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).
Incidence
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
Diagnosis
unlikely to have TTS
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
possible TTS
any patient presenting with acute thrombosis or new onset thrombocytopenia within 42 days of receiving COVID 19 vaccination
probable case of TTS
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
definite case of TTS
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
Differential Dx
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
ED work up for a patient referred with abdominal pain, headache or thrombotic concern post Astra Zeneca Covid-19 vaccine
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
this Mx plan is based upon Royal College Physicians UK guidance and is as per April 2021 and updated with the May 2021 UK guidance however the situation may change rapidly, please check your local guidelines
ED work up for patient with new thrombotic event 4-42 days post A-Z Covid-19 vaccine
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
Management of proven TTS
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)
DO NOT GIVE heparin or platelets and avoid aspirin - consult with haematologist to advise on treating with
NON-heparin therapeutic anticoagulation such as such as DOACs, fondaparinux, danaparoid or argatraban
URGENT IV Ig 1g/kg in two divisions over 2 days if needed
high doses steroids
especially if platelets < 50
benefits likely to outweigh harm especially in cerebral venous thrombosis
plasma exchange
early use may be indicated in those with extensive thrombosis (especially cerebral venous thrombosis) and platelets < 30 x 109/L2)
platelets and cryoprecipitate may be indicated if urgent neurosurgery is being considered3)
fibrinogen replacement
replace fibrinogen supplementation if needed, to ensure level does not drop below 1.5 g/L, using fibrinogen concentrate or cryoprecipitate