Thrombotic Thrombocytopenic Purpura

Overview

Thrombotic Thrombocytopenic Purpura (TTP) is a rare, life-threatening blood disorder characterized by the formation of small clots (thrombi) in small blood vessels throughout the body. These clots can limit or block blood flow to vital organs, leading to severe complications. TTP is marked by a combination of thrombocytopenia (low platelet count), microangiopathic hemolytic anemia (destruction of red blood cells), and potential organ dysfunction, most commonly affecting the brain and kidneys. TTP is a medical emergency that requires prompt diagnosis and treatment to prevent fatal outcomes.

Causes

TTP is primarily caused by a deficiency or inhibition of an enzyme called ADAMTS13, which normally cleaves large von Willebrand factor (vWF) multimers. When ADAMTS13 is missing or blocked, these large vWF multimers persist and promote abnormal platelet clumping in small blood vessels, resulting in thrombosis and platelet depletion. There are two main types of TTP based on the underlying cause:

1. Acquired (Immune-Mediated) TTP:

• Caused by autoantibodies that inhibit the function of ADAMTS13.

• Most common form, often idiopathic but can be associated with autoimmune diseases (e.g., lupus), infections, pregnancy, or medications.

2. Congenital (Hereditary) TTP:

• Also known as Upshaw-Schulman syndrome.

• Caused by inherited mutations in the ADAMTS13 gene leading to reduced enzyme activity.

• Typically presents in infancy or early childhood but can remain undiagnosed until adulthood.

Symptoms

The clinical presentation of TTP can vary, but it classically involves a pentad of symptoms. However, not all patients will exhibit all five signs:

• Thrombocytopenia – Easy bruising, petechiae (small red/purple spots on the skin), or spontaneous bleeding due to low platelet count.

• Microangiopathic hemolytic anemia – Fatigue, pallor, and jaundice due to destruction of red blood cells.

• Neurological symptoms – Headache, confusion, seizures, stroke-like symptoms, or coma, resulting from small clots in cerebral vessels.

• Renal dysfunction – Elevated creatinine, proteinuria, or hematuria due to microthrombi in kidney vasculature.

• Fever – May be present in some cases, especially in acute episodes.

Symptoms often develop rapidly and require urgent medical evaluation and intervention.

Diagnosis

Timely diagnosis of TTP is critical due to the risk of rapid deterioration. A combination of clinical signs and laboratory findings is used to confirm the diagnosis:

• Complete blood count (CBC) – Reveals thrombocytopenia and anemia.

• Peripheral blood smear – Shows schistocytes (fragmented red cells), a hallmark of microangiopathic hemolytic anemia.

• Lactate dehydrogenase (LDH) – Elevated due to red cell destruction.

• Haptoglobin – Low levels indicate hemolysis.

• Indirect bilirubin – Often elevated in hemolysis.

• Coombs test – Negative (helps rule out autoimmune hemolytic anemia).

• Creatinine and urinalysis – Assess kidney involvement.

• ADAMTS13 activity assay – Confirms diagnosis by demonstrating severely reduced enzyme activity (<10%) and presence of inhibitory autoantibodies in acquired TTP.

Diagnosis is clinical in the acute setting, and treatment should not be delayed while awaiting ADAMTS13 results if TTP is strongly suspected.

Treatment

TTP is a medical emergency, and treatment must begin as soon as the condition is suspected. The primary goal is to remove the inhibitory antibodies and replenish functional ADAMTS13 enzyme activity.

1. Plasma Exchange (Plasmapheresis):

• First-line treatment – Daily plasma exchange removes autoantibodies and provides normal ADAMTS13 through donor plasma.

• Continued daily until platelet counts normalize and hemolysis subsides.

2. Immunosuppressive Therapy:

• Corticosteroids – Prednisone or methylprednisolone to suppress immune response.

• Rituximab – A monoclonal antibody used in refractory or relapsing TTP, targeting B-cells that produce autoantibodies.

3. Caplacizumab:

• An anti-vWF nanobody approved for acquired TTP that inhibits platelet-vWF interaction, rapidly reducing clot formation.

• Used alongside plasma exchange and immunosuppressants to speed recovery.

4. Supportive Care:

• Blood transfusions for severe anemia.

• Renal support if acute kidney injury occurs.

• Avoid platelet transfusions unless there is life-threatening bleeding, as they may exacerbate clot formation.

5. Treatment for Congenital TTP:

• Regular plasma infusions to supply functional ADAMTS13 enzyme.

• Prophylactic treatment may be needed during stress, illness, or pregnancy.

Prognosis

With timely and appropriate treatment, the prognosis for patients with TTP has greatly improved:

• Survival rates – Over 90% with prompt plasma exchange and immunosuppression.

• Relapse risk – Up to 30–50% of patients with acquired TTP may experience relapse and require additional therapy.

• Long-term complications – Some patients may develop chronic kidney disease, neurocognitive deficits, or fatigue.

• Congenital TTP – Requires lifelong monitoring and plasma replacement but has a good prognosis with adherence to treatment.

Regular follow-up with a hematologist, monitoring of ADAMTS13 levels, and early treatment of relapses are essential to prevent life-threatening complications and maintain long-term health in patients with TTP.