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What is thrombotic thrombocytopenic purpura (TTP)?

  • Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy resulting in a consumptive thrombocytopenia, haemolytic anaemia and ischaemic end-organ damage
  • It occurs due to a deficiency in the activity of a specific von Willebrand factor cleaving protein (vWF-CF) known as ADAMTS13
  • It is an intensive care and haematological emergency 

Epidemiology, Clinical Course & Prognosis

How common is TTP?

  • TTP is a rare condition:
    • Prevalence is only 10-15 per 1,000,0000
    • Low incidence hinders the development of strong evidence base
  • Has a female preponderance with a ratio of 2:1
  • Peak incidence is in adulthood before the age of 50

What is the mortality rate of TTP?

  • Untreated the mortality is 90%
  • The current mortality in the UK (from the TTP register) is 10-20%)
    • Has significantly decreased since the introduction of early PEX
    • Most deaths from cardiac and neurological complications
  • Relapse rate is 30-50%

Which factors are associated with worse outcomes in TTP?

  • Age >60

  • Elevated troponin

  • CNS involvement

  • Delayed diagnosis

  • Use of platelet transfusion

  • Elevated LDH

  • Refractory disease unresponsive to PLEX

  • Episodes of relapse

  • African or Caribbean ethnicity


What are the underlying pathophysiological mechanisms in TTP?

  1. vWF is a large glycoprotein present in the plasma whose functions include binding factor VIII, and activating and binding platelets in response to endothelial injury.
  2. It is produced in the endothelium as ultra-large multimers that are inactivated when cleaved by Von-Willebrand factor-cleaving protease (vWF-CP), also known as ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13
  1. The pathological hallmark in TTP is a deficiency of von Willebrand factor-cleaving protease (vWF-CP) or ADAMTS13. This may be genetic (absence of enzyme) or acquired (presence of autoantibody to vWF-CP).
  2. In TTP, these multimers are not cleaved resulting in ultra-large multimers
  3. The VWF multimers bind to platelets and result in uncontrolled platelet activation. Fibrin is deposited and thrombus propagated
  4. The end result is ischaemia distally, and red cells are shredded as they pass the fibrin/platelet mesh (microangiopathic haemolytic anaemia, MAHA).

What are the causes of TTP?

  • Congenital (5%) - typically present in late infancy or childhood
  • Acquired idiopathic (autoimmune)

(To a known Trigger)

  • Infection:
    • HIV
    • CMV
    • HBV / HCV
  • Pregnancy
  • Bone marrow transplant
  • Drugs:
    • COCP and hormonal treatments
    • Quinine
    • Interferon and immunosuppressants
    • Simvastatin
    • Antiplatelets
  • Malignancy
  • Acute pancreatitis


How does TTP present?

  • TTP is said to present with a classic pentad of features:
    • However, not all features are required to be present to make a diagnosis
    • Additional features are also commonly seen in TTP
  • Patients report feeling unwell for several weeks before presenting:
    • Usually, experience flu-like symptoms
    • Relapses present much quicker
Classic 'Diagnostic' Pentad
  • Microangiopathic haemolytic anaemia
  • Thrombocytopaenia - often initial diagnostic feature
  • Acute kidney injury (35%)
  • Fever (25%)
  • Neurological dysfunction (80%) - Altered mental state, headaches, confusion, seizures, intracranial haemorrhage, focal deficits
Additional Features
  • Cardiac dysfunction (40%) - elevated troponin, large territory ECG changes not common as microvascular involvement
  • GI dysfunction (35%)
  • Flu-like symptoms - often experienced for several weeks before presentation

What are the laboratory features of TTP?

  • Features of MAHA:
    • Anaemia on FBC
    • Blood film: low platelets, schistocytes, polychromasia
    • Increased reticulocytes, bilirubin and LDH
    • Negative DAT Coomb’s test
  • Marked thrombocytopenia
  • Decreased ADAMTS13 activity
    • Anti-ADAMTS13 IgG may be identified

What are the features of severe disease?

Severe disease is complicated by organ failure:

  • Seizures
  • Paralysis
  • Ischaemic Changes
  • Cerebral Bleeding
  • Coma
  • Renal Failure
  • Acute myocardial infarction
  • Arrhythmias
  • Heart failure
  • Cardiogenic shock
Other organs
  • Pancreatitis
  • GI Bleeding
  • Mesenteric Ischaemia

Differential Diagnosis

How do you differentiate TTP and haemolytic uremic syndrome (HUS)?

  • Can be difficult as share similar clinical and pathophysiological features
  • Differentiating clinical features include:
    • ↑ presence of focal neurological symptoms in TTP
    • ↑ presence of renal failure in HUS
  • Typical HUS:
    • Associated with exposure to shiga toxin – may be preceded by history of bloody diarrhoea
    • Commonly presents in children <5
    • Is associated with a higher platelet count than TTP (usually >35 x 109/L

What are the differential diagnoses for TTP / HUS?

