see also:

• Covid-19 vaccination
  • Australian Advisory Group (ATAGI) statement on Astra Zeneca Covid-19 vaccine and TTS
  • ATAGI statement to healthcare providers April 2021
  • ACEM Guideline June 2021
• cerebral dural venous sinus thrombosis (CVST)
• heparin
• vaccines
• platelet factor 4 antibody thrombotic and thrombocytopenia syndromes

• thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially life threatening syndrome which is usually precipitated by response to AstraZeneca Covid-19 vaccine (it appears PF4 may bind to the vaccine and trigger platelet activation) or to heparin (when it is called type 2 HITS and due to antibodies against platelet factor 4-heparin complex)
• has also been called vaccine induced prothrombotic immune thrombocytopenia (VIPIT) and vaccine-induced immune thrombotic syndrome (VITT)
• early detection and treatment as in Australia has reduced mortality to 4% down from 20% that had been reported in Europe in early 2021.
• it has been long known that IV adenovirus injection can cause thrombocytopenia via VWF and P-selectin interplays ¹⁾ and this has been shown to also be the mechanism of AZ vaccines
  • in 2023, the genetic risk factor (an antibody gene termed IGLV3.21*02) for TTS due to adenoviral infection or the AstraZeneca Covid-19 vaccine has been discovered, and in 2024, they showed both these causes share identical molecular fingerprints or signatures to trigger the antibody production (NEJM May 2024).

• appears to occur in 1 in 100,000 in the 4-30 days after 1st dose vaccination with Covid-19 vaccination with Astra-Zeneca or J&J vaccines
• peak time period for initial symptoms is between days 6 to 14 after vaccination

• reduced platelet count without thrombosis with D dimer at or near normal and normal fibrinogen
• thrombosis with normal platelet count and D dimer <2000 and normal fibrinogen

• any patient presenting with acute thrombosis or new onset thrombocytopenia within 42 days of receiving COVID 19 vaccination

• 4-42 days after vaccination with thrombosis features and D Dimers > 4000 mcg/L with or without low fibrinogen (or D Dimer > 2000 with strong clinical suspicion, especially if also low fibrinogen levels)
• Mx as per “proven TTS” below

• presenting 5-30 days after vaccination and characterised by thrombocytopenia, raised D Dimers and thrombosis, which is often rapidly progressive.
  • NB. 5% have normal platelet count on presentation but most of these develop thrombocytopenia over the next few days
  • NB. deep vein thromboses (DVT) and pulmonary emboli can present up to 42 days after vaccination and it is presumed the DVT develops subclinically between days 5-30.
• PF4 antibodies positive by ELISA
• Mx as per “proven TTS” below

• thrombocytopenia from other causes including immune thrombocytopenia post Covid-19 vaccine (which does not need to be treated as per TTS)
• thrombosis from other causes
• raised D-Dimer from other causes such as infection, post-surgery, cancers, etc

• thrombocytopenia
  • NB. not present in 5% of patients with TTS on initial presentation
• clinical features of concern for TTS thrombosis:
  • arterial or venous thrombotic event with raised D-Dimer pathology test such as
    • cerebral dural venous sinus thrombosis (CVST) on day 4-28
      • persistent or severe new headaches, seizures or focal neurology
    • abdominal splanchnic venous thrombosis on day 4-28
      • unexplained atypical abdominal pain or GIT symptoms or back pain
    • DVT / PE:
      • persistent chest pain or SOB on day 4-42 - see Ix of suspected pulmonary embolism (PE)
    • arterial thrombosis
      • swelling, redness, pallor or cold lower limbs on day 4-28 (see peripheral vascular disease (PVD or PAD))

• see above for possible features which raise thrombotic concern
• did the headache or possible thrombotic condition commence before 4 days post vaccination or after 28 days
  • ⇒ NOT vaccine related thus manage patient on their clinical merits
• symptoms of thrombotic concern developed 4 to 42 days post-vaccination:
  • send full blood examination (FBE / FBC)
    • if platelets > 150 x 10⁹/L then very unlikely to be TTS HOWEVER 5% of patients have normal platelets initially
      • if no clinical features of emergency concern discharge home with advice to return if develop concerning symptoms for possible re-testing of FBE
      • if clinical features of concern:
        • send D-Dimer and clotting (coagulation profile with fibrinogen levels)
        • and/or repeat platelet count the next day
        • Mx on their merits but if above are normal then do not need to treat as for TTS
    • if platelets < 150 x 10⁹/L then:
      • send D-Dimer and clotting (coagulation profile with fibrinogen levels)
        • if D-Dimer < 2000 mcg/L or < 5x upper limit of normal
          • very unlikely to be TTS, investigate for other causes as indicated
        • if D-Dimer > 2000 mcg/L or > 5x upper limit of normal +/- low fibrinogen
          • suspect TTS, contact haematologist for advice and consider imaging as indicated such as:
            • CT brain venogram if headache or neurologic features although MRI venography may be preferred in some centres
            • CTPA for chest pain/SOB
            • CT abdopelvis with contrast for abdominal pain

• send bloods for FBE, D-Dimer, coagulation profile
• if normal platelet count
  • send blood for antibodies to Platelet Factor 4 (PF4)
  • repeat platelet count next day
  • Mx thrombotic event but consider avoiding giving heparin type anticoagulants or platelets until TTS fully excluded
• if TTS proven then manage as per below

• manage as per thrombotic condition but note the warning below
• if no thrombotic event evident but clinical picture suggests TTS then anticoagulate with non-heparins as below
• do not give a second dose of the Astra Zeneca Covid-19 vaccine
• before treating take extra 8 tubes of blood samples for ELISA testing if needed (4 tubes citrate and 4 tubes serum tubes)