Thrombotic Thrombocytopenic Purpura is a rare blood disorder that involves both blood clotting and bleeding. “Thrombotic” refers to the formation of small blood clots in vessels throughout the body. “Thrombocytopenic” indicates a low number of platelets, which are the blood cells responsible for normal clotting. “Purpura” describes the purple-colored bruises that appear on the skin due to bleeding underneath.
Instead of forming clots only at the site of an injury, TTP causes clots to develop spontaneously within small blood vessels. This abnormal clotting can obstruct blood flow to major organs, leading to serious health complications. The process also consumes a large number of platelets, paradoxically increasing the risk of uncontrolled bleeding elsewhere.
Underlying Causes and Triggers
The cause of Thrombotic Thrombocytopenic Purpura is a severe deficiency in the activity of an enzyme called ADAMTS13. This enzyme manages a protein involved in clotting known as von Willebrand factor (vWF). ADAMTS13 works by cleaving large vWF multimers into smaller, less sticky pieces, which helps regulate clot formation. Without sufficient ADAMTS13 activity, these large vWF multimers accumulate and cause platelets to form widespread microthrombi.
There are two forms of TTP, distinguished by the cause of the ADAMTS13 deficiency. The most prevalent form is acquired TTP, an autoimmune condition where the immune system produces autoantibodies that attack the ADAMTS13 enzyme. This response can be initiated by triggers such as infections, pregnancy, certain medications, or other autoimmune diseases.
The rarer form is congenital TTP, also known as Upshaw-Schulman syndrome. This inherited type results from mutations in the ADAMTS13 gene, preventing the body from producing a functional enzyme. Unlike the acquired form which appears in adulthood, congenital TTP manifests in infancy or early childhood.
Signs and Symptoms
One of the most visible indicators of TTP is bleeding under the skin, which appears as purpura (larger, purple bruises) or petechiae (small, red or purple dots). Patients may also experience more overt bleeding, such as frequent nosebleeds or bleeding from the gums.
The restriction of blood flow from clots can lead to systemic symptoms. Anemia resulting from the destruction of red blood cells as they pass these clots, known as microangiopathic hemolytic anemia, causes fatigue, weakness, shortness of breath, and pale or jaundiced skin. Fever is also a common symptom.
Damage from these microthrombi can affect any organ, but the brain and kidneys are particularly susceptible. Neurological symptoms are common and can range from headaches and confusion to more severe events like seizures or stroke-like symptoms. If the clots affect the kidneys, it can lead to abnormal kidney function or even acute kidney injury.
Diagnosis Process
Diagnosing TTP is a medical emergency, as the condition can become fatal without prompt intervention. The process begins with a clinical evaluation of symptoms, but confirmation relies on laboratory tests. Because of the urgency, treatment is often started based on strong clinical suspicion before all test results are available.
The initial laboratory workup includes a complete blood count (CBC), which will reveal severe thrombocytopenia (a very low platelet count) and anemia. A peripheral blood smear is then examined under a microscope. A primary finding on the blood smear is the presence of schistocytes, which are fragmented red blood cells.
The definitive test is an ADAMTS13 assay, which measures enzyme activity in the blood. Activity of less than 10% confirms the diagnosis. The test can also detect autoantibodies against the enzyme, helping distinguish the acquired from congenital form. Since these results can take several days, initial treatment is based on the CBC and blood smear.
Treatment Approaches
The primary treatment for acquired TTP is therapeutic plasma exchange (PEX), also called plasmapheresis. This procedure involves removing the patient’s blood plasma, which contains the autoantibodies that are attacking the ADAMTS13 enzyme. The removed plasma is then replaced with fresh frozen plasma from donors, which provides a supply of functional ADAMTS13 enzyme. PEX is performed daily until the patient’s platelet count returns to a stable level and signs of organ damage have subsided.
In conjunction with PEX, immunosuppressive therapy is administered to address the underlying autoimmune cause. High-dose corticosteroids, such as prednisone, are used to suppress the immune system and reduce the production of autoantibodies. This helps to halt the attack on the ADAMTS13 enzyme and allows its levels to recover.
For patients who do not respond to PEX and steroids, more targeted therapies may be added. Rituximab is a monoclonal antibody that depletes B-cells, the immune cells that produce autoantibodies against ADAMTS13. Another agent, caplacizumab, is a nanobody that inhibits von Willebrand factor, preventing it from binding to platelets and blocking microthrombi formation. This provides rapid protection while other treatments work to restore ADAMTS13 function.
Recovery and Long-Term Outlook
After successful initial treatment and achieving remission, patients enter a phase of long-term management. Remission is defined as the normalization of the platelet count and the resolution of acute symptoms for at least 30 days after stopping PEX. Recovery from TTP requires ongoing vigilance, as the condition carries a lifelong risk of relapse, particularly for the acquired autoimmune form. Regular follow-up appointments are necessary to monitor blood counts and ADAMTS13 activity levels.
The risk of relapse is significant, as up to 40% of patients with acquired TTP may experience a recurrence. A decrease in ADAMTS13 activity during remission can be a warning sign of an impending relapse, allowing for preemptive treatment with drugs like rituximab to prevent a full episode. Patients are educated to recognize the initial symptoms of TTP, such as unusual bruising or fatigue, so they can seek immediate medical attention.
Even after recovery, some individuals may experience long-term health consequences, such as persistent neurocognitive difficulties with memory and concentration, or an increased risk of stroke. Despite these challenges, the prognosis for TTP has improved with modern therapies. Most patients who receive prompt treatment survive the acute episode.