Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by deficiency of ADAMTS-13, a von Willebrand factor (VWF) cleaving protease.
- Annual incidence: 3 cases per million in the United States (rare)
- Woman:man ratio is 2:1.
- More common in African Americans
- Affects adults predominantly:
- Average age: 41 years old
- Age range: 9–78 years old
- Deficiency of active metalloproteinase ADAMTS-13 (< 10% activity)
- Congenital/hereditary (rare):
- Also known as Upshaw-Schulman syndrome
- Autosomal recessive condition (> 200 pathogenic mutations)
- TTP in children is more likely hereditary.
- May 1st manifest in young women during pregnancy
- Development of autoantibody (inhibitor) to ADAMTS-13
- 30x more common than hereditary TTP
- Predisposing conditions:
- Bone marrow transplant
- Drugs (acyclovir, antiplatelet agents (clopidogrel), quinine, oral contraceptives, chemotherapeutics)
- ADAMTS-13 is a protease that cleaves large multimers of VWF.
- Accumulation of large multimers results in activation of platelet aggregation.
- Activation and recruitment of excessive amounts of platelets will cause thrombocytopenia.
- Excess circulating multimers of VWF promote adhesion of platelets to endothelium.
- Aggregation of platelets leads to thrombosis and narrowing of the vessel.
- Narrowing of vessels → fragmentation of RBCs (schistocytes)
- Fragmented RBCs are then cleared by the spleen (hemolysis).
Classic TTP pentad:
- Only present in < 5% of patients
- A complete pentad usually indicates late, untreated disease with high mortality.
- Findings include:
- Microangiopathic hemolytic anemia
- Acute renal failure
- Severe neurologic symptoms
- Easy bruising
- Purpura, petechiae
- Major bleeding is rare.
- Gastrointestinal symptoms:
- Abdominal pain
- Minor neurologic findings:
- Visual disturbances
- Major neurologic findings:
- Transient focal abnormalities (speech impairment, weakness/numbness)
- Renal involvement:
- Renal insufficiency, edema
- Acute anuric renal failure is rare.
- Cardiac symptoms:
- Heart failure
- Sudden cardiac death
- Fever (rare)
- Not all patients are critically ill (some present with vague complaints).
Unlike acquired TTP, congenital TTP does not present with acute episodes.
Symptoms are usually mild, vague, and continuous:
- Loss of concentration
- Abdominal discomfort
Severe and life-threatening exacerbations are most likely during 2 life periods:
- Most critical are the 1st few days of life.
- Severe hemolysis
- May subsequently present with intermittent thrombocytopenia
- May remain asymptomatic until adulthood
- Severe preeclampsia before 20-weeks gestation
- Transient neurologic symptoms
- Acute kidney injury
- Fetal death
- Easy bleeding/bruising
- Abdominal pain/discomfort
- Fatigue, headaches, lethargy
- Transient neurologic impairments
- Disorders of immune system/malignancies
- Family history of bleeding disorders
- Can be nonrevealing
- Skin: petechiae, purpura, bruising
- Generalized edema (renal insufficiency)
- Focal neurologic abnormalities
- Abnormal mental status
- Thrombocytopenia (platelets < 50 X 109/L)
- ↓ Hemoglobin (< 10 g/dL; hemolysis)
- Coagulation studies:
- Increased bleeding time
- Normal PT, aPTT, INR, and fibrinogen
- Renal function:
- ↑ Creatinine
- ↑ BUN
- Liver function tests:
- ↑ Unconjugated bilirubin
- ↓ Haptoglobin
- ↑ LDH
- ADAMTS-13 activity assays:
- < 10% activity
- > 60% activity usually rules out TTP diagnosis.
- Inhibitor levels can be measured.
- If no inhibitors detected, genetic testing for hereditary TTP
- Blood smear:
- Fragmented RBCs (schistocytes)
- CT or MRI of the brain
- Indicated for neurologic symptoms
- Rule out ischemic/hemorrhagic stroke.
The PLASMIC score predicts the probability of TTP in the presence of schistocytes on blood smear.
