMTS13 enzyme, a specific metalloprotease. ADAMTS13 normally acts like a molecular scissor, cleaving large, sticky chains of von Willebrand factor (VWF) into smaller, less adhesive units. This function prevents inappropriate platelet aggregation and clot formation in the microvasculature.
In TTP, this enzyme’s activity is severely deficient, falling below 10% of the normal level. This severe deficiency causes ultra-large VWF multimers to accumulate, leading to uncontrolled platelet-rich clot formation throughout the small blood vessels. The ADAMTS13 activity test is the gold standard for confirming TTP and differentiating it from other conditions that cause MAHA and thrombocytopenia, such as Shiga toxin-associated hemolytic uremic syndrome (HUS), where ADAMTS13 activity is usually normal.
Because the ADAMTS13 assay often takes several days to process, treatment cannot wait for the final result. Samples for the ADAMTS13 test are collected immediately, but empirical treatment with therapeutic plasma exchange is initiated based on the clinical suspicion and the initial laboratory findings. The test result then confirms the diagnosis retrospectively and is essential for guiding long-term management strategies.
Defining the TTP Subtype
Once the diagnosis is confirmed by severely deficient ADAMTS13 activity, the final diagnostic step is to determine the underlying cause, classifying the TTP as either acquired (immune-mediated) or hereditary. Acquired TTP, which accounts for the majority of cases, is an autoimmune disorder where the body produces autoantibodies that inhibit or destroy the ADAMTS13 enzyme.
Testing for these specific autoantibodies, often called ADAMTS13 inhibitors, is performed concurrently with the activity assay. If the severe enzyme deficiency is accompanied by the presence of these inhibitors, the diagnosis is confirmed as acquired TTP. The absence of these inhibitors, coupled with the severe ADAMTS13 deficiency, strongly suggests the hereditary form, known as Upshaw-Schulman syndrome.
Hereditary TTP is caused by an inherited mutation in the gene responsible for producing ADAMTS13. This diagnosis is confirmed through genetic testing of the ADAMTS13 gene. Distinguishing between acquired and hereditary forms is important because it dictates the selection of long-term management and relapse prevention strategies.