Thrombotic Thrombocytopenic Purpura

Aka: Thrombotic Thrombocytopenic Purpura, TTP

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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 or Caplacizumab (Cablivi)
      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. Jones (2024) Am Fam Physician 110(1): 58-64 [PubMed]
  6. Kessler (2012) J Emerg Med 43(3): 538-44 [PubMed]
  7. Nabhan (2003) Hematol Oncol Clin North Am 17:177-99 [PubMed]

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Related Studies

Ontology: Purpura, Thrombotic Thrombocytopenic (C0034155)

Definition (CHV) a kind of blood disorder that causes blood clots to form in blood vessels around the body
Definition (CHV) a kind of blood disorder that causes blood clots to form in blood vessels around the body
Definition (CHV) a kind of blood disorder that causes blood clots to form in blood vessels around the body
Definition (CHV) a kind of blood disorder that causes blood clots to form in blood vessels around the body
Definition (NCI) An acute or subacute syndrome characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurologic abnormalities such as seizures, hemiplegia, and visual disturbances. Drugs and bacteria have been implicated as etiologic factors. The introduction of plasma exchange has significantly lowered the mortality rate. If untreated, the mortality rate is high.
Definition (NCI_CTCAE) A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Definition (MSH) An acquired, congenital, or familial disorder caused by PLATELET AGGREGATION with THROMBOSIS in terminal arterioles and capillaries. Clinical features include THROMBOCYTOPENIA; HEMOLYTIC ANEMIA; AZOTEMIA; FEVER; and thrombotic microangiopathy. The classical form also includes neurological symptoms and end-organ damage, such as RENAL FAILURE.
Concepts Disease or Syndrome (T047)
MSH D011697
ICD10 M31.1
SnomedCT 360402008, 195358008, 195359000, 155443009, 78129009
English Disease, Moschkowitz, Moschkowitz Disease, Purpura, Thrombotic Thrombocytopenic, Purpura, Thrombotic Thrombopenic, Thrombocytopenic Purpura, Thrombotic, Thrombopenic Purpura, Thrombotic, Thrombotic Thrombopenic Purpura, THROMBOTIC THROMBOCYTOPENIC PURPURA, PURPURA THROMBOPENIC THROMBOTIC, TTP - Thromb thrombocytop purp, Thrombot thrombocytopen purpur, MOSCHKOWITZ DIS, Moschcowitz Disease, Disease, Moschcowitz, thrombotic thrombocytopenic purpura (diagnosis), TTP (thrombotic thrombocytopenic purpura), thrombotic thrombocytopenic purpura, Thrombocytopenic purpura, thrombotic, Purpura thrombopaenic thrombotic, Purpura thrombopenic thrombotic, Moschowitz Disease, Purpura, Thrombotic Thrombocytopenic [Disease/Finding], ttp, thrombotic thrombocytopenic purpura (TTP), thrombotic thrombopenic purpura, moschcowitz's syndrome, Thrombotic Thrombocytopenic Purpura, TTP, Moschowitz's syndrome, Thrombotic thrombocytopenic purpura, TTP - Thrombotic thrombocytopenic purpura, Moschcowitz syndrome, Thrombotic thrombocytopenic purpura (disorder), Moschcowitz, purpura; thrombocytopenic, thrombotic, purpura; thrombotic thrombocytopenic, thrombocytopenic; purpura, thrombotic, thrombotic thrombocytopenic; purpura, Thrombotic thrombocytopenic purpura [Ambiguous], Moschcowitz's syndrome