Differentiating Features
Other Thrombotic Microangiopathies
Other Thrombotic Microangiopathies
Other Thrombotic Microangiopathies
Inflammatory mediated consumptive coagulopathy
  • History of infection, malignancy or predisposing factors
  • Low fibrinogen
  • Schistocytes may be absent
Inflammatory mediated consumptive coagulopathy
  • Hypertension and proteinuria always present
  • Seizures prominent
  • LFTs usually elevated
  • Schistocytes may be absent
Immune mediated platelet destruction
  • Clinically well
Immune mediated platelet destruction
  • History of heparin exposure
  • No evidence of haemolytic anaemia
  • Large vessel thrombosis may be present
  • Anti-PF4 antibodies may be identified
Heart Valve Haemolysis
Mechanical fragmentation of red blood cells with consumption of platelets
  • History of mechanical heart valve
  • Heart valve defect on echocardiography
Evan's Syndrome
Immune thrombocytopenia with Coombs positive autoimmune haemolysis
  • Schistocytes absent
  • Positive Coombs test
Likely combination of mechanical fragmentation and consumptive coagulopathy
  • Vegetations on echocardiography
  • Positive blood cultures
Catastrophic anti-phospholipid syndrome
Arterial and venous thrombi with secondary endothelial damage
  • Prolonged aPTT
  • Positive cardiolipin antibody

Work-Up Summary

How do you work-up the patient with suspected TTP?

To Determine Diagnosis
To establish MAHA diagnosis - based upon history, examination and laboratory picture:
  • FBC
  • Blood film
  • Reticulocyte count
  • LDH and bilirubin
  • Coagulation including fibrinogen
  • Coombs test (Direct Antiglobulin Test)
  • Urinalysis
Definitive testing:
If suspected, do not wait to treat!
  • ADAMTS13 activity
  • Anti-ADAMTS13 Ab
  • Sequencing of ADAMTS13 gene
To Determine Aetiology
  • Pregnancy test
  • Virology screen - before PLEX:
    • HIV
    • HBV / HCV
    • CMV
  • Autoimmune screen (assess for SLE / APL):
    • ANA / ACA / RF
    • Lupus anticoagulant
  • Thyroid Function Tests (for Graves)
  • If diarrhoea: stool culture for e.coli
To Assess for Complications
Determine organ involvement:
  • Renal function tests and urinalysis
  • ECG and troponin
  • CT / MRI Brain
  • Amylase
To Exclude Differentials
  • Shiga toxin
  • Echo suspicion of endocarditis / valve dysfunction
  • Laboratory Investigations

    How is TTP Diagnosed?

      • The hallmark of TTP is absence of ADAMTS13 activity
      • A level <5–10% is now required to confirm the diagnosis

      How can ADAMTS13 activity deficiency be detected?

      • ADAMTS13 activity is tested using specialist functional assays which are conducted at reference centres:
        • Principle involves degradation of vWF substrate (either full length or small peptides)
        • The value is expressed as a % compared against activity from normal pooled plasma which is considered as 100%

      When should the assay be performed?

      • A blood sample for an ADAMTS13 assay should be obtained as soon as the diagnosis of TTP is suspected:
        • Helps to avoid false-negative results
        • However ADAMTS13 activity was usually still severely decreased within the first 3 days after PLEX initiation
      • The treatment of TTP should be started before the ADAMTS13 activity assay results become available:
        • May take several days to get results

      How can the cause of ADAMTS13 deficiency be identified?

      If ADAMTS-13 activity deficiency confirmed further testing can include:

      • Identification of autoantibodies against ADAMTS-13
      • Searching for an ADAMTS-13 inhibitor
      • ADAMTS-13 gene sequencing

      Management Summary

      How do you manage the patient with TTP?

