|Year : 2022 | Volume
| Issue : 1 | Page : 3-7
NOTTO guidelines for vaccine-induced thrombotic thrombocytopenia in organ donation and transplantation
Vivek B Kute1, Sonal Asthana2, Subhash Gupta3, Sanjay K Agarwal4, Swarnalatha Guditi5, Manisha Sahay6, Sujoy Pal7, S Sudhindran8, Ashish Sharma9, Sandeep Seth10, Alla Gopala Krishna Gokhale11, Milind Dhahir Hote12, Arpita Ray Chaudhury13, Arvinder Singh Soin14, Mohamed Rela15, Rajesh Malhotra16, Virinder K Bansal17, Devinder Singh Rana18, Rajneesh Sahai19, Vasanthi Ramesh19
1 Department of Nephrology, Institute of Kidney Diseases and Research Center, Dr HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India
2 Department of Hepato Pancreato Biliary and Multi-organ Transplant, Aster Medicity Hospital, Bengaluru, Karnataka, India
3 Department of Gastrointestinal Surgery and Liver transplantation, Max Hospital, All India Institute of Medical Sciences, New Delhi, India
4 Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
6 Department of Nephrology, Osmania Medical College, Hyderabad, Telangana, India
7 Department of Gastrointestinal, All India Institute of Medical Sciences, New Delhi, India
8 Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences, Kochi, Kerala, India
9 Department of Renal Transplant Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
10 Department of Cardiology Surgery, and Liver transplantation, All India Institute of Medical Sciences, New Delhi, India
11 Department of Cardiothoracic and Vascular Surgery, Apollo Hospitals, Jubilee Hills, Hyderabad, Telangana, India
12 Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, New Delhi, India
13 Department of Nephrology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
14 Department of Liver Transplant Surgery, Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurugram, India
15 Dr. Rela Institute and Medical Centre, The Institute of Liver Disease and Transplantation, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, India
16 Department of Orthopaedics, Trauma Centre, All India Institute of Medical Sciences, New Delhi, India
17 Department of Surgery, All India Institute of Medical Sciences, New Delhi, India
18 Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India
19 National Organ and Tissue Transplant Organisation, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
|Date of Submission||30-Dec-2021|
|Date of Acceptance||14-Jan-2022|
|Date of Web Publication||03-Mar-2022|
National Organ and Tissue Transplant Organisation, Vardhman Mahavir Medical College and Safdarjung Hospital, A-7-3, M.S. Flats, Sector 13, R.K. Puram, New Delhi - 110 066
Source of Support: None, Conflict of Interest: None
From the context of organ donation, COVID-19 vaccine-induced thrombotic thrombocytopenia (VITT) is important as there is an ethical dilemma in utilizing versus discarding organs from potential donors succumbing to VITT. This consensus statement is an attempt by the National Organ and Tissue Transplant Organization (NOTTO) apex technical committees, India, to formulate the guidelines for deceased organ donation and transplantation in relation to VITT to help in appropriate decision-making. VITT is a rare entity, but a meticulous approach should be taken by the organ procurement organization's (OPO) team in screening such cases. All such cases must be strictly notified to the national authorities (NOTTO) as a resource for data collection and ensuring compliance with protocols in the management of adverse events following immunization. Organs from any patient who developed thrombotic events up to 4 weeks after adenoviral vector-based vaccination should be considered to be linked to VITT and investigated appropriately. The viability of the organs must be thoroughly checked by the OPO, and the final decision in relation to organ use should be decided by the expert committee of the OPO team consisting of a virologist, a hematologist, and a treating team. Considering the organ shortage, in case of suspected/confirmed VITT, both clinicians and patients should consider the risk‒benefit equation based on limited experience. An appropriate written informed consent of potential recipients and family members should be obtained before the transplantation of organs from suspected or proven VITT donors.
Keywords: COVID-19, deceased donor, National Organ and Tissue Transplant Organization, organ donation, transplantation, vaccine-induced thrombotic thrombocytopenia
|How to cite this article:|
Kute VB, Asthana S, Gupta S, Agarwal SK, Guditi S, Sahay M, Pal S, Sudhindran S, Sharma A, Seth S, Krishna Gokhale AG, Hote MD, Chaudhury AR, Soin AS, Rela M, Malhotra R, Bansal VK, Rana DS, Sahai R, Ramesh V. NOTTO guidelines for vaccine-induced thrombotic thrombocytopenia in organ donation and transplantation. Indian J Transplant 2022;16:3-7
|How to cite this URL:|
Kute VB, Asthana S, Gupta S, Agarwal SK, Guditi S, Sahay M, Pal S, Sudhindran S, Sharma A, Seth S, Krishna Gokhale AG, Hote MD, Chaudhury AR, Soin AS, Rela M, Malhotra R, Bansal VK, Rana DS, Sahai R, Ramesh V. NOTTO guidelines for vaccine-induced thrombotic thrombocytopenia in organ donation and transplantation. Indian J Transplant [serial online] 2022 [cited 2022 Dec 8];16:3-7. Available from: https://www.ijtonline.in/text.asp?2022/16/1/3/338986
| Introduction|| |
The COVID-19 pandemic has affected humanity globally, leading to significant morbidity and mortality. In addition to preventive measures such as the use of masks, social distancing, and handwashing, vaccination has proven to be a highly successful strategy for controlling severe COVID-19 infection. Several vaccines using novel technologies have been deployed in large population cohorts in a relatively short period of time with variable efficacy. While vaccination is effective in controlling severe infection as well as the spread of infection, there are reports of adverse effects following vaccination, although infrequent and minor. One such side effect is vaccine-induced thrombotic thrombocytopenia (VITT).
