• Clinical science

Thrombotic thrombocytopenic purpura (TTP)

Summary

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, a condition in which microthrombi, consisting primarily of platelets, form and occlude the microvasculature (i.e., the arterioles and capillaries). The other main thrombotic microangiopathy is hemolytic uremic syndrome (HUS). TTP occurs primarily in adults and is typically due to acquired autoantibodies against a proteolytic enzyme that cleaves von Willebrand factor (vWF). It is a clinical diagnosis based on the following pentad of findings: fever, neurological abnormalities, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function. If TTP is strongly suspected and initial laboratory tests support the diagnosis, treatment should begin immediately, as the condition may be fatal if left untreated. First-line treatment is plasma exchange therapy.

Epidemiology

  • Primarily adult individuals (median age at diagnosis: ∼ 40 years)
  • More common in women and in black populations

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[3][4][5][6]

Pathophysiology

TTP is a thrombotic microangiopathy, a condition in which microthrombi form and occlude the microvasculature; . The other main thrombotic microangiopathy is hemolytic uremic syndrome (HUS). Although TTP and HUS share similarities in both pathophysiological findings and clinical features, these conditions differ in etiology; TTP, unlike HUS, is caused by a deficiency of ADAMTS13.

  1. Autoantibodies or gene mutationsdeficiency of ADAMTS13 (a metalloprotease that cleaves von Willebrand factor)
  2. ↓ Breakdown of vWF multimers → vWF multimers accumulate on endothelial cell surfaces
  3. Platelet adhesion and microthrombosis
  4. Microthrombi → fragmentation of RBCs with schistocyte formation → hemolytic anemia
  5. Arteriolar and capillary microthrombosis → end-organ ischemia and damage, especially in the brain and kidneys (potentially resulting in acute kidney injury or stroke)

ADAMTS13 deficiency → excess vWF microthrombus formation → blockage of small vessels RBC fragmentation (hemolysis) and end-organ damage

References:[7][3][2][4]

Clinical features

TTP patients are typically previously healthy adults. The pentad of clinical findings consists of:

  1. Fever
  2. Neurological signs and symptoms
  3. Low platelet count (i.e. thrombocytopenia)
  4. Microangiopathic hemolytic anemia
  5. Impaired renal function

The typical patient is a previously healthy adult presenting with mental status changes, fever, petechiae, fatigue, and pallor. Laboratory tests will then indicate hemolytic anemia and possibly acute kidney injury (AKI). Impaired kidney function may not be present, and only a minority of patients will present with all five clinical findings.

Mnemonic for TTP symptoms: “Nasty Fever Ruined My Tubes” (N Neurological symptoms, F Fever, R Renal function impairment, M Microangiopathic hemolytic anemia, T Thrombocytopenia)


References:[7][1][8]

Diagnostics

While PT and aPTT are normal or only mildly elevated in TTP and HUS (no consumption coagulopathy), they are markedly elevated in DIC (consumption of platelets and all coagulation factors).

References:[9][1][5]

Differential diagnoses

See differential diagnosis of platelet disorders.

The differential diagnoses listed here are not exhaustive.

Treatment

Treatment should be started after a presumptive diagnosis is made based on clinical features and initial labs (e.g., blood count, peripheral smear, creatinine).

  • Monitoring and correction
    • Fluid status abnormalities
    • Electrolyte disturbances
    • Acid-base abnormalities
    • RBC transfusions
  • Prompt initiation of plasma exchange therapy (PEX)
  • Glucocorticoids (e.g., prednisone)
  • Rituximab is reserved for severe cases.
  • Platelet transfusion should only be reserved for patients who are bleeding or require an invasive procedure.

TTP requires urgent diagnosis and treatment! Waiting for test results to confirm ADAMTS13 deficiency should not delay treatment.

References:[10]

Complications

TTP can result in microthrombus formation and complications in many organs of the body.

References:[9][10][1][11]

We list the most important complications. The selection is not exhaustive.

Prognosis

The prognosis depends primarily on prompt initiation of treatment. Timely treatment can prevent acute complications (AKI, coma, and death), as well as progression to chronic renal failure.

References:[9][10]