II. Epidemiology

  1. Peak age 30 to 40 years old
  2. Slightly more common in women
  3. Rare: 2 to 4 (up to 11) cases per 1 million people per year in the United States

III. Pathophysiology

  1. TTP is a Microangiopathic Hemolytic Anemia
  2. ADAMTS13 Protease dysfunction
    1. Von Willebrand Factor (vWF) is exposed when intravascular injury occurs
      1. vWF is analogous to a net that traps Platelets, forming a transient plug
      2. The plug is typically limited and stops bleeding without thrombosing the vessel
    2. ADAMTS13 normally cleaves the long chain Von Willebrand Factor (vWF), thus limiting the plug
      1. When ADAMTS13 is defective or absent, vWF forms traps large complexes of Platelets
      2. Vessel blocks with these large complexes of vWF and Platelets resulting in thrombosis
    3. ADAMTS13 deficiency predisposes to TTP
      1. ADAMTS13 deficiency may be acquired (e.g. autoantibodies)
      2. ADAMTS13 deficiency may also occur with genetic mutation (Upshaw-Schulman Syndrome)
      3. Those with ADAMTS13 deficiency may develop TTP in response to stress or infection
  3. Overlap with several Gastroenteritis related conditions
    1. Shiga-toxin Enterocolitis
    2. Hemolytic Uremic Syndrome (E. coli 0157:H7 esp. in children)

IV. Risk Factors

  1. Obesity
  2. African American
  3. Female gender
  4. HIV Infection
  5. Rheumatologic Disease
  6. Clopidogrel (Plavix)

V. Symptoms

  1. Headaches
  2. Paresthesias
  3. Gastrointestinal symptoms (up to 70% of cases, depending on cause)
    1. Abdominal Pain
    2. Nausea or Vomiting
    3. Diarrhea

VI. Signs: Classic Presentation

  1. Consider in any patient presenting with Anemia and Thrombocytopenia
  2. Triad: Most common presentation (75% of cases)
    1. Thrombocytopenic Purpura
    2. Microangiopathic Hemolytic Anemia
    3. Neurologic changes (Seizures, Transient Ischemic Attack) at presentation or prior and resolved
  3. Additional features as part of full classic presentation (5 features present in only 7-33% of patients)
    1. Fever
    2. Acute Renal Failure

VII. Signs

  1. Fever
    1. Present in 10% of cases at presentation (but up to 90% of patients will experience fever during course)
  2. Skin
    1. Petechiae or Purpura (50%)
    2. Bleeding sites (rare)
    3. Jaundice
  3. Neurologic changes (often transient effects due to unstable Platelet clots)
    1. Major Neurologic Changes (40% of patients)
      1. Altered Level of Consciousness to coma
      2. Transient Ischemic Attack or Cerebrovascular Accident
      3. Seizures
    2. Minor Neurologic Changes (25% of patients)
      1. Headache
      2. Transient confusion
  4. Abdominal exam
    1. Splenomegaly (most patients with TTP)

VIII. Differential Diagnosis

  1. See Thrombocytopenia
  2. See Hemolytic Anemia
  3. Disseminated Intravascular Coagulation (DIC)
    1. Increased Fibrinogen and coagulation studies
  4. Hemolytic Uremic Syndrome (HUS)
    1. Most common in children (esp. 6 months to 4 years old)
      1. Children rarely have TTP without HUS, but adults can uncommonly present with HUS during outbreaks
    2. Presents as TTP and Acute Renal Failure, bloody Diarrhea and Abdominal Pain
    3. Associated with Shiga toxin-producing Escherichia coli infection (E Coli 0157)
    4. HUS is associated with worse Renal Injury and increased Serum Creatinine
    5. HUS-related Thrombocytopenia is not as severe as with TTP
  5. Evans Syndrome
    1. Thromboyctopenia with Microangiopathic Hemolytic Anemia (MAHA)
    2. However ADAMTS levels are normal
    3. Treated with Corticosteroids
    4. Better prognosis than standard Thrombotic Thrombocytopenic Purpura