Spanish PURPURA TROMBOTICA TROMBOPENICA, Purpura trombopénica trombótica, Síndrome de Moschcowitz, PTT, púrpura trombocitopénica trombótica (trastorno), púrpura trombocitopénica trombótica, síndrome de Moschowitz, Púrpura trombocitopénica trombótica, Enfermedad de Moschkowitz, Púrpura Trombocitopénica Trombótica, Púrpura Trombótica Trombopénica
Dutch trombocytopenische trombotische purpura, ziekte van Moschcowitz, purpura; trombocytopenisch, trombotisch, purpura; trombotisch trombocytopenisch, trombocytopenisch; purpura, trombotisch, trombotisch trombocytopenisch; purpura, trombotische trombocytopenische purpura, Microangiopathie, trombotische, Moschkowitz-ziekte, Purpura, trombotische trombocytopenische (TTP), TTP, Trombotische trombocytopenische purpura
French PTP, PURP THROMBOCYTOPENIQUE THROMBOT, PTT (Purpura Thrombotique Thrombocytopénique), Purpura thrombocytopénique thrombotique, Purpura thrombotique thrombocytopénique, Syndrome de Moschcowitz, Maladie de Moschcowitz, Micro-angiopathie thrombotique thrombocytopénique, Microangiopathie thrombotique thrombocytopénique, Purpura thrombopénique thrombotique
German Thrombozytopenische Purpura, thrombotisch, TTP, Purpura thrombopenisch thrombotisch, PURPURA THROMBOZYTOPENISCH THROMB, trombotisch-thrombozytopenische Purpura, Mikroangiopathie, thrombotische, Purpura, thrombotisch-thrombopenische, Purpura, thrombotisch-thrombozytopenische, Moschcowitz-Syndrom
Portuguese Púrpura trombopénica trombótica, PURPURA TROMBOCITOPENICA TROMBOTI, Síndrome de Moschcowitz, Púrpura Trombótica Trombocitopênica, Púrpura Trombótica Trombocitopênica Congênita, Púrpura Trombótica Trombocitopênica Familiar, Púrpura trombocitopénica trombótica, Doença de Moschkowitz, Púrpura Trombocitopênica Trombótica, Púrpura Trombótica Trombopênica
Japanese ＴＴＰ, ｹｯｾﾝｾｲｹｯｼｮｳﾊﾞﾝｹﾞﾝｼｮｳｾｲｼﾊﾝﾋﾞｮｳ, TTP, ベール･シフリン病, Moschkowitz病, 紫斑病-血栓性血小板減少性, モスコウィッツ症候群, ﾓｽｺｳｨｯﾂｼｮｳｺｳｸﾞﾝ, モシュコビッツ症候群, 血栓性血小板減少性紫斑病, Moschowitz病, Moschowitz症候群, モシュコビッツ病, モスコウイッツ病, モスコウイッツ症候群
Swedish Purpura, trombotisk trombocytopen
Finnish Tromboottinen trombosytopeeninen purppura
Russian PURPURA TROMBOTICHESKAIA TROMBOTSITOPENICHESKAIA, MOSHKOVICHA BOLEZN', PURPURA TROMBOTICHESKAIA TROMBOPENICHESKAIA, МОШКОВИЧА БОЛЕЗНЬ, ПУРПУРА ТРОМБОТИЧЕСКАЯ ТРОМБОПЕНИЧЕСКАЯ, ПУРПУРА ТРОМБОТИЧЕСКАЯ ТРОМБОЦИТОПЕНИЧЕСКАЯ
Czech TTP, Trombotická trombocytopenická purpura, trombotická trombocytopenická purpura, Moschcowitzova choroba, Moschcowitzova nemoc, purpura trombotická trombocytopenická, Syndrom Moschowitzové
Italian Sindrome di Moschkowitz, Sindrome di Moschcowitz, Porpora trombotica trombocitopenica
Polish Plamica małopłytkowa zakrzepowa, Zespół Moschcowitza
Hungarian TTP, thrombotikus thrombocytopeniás purpura, thrombotikus thrombopaenica purpura, Moschcowitz-syndroma
Norwegian Purpura thrombotica thrombocytopenica, Trombotisk trombocytopenisk purpura, Mikroangiopatisk hemolytisk anemi, Moschowitz’ sykdom
Derived from the NIH UMLS (Unified Medical Language System)

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