What are Thrombotic Thrombocytopenic Purpura (TTP) and Thrombotic Thrombocytopenic Purpura-like conditions (TTP-like conditions)?

What is TTP?

Thrombotic Thrombocytopenic Purpura (TTP) is a rare, life-threatening thrombotic microangiopathy caused by severe deficiency (<10% activity) of ADAMTS13, the von Willebrand factor-cleaving protease, resulting in microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia from disseminated microvascular platelet-rich thrombi. 1, 2

Pathophysiology

• ADAMTS13 deficiency (activity <10%) prevents cleavage of ultra-large von Willebrand factor multimers, which remain in their elongated active form and cause spontaneous platelet activation and aggregation in arterioles and capillaries throughout the microcirculation 1, 3, 4

• Two forms exist: acquired TTP (iTTP) is most common in adults and caused by autoantibodies against ADAMTS13, while congenital TTP (cTTP) results from biallelic mutations in the ADAMTS13 gene and typically presents in childhood or during pregnancy 2, 4

• The microthrombi formation leads to mechanical shearing of red blood cells as they pass through occluded vessels, producing the characteristic schistocytes seen on peripheral smear 3

Clinical Presentation

• Classic pentad includes microangiopathic hemolytic anemia, thrombocytopenia, neurological abnormalities, renal dysfunction, and fever, though not all five features are present in every case 1

• Neurological manifestations are the most prominent feature distinguishing TTP from other thrombotic microangiopathies, including confusion, headache, focal deficits, seizures, and altered consciousness due to cerebral microvascular thrombosis 1, 2, 3

• Visual disturbances such as blurred vision or visual field defects may occur 1

• Renal dysfunction presents with elevated creatinine but is typically less severe than in hemolytic uremic syndrome (HUS), which helps differentiate the two conditions 1

Laboratory Findings

• Severe thrombocytopenia with platelet counts often <30,000/μL due to consumption in microthrombi formation 1, 2

• Microangiopathic hemolytic anemia characterized by schistocytes on peripheral smear, elevated LDH, elevated indirect bilirubin, and reticulocytosis 1

• Negative direct antiglobulin test (DAT/Coombs) distinguishes TTP from autoimmune hemolytic anemia 1, 3

• Normal coagulation studies (PT, aPTT, fibrinogen) are critical for excluding disseminated intravascular coagulation (DIC), which would show prolonged times and elevated INR 1

• ADAMTS13 activity <10% with or without detectable anti-ADAMTS13 antibodies confirms the diagnosis, though treatment must be initiated before results are available if clinical suspicion is high 1, 3, 4

Diagnostic Differentiation

TTP must be distinguished from other conditions that can present similarly:

• Hemolytic Uremic Syndrome (HUS): More severe renal dysfunction, typically follows acute gastrointestinal illness with bloody diarrhea, ADAMTS13 activity remains normal or only mildly reduced 1

• Malignant hypertension-associated TMA: Severe blood pressure elevation with advanced retinopathy, ADAMTS13 activity normal or only mildly reduced 1

• Drug-induced thrombocytopenia: Does not cause microangiopathic hemolytic anemia with schistocytes 1

• Rocky Mountain Spotted Fever (RMSF): RMSF-associated neurologic manifestations, renal failure, and thrombocytopenia have led to confusion with TTP diagnosis, but RMSF presents with fever, headache, and characteristic rash progression, and responds to doxycycline 5

Critical Diagnostic Pitfalls

• Overlooking TTP in patients with isolated neurological symptoms can delay diagnosis, as neurological manifestations may be attributed to other causes like meningitis or stroke 1

• Waiting for ADAMTS13 results before initiating treatment is dangerous—plasma exchange must be started immediately when clinical probability is high, as it may take several days to obtain ADAMTS13 activity results 3

• Misdiagnosing as ITP: The presence of hemolysis with schistocytes immediately excludes isolated immune thrombocytopenic purpura (ITP), which has normal ADAMTS13 activity and no microangiopathic hemolysis 1

Treatment Urgency

• TTP is potentially lethal without prompt recognition and treatment, with survival improving from <10% to 80-90% with plasma exchange therapy 2, 6, 4

• Daily plasma exchange with fresh frozen plasma replacement is first-line therapy, supplying deficient ADAMTS13 and removing autoantibodies 2, 4

• Immunosuppression with corticosteroids and rituximab (anti-CD20 monoclonal antibody) targets ADAMTS13 autoantibodies in acquired TTP 2, 4

• Caplacizumab (anti-von Willebrand factor antibody fragment) inhibits platelet-VWF interaction and shows beneficial effects when added to standard treatment 3, 4

• Traditional anticoagulant and antiplatelet strategies are not effective in TTP despite the predominance of thrombotic manifestations 6