IX. Labs: Initial

  1. Complete Blood Count
    1. Platelet Count <50,000
      1. Platelet Count may be <20,000/uL
    2. Hemoglobin <10 g/dl
      1. Severe Microangiopathic Hemolytic Anemia is common
  2. Comprehensive Metabolic Panel
    1. Acute Kidney Injury
      1. Serum Creatinine increased in severe cases, but often normal (or mildly elevated)
  3. Coagulation Studies
    1. INR/ProTime (PT) normal
    2. Partial Thromboplastin Time (PTT) normal
    3. Fibrinogen normal
    4. D-Dimer
      1. Often elevated in TTP and may predict prognosis
      2. Wang (2020) Medicine 99(13):e19563 +PMID: 32221074 [PubMed]
  4. Hemolysis
    1. Unconjugated Bilirubin increased
    2. Reticulocyte Count increased
    3. Haptoglobin increased
    4. Lactate Dehydrogenase (LDH) increased
    5. Indirect Bilirubin increased
  5. Urinalysis
    1. Hematuria
    2. Proteinuria
  6. Peripheral Smear with Hemolysis signs (obtain on all patients suspected for TTP)
    1. Schistocytes or helmet cells (RBC fragments) suggests Microangiopathic Hemolytic Anemia (MAHA)
    2. MAHA is also seen in Hemolytic Uremic Syndrome

X. Labs: Specific

  1. ADAMTS13 Levels (Indicated in Plasmic Score >=6)
    1. ADAMTS13 activity level decreased
    2. anti-ADAMTS13 Antibody
  2. Other testing
    1. Von Willebrand Factor gel electrophoresis

XI. Diagnosis

  1. See Plasmic Score (ADAMTS13 Enzyme Activity Prediction Tool)
  2. Thrombocytopenia and Microangiopathic Hemolytic Anemia (MAHA)
    1. Without obvious alternative diagnosis, manage Thrombocytopenia and MAHA as TTP
    2. Also seen in Hemolytic Uremic Syndrome (see differential diagnosis above)

XII. Management

  1. Treat as a hematologic emergency
    1. Early Hematology Consultation
    2. Admit all patients
  2. Treatment and testing is directed by Plasmic Score (ADAMTS13 Enzyme Activity Prediction Tool)
  3. Immediate management
    1. High dose Corticosteroids
      1. Methylprednisolone 1 mg/kg/day
    2. Plasmapheresis
      1. Withdrawal via 16-18 gauge intravenous catheter
      2. Return via 18 gauge intravenous catheter
      3. Plasma exchange with Cryosupernate or Fresh Frozen Plasma (FFP)
        1. Cryosupernate (preferred) or Fresh Frozen Plasma replace withdrawn fluid
        2. Cryosupernate and FFP contain functional ADAMTS13
    3. Fresh Frozen Plasma (FFP)
      1. May be given to temporize if plasmaphoresis is delayed >6 hours
  4. Adjunctive measures
    1. Aspirin or Dipyridamole (consider as Platelet Counts are improving >50k and no signs of bleeding)
    2. Avoid Platelet Transfusion unless catastrophic bleeding (e.g. Intracranial Hemorrhage)
      1. Significant Hemorrhage is rare in TTP
    3. Obtain central venous access
    4. Seizure Management
      1. See Status Epilepticus
  5. Refractory case management
    1. Rituximab
      1. Indicated for frequent relapses or failure to respond to plasma exchange
    2. Splenectomy
    3. Gammaglobulin
    4. Vincristine

XIII. Prognosis

  1. Untreated: 80% mortality within 3 months
  2. Treatment with plasmapheresis: 17% mortality

XIV. References

  1. Arora and Herbert in Majoewsky (2013) EM:Rap 13(3):1
  2. Long and Werner (2023) EM:Rap 23(2): 9-12
  3. Marx (2002) Rosen's Emergency Med, p. 1693
  4. Merrill and Gillen (2016) Crit Dec Emerg Med 30(3): 3-8
  5. Kessler (2012) J Emerg Med 43(3): 538-44 [PubMed]
  6. Nabhan (2003) Hematol Oncol Clin North Am 17:177-99 [PubMed]

Images: Related links to external sites (from Bing)

Related Studies