      Key Principles

      • Early resuscitation and supportive care
      • Urgent and rapid treatment or transfer to specialist centre (Treat as urgent as aneurysm)
      • Avoidance of platelet transfusion
      • Early plasma exchange with FFP
      • Immunosuppressive therapy
      • Therapy to reduce thrombosis
      Initial Resuscitation & Supportive Care
      • ABC approach treating abnormalities as found:
        • 100% oxygen whilst assessing
        • Obtain IV access and perform diagnostic work-up
        • Consider early central line and vascath for plasma exchange
      • May need intubation if significant neurological sequalae
      • Management of seizures using benzodiazepines
      • Monitor urine output and consider RRT if evidence of
      • IV PPI for patients whilst on high dose steroids
      • For management of haemolysis:
        • Transfuse to target of 70g/dL
        • Commence oral folic acid 5mg OD
      Specific Management
      • Platelet transfusions contraindicated unless Major haemorrhage:
        • Worsens thrombosis
        • Usually prothrombotic - lines can be performed without
      • Plasma exchange - Mainstay of treatment:
        • Removes the autoantibodies from the patient's circulation, and replaces their plasma with plasma containing normal levels of vWF-CP
        • Ideally instigated within 3-4 hours of diagnosis
        • Using Octaplas (solvent-detergent prepared FFP deficient in ultra-large multimeric vWF)
        • Daily PEx should continue for at least 2 days after platelet recovery (i.e. pits >150 x 109/L)
      • FFP may be given has holding measure whilst awaiting transfer:
        • Not replacement for PLEX
        • Dose 15ml/Kg
      • Immunomodulatory therapy
        • IV Methylprednisolone 1g for 3 days immediately after PLEX
      • Additional therapy (severe or refractory disease)
        • Rituximab (monoclonal antibody against CD20, found on the surface of B cells)
        • MMF
        • Azathioprine
      • Therapy to reduce thrombosis
        • Aspirin 75mg Once plt >50 x 109/L
        • Prophylactic LMWH once plt >50 x 109/L
      Referral & Deposition
      • Needs urgent liaison with haematology if suspected
      • Arrange rapid transfer to specialist centre:
        • Always blue light (Agreement with regional ambulance services)
      • New cases - manage on HDU if not on ICU

      Critical Care Admission & Referral

      Which patients with TTP should be admitted to critical care?

      • UK guidance suggests that all patients with TTP should be admitted to an intensive care unit
      • As well as the proven benefit of ICU admission on outcomes, the rationales include:
        • High requirements for invasive organ support in patients with TTP:
          • 30-50% Ventilator support due to neurological / cardiac failure
          • Up to 20% RRT
        • Need for CVC insertion which is most safely performed on ICU given profound thrombocytopenia
        • Need for PLEX which is often only available on ICU
        • Need for close monitoring to recognize organ failure and adverse complications

      Which centres should patients with TTP be managed at?

      • Given the very low incidence of TTP suggested that TTP managed at a regional referral centre:
        • Have multidisciplinary teams with experience in ICU and long- term aspects of management
      • National agreement now in place with Regional Ambulance Services that TTP forms one of nine conditions designated as a ‘critical transfer’ requiring immediate life‐saving transfer:
        • Due to risk of deterioration anaesthetic escort is advised to avoid arrival of unstable patients.

      Specific Management

      How does plasma exchange (PLEX) work in TTP?

      • Removed autoantibodies to ADAMTS13
      • Replaces ADAMTS13 in plasma

      How should PLEX be performed in TTP?

      • Should be initiated as soon as possible (preferably within 4-8 hours of diagnosis):
        • Early initiation associated with better outcomes
        • May require emergency transfer to specialist centre
        • Should not wait for result of ADAMTSq3 activity assay
      • Ideally daily spun apheresis should be performed:
        • Initially, 1.5x plasma volume should be exchanged for 3 days
        • Then 1x plasma volume can be exchange
        • Once platelet count >150 x 109/L for 2 days consecutively can be discontinued
        • Duration of PLEX required to achieve remission is often highly variable
      • Detergent treated FFP should be used to reduce the risk of transfusion-transmitted infection

      Which immunosuppressants are used in the treatment of TTP?

      • Higher dose pulsed steroids associated with improved outcomes and minimal side effects
      • Usually used in combination with PLEX:
        • Intravenous daily methylprednisolone (1 g/day for three consecutive days)
        • Oral prednisolone (e.g. 1 mg/kg/day)
      • Shown to be effective and safe in refractory immune mediated TTP
      • Now recommended for all patients with:
        • Cardiac or neurological pathology on admission in conjunction with steroids and PLEX:
        • Refractory or relapsing immune-mediated TTP
      • Usually given in a dose of 375 mg/m2 has been used weekly for 4 weeks
      • PLEX should be withheld for at least 4 h after completing a rituximab infusion

      What is the role of antiplatelet therapy in TTP?

      • There is no strong evidence to support the use of antiplatelets in TTP
      • Proven to be safe with no increase in bleeding
      • Recommendations to commence low dose aspirin (75 mg OD) when platelet count >50 x 109/L

      Supportive Management

      Should thromboprophylaxis be used for patients with TTP?

      • Likely at increased risk of venous thrombosis given immobility and severity of acute illness
      • Should be given LMWH once platelet count >50 109/L


      The Guidewire
      Trainee in ICM & Anaesthesia


      The Guidewire
      Trainee in ICM & Anaesthesia