PLASMIC criteria (1 point for each):
- Platelet count < 30,000/μL
- Hemolysis (defined by reticulocyte count > 2.5%, undetectable haptoglobin, or indirect bilirubin > 2 mg/dL)
- No active cancer
- No solid organ or stem cell transplant
- MCV < 90 fL
- INR < 1.5
- Creatinine < 2.0 mg/dL
- 0–4 points: low probability of TTP
- 5 points: intermediate probability of TTP
- 6–7 points: high probability of TTP
- TTP episode/exacerbation should be treated emergently.
- Almost always fatal if not promptly treated
- With appropriate treatment, survival is > 90%.
- The mainstay of treatment is plasma exchange (PEX):
- Replenishes functional ADAMTS-13
- Removes offending antibodies
- Performed daily until recovery
- Plasma infusion (temporizing measure if no plasma exchange available)
- Additional therapies:
- Caplacizumab (anti-VWF antibody)
- Platelet transfusion for thrombocytopenia
- Hemolytic uremic syndrome: a disease mainly in children or the elderly. Shiga toxin results in severe thrombocytopenia, hemolytic anemia, and resultant kidney injury. Patients usually have a gastrointestinal prodrome before the development of thrombocytopenia and anemia. Hemolytic uremic syndrome has symptoms very similar to TTP; the difference is gastrointestinal prodrome and management (mainly supportive).
- Immune-mediated thrombocytopenic purpura (previously known as idiopathic thrombocytopenic purpura): a condition developing secondary to immune-mediated destruction of platelets resulting in thrombocytopenia. IgG antibodies tag the platelets, which are then cleared by the spleen. Immune-mediated thrombocytopenic purpura is a diagnosis of exclusion and is managed with steroids and IV immune globulin.
- Von Willebrand’s disease (VWD): The most common inherited bleeding disorder, VWD is caused by an abnormality of VWF. Bruising and mucocutaneous bleeding are common manifestations. Most individuals with VWD have a normal CBC, and many have normal coagulation studies. However, some individuals have a prolonged aPTT. Treatment is usually with desmopressin.
- Disseminated intravascular coagulation (DIC): A complication of many diseases, DIC is an imbalance between procoagulants and anticoagulants. There is an excessive consumption of platelets, coagulation factors, and fibrinogen due to thrombus formation. Presentation includes signs and symptoms of thrombocytopenia. The disease has high morbidity and mortality and requires emergent care, which involves blood product transfusion and treatment of the underlying process.
- Henoch-Schönlein purpura: an autoimmune small-vessel vasculitis typically presenting as a tetrad of abdominal pain, hematuria, arthritis, and purpuric rash. Diagnosis is commonly established clinically and management is mostly supportive with a focus on symptoms.
- Infections and drugs: many infections and medications can cause thrombocytopenia by several nonimmune mechanisms. Examples include bone marrow suppression, hypersplenism, and platelet consumption.
- George, J., and Cuker, A. (2021), Acquired TTP: Initial treatment. In Leung, L. (Ed.), UpToDate. Retrieved March 06, 2021, from https://www.uptodate.com/contents/acquired-ttp-initial-treatment
- George, J., and Cuker, A. (2021), Acquired TTP: Clinical manifestations and diagnosis. In Leung, L. (Ed.), UpToDate. Retrieved March 06, 2021, from https://www.uptodate.com/contents/acquired-ttp-clinical-manifestations-and-diagnosis
- George, J., and Nester, C. (2021), Approach to the patient with suspected TTP, or other thrombotic microangiopathy (TMA). In Leung, L. (Ed.), UpToDate. Retrieved March 06, 2021, from https://www.uptodate.com/contents/approach-to-the-patient-with-suspected-ttp-hus-or-other-thrombotic-microangiopathy-tma
- Vesely SK, George JN, Lämmle B, et al. (2003). ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003; 102:60.
- Page EE, Kremer Hovinga JA, Terrell DR, et al. (2017). Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv 2017; 1:590.
- Reese JA, Muthurajah DS, Kremer Hovinga JA, et al. (2013). Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features. Pediatr Blood Cancer.