Thrombotic thrombocytopenic purpura (TTP) is a rare but severe disseminated thrombotic microangiopathy-hemorrhagic syndrome characterized primarily by microangiopathic hemolysis, thrombocytopenic purpura, neurological abnormalities, varying degrees of renal impairment, and fever.
Pathogenesis
TTP is now known to result from a deficiency or reduced activity of von Willebrand factor-cleaving protease (vWF-cp), also known as ADAMTS13. In normal plasma, von Willebrand factor (vWF) exists as multimers with molecular weights ranging from 500,000 to 20,000,000 Da. When ADAMTS13 is deficient or its activity is reduced, it fails to adequately cleave ultralarge vWF (UL-vWF) multimers. These UL-vWF multimers exhibit heightened adhesive properties, promoting platelet adhesion and aggregation, which result in widespread intravascular platelet thrombi formation in the microvasculature. This leads to consumptive thrombocytopenia and secondary bleeding. The narrowing of microvascular lumens causes injury and functional impairment of affected organs and tissues. As red blood cells pass through these narrowed lumens, they are mechanically fragmented, resulting in hemolysis. Since this process does not activate the coagulation cascade, prothrombin time (PT) and activated partial thromboplastin time (APTT) remain normal.
Classification
TTP is classified into congenital thrombotic microangiopathic hemolytic anemia (hereditary TTP) and immune-mediated TTP based on underlying mechanisms.
Hereditary TTP
Hereditary TTP, also known as Upshaw-Schulman syndrome, arises from mutations in the ADAMTS13 gene, leading to severely reduced enzyme activity (<10%) or a complete deficiency. Episodes are often triggered by factors such as infections, stress, or pregnancy.
Immune-Mediated TTP
Immune-mediated TTP involves the production of autoantibodies (inhibitors) against ADAMTS13, which neutralize or inhibit its activity, leading to a reduction in ADAMTS13 activity (<10%). This is the primary clinical subtype of TTP. While most cases are idiopathic, some are secondary to triggers such as pregnancy, medications, autoimmune diseases, severe infections, malignancies, or hematopoietic stem cell transplantation.
Clinical Manifestations
Classic clinical presentations of TTP include a pentad of symptoms: microangiopathic hemolysis, thrombocytopenia, neurological signs and symptoms, renal impairment, and fever.
Thrombocytopenia generally manifests as bleeding from the skin and mucosa or retinal hemorrhages. Severe cases may involve visceral or intracranial bleeding.
Neurological and neuropsychiatric symptoms vary widely and may include headache, altered consciousness, apathy, aphasia, vision impairment, delirium, or hemiplegia.
Microangiopathic hemolysis may present as jaundice of the skin and sclera, along with darkened urine.
Renal findings include proteinuria, hematuria, and varying degrees of renal dysfunction.
Fever occurs in about half of patients.
Laboratory Tests
Complete Blood Count and Peripheral Smear
Findings include varying degrees of anemia, elevated reticulocyte count, and more than 1% fragmented red cells; thrombocytopenia is also present.
Biochemical Studies
Laboratory findings include elevated unconjugated bilirubin, reduced serum haptoglobin levels, increased lactate dehydrogenase (LDH), and elevated blood urea nitrogen (BUN) and creatinine, reflecting renal involvement.
Coagulation Studies
APTT, PT, and fibrinogen levels are typically within normal ranges. Analysis of vWF multimers may reveal the presence of UL-vWF.
Plasma ADAMTS13 Activity and Inhibitor Testing
ADAMTS13 activity is markedly reduced (<10%). Immune-mediated TTP is associated with the presence of inhibitors (positive inhibitor test).
Genetic Mutation Analysis
Hereditary TTP is characterized by homozygous or compound heterozygous mutations in the ADAMTS13 gene.
Diagnosis and Differential Diagnosis
Key Points for Diagnosis
The diagnosis of TTP lacks specificity. A tentative diagnosis of TTP can be considered in the presence of clinical manifestations (commonly microangiopathic hemolytic anemia and thrombocytopenia), along with characteristic findings from blood tests and biochemical evaluations. Confirmation is achieved when plasma ADAMTS13 activity is detected at levels below 10%.
Differential Diagnosis
Conditions requiring differentiation from TTP include hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), HELLP syndrome, Evans syndrome, systemic lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), and eclampsia.
Treatment
TTP is an aggressive and life-threatening condition with a high mortality rate. Treatment should begin as early as possible for suspected or confirmed cases. Platelet transfusion is generally avoided and should only be considered in cases of life-threatening bleeding.
Plasma Exchange and Fresh Frozen Plasma Transfusion
Plasma exchange is the first-line treatment. Fresh plasma or fresh frozen plasma (FFP) is used, administered at a dose of 40–60 ml/kg per session, once daily. Treatment is continued until platelet counts return to normal for at least 48 hours, after which the frequency can be gradually tapered before stopping plasma exchange. For patients without access to plasma exchange or in cases of hereditary TTP, fresh plasma or FFP may be infused, typically at a dose of 20–40 ml/(kg·day).
Pharmacological Treatment
Glucocorticoids
Glucocorticoids may be administered in conjunction with plasma exchange. Methylprednisolone is given intravenously at a dose of 1 g/day for three consecutive days, or prednisone may be given orally at 1 mg/(kg·day), followed by gradual tapering depending on the clinical response.
Anti-CD20 Monoclonal Antibody
This therapy selectively depletes B lymphocytes, reducing ADAMTS13 inhibitor levels. The recommended dose is 375 mg/m2 once weekly for four doses. The timing of administration relative to plasma exchange is recommended to be 20–24 hours.
Caplacizumab
A humanized anti-vWF monoclonal antibody, caplacizumab inhibits the interaction between vWF multimers and platelet GPⅠb, thereby preventing thrombus formation. The recommended dose is an initial intravenous infusion of 10 mg, followed by daily subcutaneous injections of 10 mg starting the next day. Administration should continue for 30 days after discontinuation of plasma exchange.
Immunosuppressants
Agents such as bortezomib and cyclosporine are utilized in refractory or relapsed cases of immune-mediated TTP.
Other Treatments
Other treatments include intravenous immunoglobulin (IVIG), antiplatelet agents, N-acetylcysteine, and supplementation with folic acid. Additionally, red blood cell transfusions may be provided as needed.