Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Clinical presentation can consist of thrombocytopenia, hemolytic anemia, hematuria, gastrointestinal symptoms, neurological symptoms, and renal involvement. Diagnosis is established based on a combination of clinical symptoms and laboratory tests. Thrombotic thrombocytopenic purpura is a medical emergency and almost always fatal if appropriate treatment is not initiated promptly. Emergency management includes plasma exchange and immunosuppressive therapies.

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Overview

Definition

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by deficiency of ADAMTS-13, a von Willebrand factor (VWF) cleaving protease.

Epidemiology

  • 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

Etiology

  • 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 
  • Acquired: 
    • Development of autoantibody (inhibitor) to ADAMTS-13
    • 30x more common than hereditary TTP
    • Predisposing conditions:
      • Cancer 
      • Pregnancy
      • Bone marrow transplant
      • HIV
      • Drugs (acyclovir, antiplatelet agents (clopidogrel), quinine, oral contraceptives, chemotherapeutics)

Pathophysiology

  • 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).
Proposed Relation among the Absence of ADAMTS-13 Activity and Thrombotic Thrombocytopenic Purpura

ADAMTS-13 in the diagnosis and management of thrombotic microangiopathies:
A: Normal physiological function of ADAMTS-13
B: Absent or severely reduced activity of ADAMTS-13 in patients with TTP prevents timely cleavage of unusually large multimers of VWF during secretion by endothelial cells.

Image: “Proposed Relation” by Hematology Laboratory, Rambam Health Care Campus; and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology; Haifa, Israel. License: CC BY 3.0

Clinical Presentation

Acquired TTP

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
    • Thrombocytopenia
    • Fever
    • Acute renal failure
    • Severe neurologic symptoms

Organ-system manifestations:

  • Bleeding: 
    • Easy bruising
    • Purpura, petechiae
    • Major bleeding is rare.
  • Gastrointestinal symptoms:
    • Abdominal pain
    • Diarrhea
    • Nausea
    • Vomiting
  • Minor neurologic findings:
    • Headache
    • Confusion
    • Dizziness
    • Visual disturbances
  • Major neurologic findings:
    • Coma
    • Stroke
    • Seizures
    • Transient focal abnormalities (speech impairment, weakness/numbness)
  • Renal involvement:
    • Renal insufficiency, edema
    • Acute anuric renal failure is rare.
  • Cardiac symptoms:
    • Arrhythmia
    • Heart failure
    • MI
    • Sudden cardiac death
  • Constitutional:
    • Fever (rare)
    • Weakness
    • Not all patients are critically ill (some present with vague complaints).
Typical petechial rash due to TTP

Typical petechial rash on a patient’s lower extremities

Image: “Typical petechial rash” by Department of Emergency Medicine, University of Florida, Gainesville, FL 32610, USA. License: CC BY 3.0

Congenital TTP

Unlike acquired TTP, congenital TTP does not present with acute episodes.

Symptoms are usually mild, vague, and continuous:

  • Lethargy
  • Headache
  • Loss of concentration
  • Abdominal discomfort

Severe and life-threatening exacerbations are most likely during 2 life periods:

  • Neonatal:
    • Most critical are the 1st few days of life.
    • Severe hemolysis
    • Hyperbilirubinemia
    • May subsequently present with intermittent thrombocytopenia 
    • May remain asymptomatic until adulthood
  • Pregnancy:
    • Severe preeclampsia before 20-weeks gestation
    • Thrombocytopenia
    • Hemolysis
    • Transient neurologic symptoms
    • Acute kidney injury
    • Fetal death

Diagnosis

History

  • Easy bleeding/bruising
  • Abdominal pain/discomfort
  • Fatigue, headaches, lethargy
  • Transient neurologic impairments
  • Disorders of immune system/malignancies
  • Family history of bleeding disorders

Physical exam

  • Can be nonrevealing
  • Skin: petechiae, purpura, bruising
  • Generalized edema (renal insufficiency)
  • Focal neurologic abnormalities
  • Abnormal mental status

Laboratory studies

  • CBC:
    • 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)
    •  Thrombocytopenia
Peripheral blood film showing schistocytes

Thrombotic thrombocytopenic purpura (TTP):
Peripheral blood smear showing schistocytes (arrows) and a marked decrease in platelet numbers, indicating microangiopathic hemolytic anemia

Image: “Peripheral blood film showing schistocytes” by Department of Medicine, Division of Hematology, Division of Hematopathology, Queen Elizabeth II Health Sciences Centre, Capital District Health, Authority and Dalhousie University, Halifax, Nova Scotia Canada. License: CC BY 4.0

Imaging

  • CT or MRI of the brain
  • Indicated for neurologic symptoms
  • Rule out ischemic/hemorrhagic stroke.
Emergent head CT demonstrating the larger of two frontoparietal hemorrhages

Head CT in a patient demonstrating the larger of 2 frontoparietal hemorrhages

Image: “Emergent head CT demonstrating the larger of two frontoparietal hemorrhages” by Divisions of Infectious Disease, The George Washington University, School of Medicine and Health Sciences, Washington, DC, USA. License: CC BY 3.0

PLASMIC score

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

Score:

  • 0–4 points: low probability of TTP
  • 5 points: intermediate probability of TTP
  • 6–7 points: high probability of TTP

Management

  • 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:
    • Steroids
    • Rituximab
    • Caplacizumab (anti-VWF antibody)
    • Platelet transfusion for thrombocytopenia

Differential Diagnosis

  • 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.

References

  1. 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
  2. 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
  3. 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
  4. 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.
  5. 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.
  6. 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.

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