Webinar Series on COVID-19 vaccine: Jointly organized by Malaysian Society of Infection Control and Infectious Diseases (MyICID) & Institute for Clinical Research (ICR), NIH Speaker: Dr. Veena Selvaratnam is a Haematologist, Ampang Hospital, Ministry of Health Malaysia.

1. Vaccine Side Effects:
Hematology Related
Veena Selvaratnam
Department of Hematology
Hospital Ampang

2. Disclaimers
•This slide was prepared for the Webinar Series on
COVID-19 session on 21st April 2021, by Dr.Veena
Selvaratnam, Department of Hematology, Hospital
Ampang, Malaysia.
•This is intended to share within healthcare
professionals, not for public.
•Kindly acknowledge “Clinical Updates in COVID-19
http://www.nih.gov.my/covid-19” should you plan to
share the information obtained from this slide with
your colleagues.
Jointly organized by Malaysian Society of Infection Control and Infectious Diseases (MyICID) & Institute for Clinical Research, NIH

3. Lecture Outline
•Vaccine Induced Prothrombotic Immune
Thrombocytopenia (VIPIT)/ Vaccine Induced
Immune Thrombotic Thrombocytopenia
(VITT)
•Immune Thrombocytopenia Purpura

4. “History of VITT - began on
10 March 2021”
•European Medicines Agency reported 4 cases of thrombosis
in Austria
•Similar reports were then gathered all around Europe
•By 31st March : UK’s Medicines and Healthcare Products
Regulatory Agency had received 79 reports of thrombosis
(44 CVST)
However by then millions of doses of AZ vaccine has been
administered worldwide
Some countries had no reported incidence of thrombotic
complications

5. Discovery of ViTT antibodies
•German researches from Paul Ehrlich Institute lead
by Andreas Greinacher
•Studied serum from 31 patients who presented with
thrombosis and thrombocytopenia post vaccine
•Serum contained antibodies that mimicked HiTT
antibodies which was detected via ELISA assay
•HIPA and modified HIPA test were positive

7. What is HiTT
• Development of Ab against
PF4-Heparin complex
• 5-10 days post heparin
exposure
• Suspicion based in 4T score
• Confirmation test :
a) Detection of Ab against
PF4-Heparin complex
b) Platelet aggregation test – HIPA
/ SRA / PAT
• Rx :
a) Stop Heparin
b) Start alternative anticoagulant

8. ViTT :What We Know So Far
•General reported incidence of thrombosis is similar
•Apparent increase in HiTT like thrombosis ie presence of
Thrombosis & Thrombocytopenia
•Occurs 4-20 days post vaccination (average 14 days post
vaccine)
•Increased cases of thrombosis at unusual sites ie :
CVST & Splanchnic vein thrombosis ; arterial thrombosis seen
•Seen more in younger females

9. Incidence of ViTT
•J&J : 9 of 7 million doses (The Wall Street Journal ; 20 April 2021)
•AZ: 222 reported cases in 34 million Europeans vaccinated
(The Economic Times ; 13 April 2021)
•Pfizer: Not established yet
•Moderna: Not established yet

10. Biological Plausibilities for ViTT
1. Direct relationship to the adenovirus vector used
•ChAdOx1 may bind directly to platelet PF4 – small viral quantity
•Adenovirus is known to cause thrombocytopenia, increased vWD factor Ag,
Platelet activation
•Free DNA is vaccine form multimolecular complexes with PF4 – binding to
Ab in patients with HiTT or induce Ab against Heparin-PF4 in mice models.
2. Reaction to the spike protein
study comparing the immunogenic epitopes of PF4 and SARS-CoV-2 spike
protein found that immune response to spike protein to induce ViTT is unlikely
Rapid Reports and Perspectives From the Field
Using the Bradford-Hill criteria to assess causality in the association between CHADOX1 NCOV-19 vaccine and thrombotic immune thrombocytopenia

11. Difference between HiTT and ViTT
(what we know in April 2021)
Heparin Induced Thrombotic
Thrombocytopenia (HiTT)
Vaccine induced Immune Thrombotic
Thrombocytopenia (ViTT)
Related to Heparin Exposure Not related to Heparin exposure
Antibody against PF4-Heparin complex Antibody against PF4
Positive HIPA test Positive modified HIPA test
Heparin allergy / hypersensitivity NO heparin allergy / hypersensitivity
Both small and large vessels
thrombosis
Only reports of large vessel thrombosis so
far
Further Heparin therapy
contraindicated
Relationship to heparin therapy unknown

12. When to suspect ViTT
• Recent vaccine
administration (< 30 days)
• Prolonged periods of being
unwell ie > 48H
•Thrombocytopenia <150 (with or
without thrombosis)
•Very raised D-Dimer (due to
underlying subtle DIC)
•Low / Normal Fibrinogen assay
Warning signs :
• Headache
• Blurring of vision
• Abdominal pain
• Nausea / Vomiting
• Chest pain / SOB
• LL swelling
• Bleeding / Petechia /

