Thrombotic thrombocytopenic purpura

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). TTP occurs primarily in adults and is typically due to acquired autoantibodies against a proteolytic enzyme (ADAMTS13) that cleaves von Willebrand factor (vWF). The classic pentad of findings (fever, neurological abnormalities, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function) is seen in a minority of patients. TTP is a hematologic emergency. If TTP is strongly suspected and initial laboratory tests support the diagnosis, treatment with plasma exchange should begin immediately, as the condition may be fatal if left untreated.

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

Epidemiological data refers to the US, unless otherwise specified.

• ADAMTS13 deficiency/inhibition ^[1]
  • Acquired TTP (∼ 95%): autoantibodies against ADAMTS13 (see “Pathophysiology” below)
  • Congenital TTP (∼ 5%): gene mutations resulting in deficiency of ADAMTS13
• Risk factors ^[1]
  • Systemic disease: cancer, HIV, SLE, infections
  • Pregnancy
  • Drugs

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 mutations → deficiency 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

TTP patients are typically previously healthy adults. Microangiopathic hemolytic anemia and thrombocytopenia may be the only presenting signs. However, the classic pentad of clinical findings consists of: ^[2][3][4]

• Fever
• Neurological signs and symptoms
  • Altered mental status, delirium
  • Seizure, focal defects, stroke
  • Headache, dizziness
• Low platelet count (i.e. thrombocytopenia)
  • Petechiae, purpura
  • Mucosal bleeding
  • Prolonged bleeding after minor cuts
• Microangiopathic hemolytic anemia
  • Fatigue, dyspnea, and pallor
  • Jaundice
• Impaired renal function
  • Hematuria, proteinuria
  • Oliguria, anuria (uncommon)

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.

“Nasty Fever Ruined My Tubes:” Neurological symptoms, Fever, Renal function impairment, Microangiopathic hemolytic anemia, Thrombocytopenia are the clinical features of TTP.

Approach ^[4]

• Suspect TTP in patients with microangiopathic hemolytic anemia and thrombocytopenia.
• Obtain laboratory studies and targeted clinical history to:
  • Calculate PLASMIC score
  • Assess disease severity
  • Confirm diagnosis (with ADAMTS13 testing)
• Obtain further diagnostic studies as indicated to identify a secondary cause and rule out thrombotic complications.

Laboratory studies ^[4][5]

Initial tests ^[3][6][7]

• CBC
  • ↓ Platelets (typically < 30,000/mm³)
  • ↓ Hemoglobin
• Peripheral blood smear
  • Large number of schistocytes (up to 4–8% of RBCs)
  • Low number of platelets
• Hemolysis studies
  • ↑ Reticulocytes
  • ↓ Haptoglobin
  • ↑ LDH
  • Negative direct Coombs test
• Coagulation studies
  • Normal or mildly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT)
  • Normal or mildly elevated fibrin degradation products and D-dimer levels
• Liver chemistries: ↑ indirect bilirubin
• BMP: ↑ BUN and ↑ creatinine may be seen.
• Troponin: to rule out cardiac ischemia ^[4]
• Urinalysis: hematuria, proteinuria

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

Confirmatory tests ^[5][6]

Obtain ADAMTS13 activity and inhibitor testing in all patients.

• ADAMTS13 activity
  • < 10%: positive (severe deficiency)
  • 10–20%: borderline
  • > 20%: negative
• ADAMTS13 inhibitor or anti-ADAMTS13 IgG
  • Positive: immune-mediated TTP
  • Negative: Further testing (e.g., genetic testing) may be indicated to assess for congenital TTP.

Obtain ADAMTS13 testing before the initiation of plasma exchange or administration of blood products; do not delay treatment waiting for results. ^[4]

PLASMIC score

The PLASMIC score is a clinical risk assessment tool, based on easily attainable clinical information, that is used to predict the likelihood of severe ADAMTS13 deficiency in patients with suspected TTP. The total score helps direct further management.

PLASMIC score criteria include Platelets, hemoLysis, no Active malignancy, no Solid or Stem-cell transplant, MCV, INR, Creatinine.

Additional testing ^[3]

Consider the following studies as indicated to identify serious complications and secondary causes of TTP.

• Studies to identify secondary causes (e.g., pregnancy, SLE, HIV, malignancy)
• ECG: to assess for myocardial infarction; may show repolarization abnormalities
• CT or MRI brain: to assess for stroke

See “Differential diagnosis of platelet disorders”, “Diagnostic studies for hemolytic anemia”, and “Diagnostics in suspected MAHA.”

The differential diagnoses listed here are not exhaustive.

Approach ^[4][5]

• Admit all patients with suspected or confirmed TTP to an ICU.
• Obtain prompt central venous access.
• Provide supportive care for all patients.
• Consult hematology for guidance.
• Initiate empiric treatment with:
  • Plasma exchange therapy
  • Glucocorticoids
• Provide targeted treatment if ADAMTS13 activity levels are available.

TTP requires urgent diagnosis and treatment. Do not delay treatment while awaiting test results to confirm ADAMTS13 deficiency.

Supportive care ^[4]

• Monitoring
  • Continuous pulse oximetry and cardiac telemetry
  • Serial neurological examinations
• Fluids and electrolytes
  • Correct electrolyte disturbances.
  • Provide intravenous fluid therapy as indicated.
  • Identify and correct acid-base disorders.
• Transfusions
  • Avoid prophylactic platelet transfusions.
  • Consider therapeutic platelet transfusions for patients who are bleeding or require an invasive procedure.
  • RBC transfusions: Follow a restrictive transfusion strategy (consider pRBC transfusion if Hb is ≤ 7 g/dL). ^[9]
• VTE prophylaxis
  • Mechanical VTE prophylaxis: if platelet level is < 50,000/mm³
  • Pharmacological VTE prophylaxis: if platelet level is ≥ 50,000/mm³

Empiric therapy ^[4]

• Initiate treatment in consultation with hematology.
• Prompt initiation of plasma exchange therapy (PEX)
• High-dose glucocorticoids (off label)
  • Prednisone ^[4]
  • OR methylprednisolone ^[4]
• Patients with a high pretest probability of TTP (based on clinical judgment or PLASMIC score ≥ 6)
  • Consider early caplacizumab if ADAMTS13 activity testing is available. ^[10]
    • Humanized bivalent variable-domain antibody used in the treatment of acquired or immune-mediated TTP
    • Prevents microvascular thrombosis by inhibiting the interaction of vWF and platelets
  • Consider rituximab if ADAMTS13 activity testing is not available.

Do not start caplacizumab if there is no access to ADAMTS13 activity testing, regardless of the pretest probability of TTP. ^[5]

Response to treatment ^[11]

Clinical signs of response include : ^[7]

• Platelet level: sustained ≥ 150,000/mm³
• LDH: < 1.5× the ULN
• No signs of new or worsening ischemic organ injury

TTP can result in microthrombus formation and complications in many organs of the body. ^[12]

• CNS: seizures, coma, stroke, paresis
• GI tract: hemorrhagic colitis; bowel necrosis, perforation, stricture; peritonitis; intussusception
• Heart: ischemia and fluid overload
• Pancreas: transient or permanent diabetes mellitus
• Liver: hepatomegaly, transaminase elevations
• Kidney: hypertension, chronic kidney disease (CKD), end-stage renal disease (ESRD)

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

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.

• The mortality rate of TTP is favorable with treatment: 10–20%