13. Investigation Algorithm
Suspect
ViTT
• Recent vaccine exposure (<30 days)
• Warning Signs
• Thrombocytopenia +/- Thrombosis
Primary
Ix
• FBC /FBP
• D-Dimer* / Coagulation screen
• Fibrinogen ( may not be readily available)
• Imaging to look for thrombosis / bleeding
Confirmatory
Ix
• Antibody against PF4 (ELISA based)
–centralised to be cost effective

14. Clinical Subgroups based on results:
NOT VITT Probable ViTT Confirmed ViTT
Onset > 30 days 4-30 days 4-30 days
Thrombosis +/- +/- +/-
Platelet >150 x 109
/l <150 x 109
/l <150 x 109
/l
Fibrinogen High Normal Normal / Low
D-Dimer <2000mcg/L 2000-4000 mcg/L >4000mcg/L
Anti PF4
Antibody Test
Absent Anti PF4 Antibodies
Present

15. Detection of Anti PF4 Antibodies
•Many established test available for HiTT
•ELISA, Particle Agglutination, Functional assays
•Most Rapid test are designed to detect Heparin-PF4 complex
However for ViTT:
•NO association with heparin and therefore no Heparin-PF4 complex
•Antibody directed exclusively against PF4
•Only the ELISA and Platelet functional test have been shown to be
associated

16. ELISA for PF4 antibodies
• Approximately 30 samples at one run
• Currently offered in MRKH, Hospital Ampang
Suggested mechanism for sample:
• Send 2 plain tube & 1 EDTA
• Fresh sample (<4H) or Spin – Freeze - Send frozen
• Will run once 30 samples have been collected or once a
week; whichever comes first ** subject to change**
• Expected TAT : 5 working days

17. Management:
•Give high dose IVIG urgently : 1g/kg x 2/7
•Avoid platelet transfusion – if needed administer after / with IVIG
•Avoid Heparin
•Start non heparin anticoagulant – balance bleeding vs thrombosis
•Keep fibrinogen > 1.5g/dl – transfuse cryoprecipitate
•Administer steroids if there is delay in IVIG
•Plasma exchange maybe useful – use plasma not albumin
•No antiplatelets / Thrombopoietin Agonist

18. Management: Anticoagulation
•Use non cross-reacting anticoagulant
•Fondaparinux ; Danaparoid; Argatroban; DOACs
•However there is no clear evidence to suggest any relationship
with Heparin use at the moment
• Keep platelet > 30 and Fibrinogen > 1.5
In the presence of thrombosis:
•Treatment dose must be started
•Continued for a total of 3 months and stop
In the absence of thrombosis : prophylaxis dose is sufficient

19. Clinical Key points when managing ViTT
•Neurosurgery should not be delayed if deemed necessary.
•If platelet transfusion is required, give IVIG before/with platelet transfusion.
•If coronary artery thrombosis was in healthy; not atherosclerosed vessels,
anticoagulation is preferred. Can switch to antiplatelets when fibrinogen,
D-dimer and platelet normalise.
•Lower dose of fondaparinux or DOAC can be used initially if bleeding risk
is high. Increase to standard dose later given that these patients are highly
prothrombotic.
•Second dose of vaccine is contraindicated in these patients

20. Immune Thrombocytopenia
Purpura (ITP)

21. Vaccine induced ITP
•Reported with Pfizer and Moderna Vaccine ; rare
•No clear relationship with ViTT
•Onset: 5-23 days post vaccine
•Previously unknown to have ITP ; though postulation that it can
temporarily worsen underlying ITP
•Present with mainly bleeding symptoms ie
petechia/bruising/mucosal bleeding
•Treatment : IVIG / Steroids / Rituximab

22. Vaccine induced ITP
•In severe bleeding , platelet transfusion is advocated with
concurrent administration of immuno-suppressive agents
•Aggressive use of immunosuppressive agents may jeopardies the
immune response required for antibody production intended of the
vaccine
•Whether second dose of vaccine should be administered remains
unanswered ; perhaps will depend on the severity of the initial
response

23. How to manage patients with
underlying ITP?
•No clear evidence to show that underlying ITP will worsen
•Some reported cases of transient worsening
thrombocytopenia
Suggestion:
•Baseline FBC before vaccine administration (platelet >50k)
•Watch for signs & symptoms of thrombocytopenia
•Seek advise if new bleeding symptoms occur

24. Conclusion
•Significant temporal relationship between vaccine and ViTT / ITP
•Treatment for both are IVIG / Steroids
•High index of clinical suspicion is required
•Please report ALL suspected cases ; it’s ok to over report so that
investigation can be done
•Always call for help when in doubt