VITT, also termed vaccine-induced prothrombotic immune thrombocytopenia, is a rare syndrome that has been encountered in some individuals who have received adenoviral vector-based vaccines, ChAdOx1 nCoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India), and Ad26. COV2. S vaccine (Janssen; Johnson and Johnson). Although the incidence of VITT is exceedingly rare, there are high chances of underreporting of such cases as asymptomatic subjects are not routinely subjected to investigations to diagnose VITT. The adverse event following immunization (AEFI) data in India showed that there is a miniscule but definitive risk of thromboembolic events following the administration of Covishield vaccine, with a reporting rate of 0.61 cases/million doses, which is much lower than the four cases/million reported by the UK's regulator medical and health regulatory authority. Germany has reported 10 events per million doses. There were no potential thromboembolic events reported following the administration of the Covaxin vaccine. Routine platelet count or D-dimer testing following COVID-19 vaccination is not advised.
Risk factors for VITT are unknown. The etiopathogenesis is not well defined but autoantibodies to platelet factor 4 (PF4) are found to have a strong association with VITT which acts through antibody-dependent platelet activation, resulting in increased consumption of platelets, leading to thrombosis followed by thrombocytopenia and bleeding manifestation.
Clinical features of VITT usually develop within 4 weeks after COVID-19 vaccination., Thrombosis, the most frequently cerebral venous sinus thrombosis, followed by portal venous thrombosis but venous or arterial thrombosis may occur at any site. These are commonly associated with
- Intracranial hemorrhage
- Thrombocytopenia (platelet count of <150 × 109/l)
- High levels of D-dimer (usually >4000 μg/L)
- Often associated with low fibrinogen levels
- Positive testing for antibodies to PF4 by an enzyme-linked immunosorbent assay (ELISA). ELISA-based anti-PF4 antibodies are almost 100% sensitive while taking optical density >2.0–3.0. Non-ELISA rapid immunoassays for PF4 are neither sensitive nor specific and should not be used. The recommendation for regular PF4 antibody testing in the donor and the recipient may be hampered by the specific availability of this test in hematology laboratories, even in transplant centers, and thus can be done from accredited laboratories at the regional/state level. There are other causes of thrombocytopenia and/or thrombosis that should be considered, especially in individuals with negative PF4 antibody testing.
From the context of organ donation, VITT is important as there is an ethical dilemma in utilizing versus discarding organs from potential donors succumbing to VITT, as there is a possibility that organs derived from patients who have undergone cerebral venous sinus thrombosis following VITT may result in immune thrombocytopenia triggered by passenger lymphocytes following organ transplant. Organs with a high passenger leukocyte burden (e.g., liver, lung, small intestine, and pancreas) from donors with VITT are more likely to confer an additional risk in the transplant recipient. Organs with low leukocytes burden and tissues, such as blood vessels grafts, bone, tendons, menisci, skin, and cornea/sclera, are not considered to pose a significant risk of passenger lymphocyte syndrome. The UK National Health Service is monitoring 26 patients who received kidney (15), simultaneous pancreas and kidney (1), liver (7), lung (1), islet (1), or heart (1) transplants from confirmed Thrombosis with thrombocytopenia syndrome(TTS) donors for outcomes.
Organs from any patient who developed thrombotic events up to 4 weeks after adenoviral vector-based vaccination should be considered to be linked to VITT and investigated appropriately. The risk of developing immune-mediated thrombocytopenia and associated complications must be weighed against the benefit of organ transplantation. These organs should be graded as marginal, with a careful explanation of the risks to the recipient, which may be well-documented. As these are classified as marginal donors, principles of recipient selection should be based on any marginal donor. These may include patients with rare blood groups, those wait-listed for prolonged periods, high The model for liver disease(MELD) score, acute liver failure, acute on chronic liver failure, hepatic artery thrombosis, or primary nonfunction following liver transplantation, highly sensitized renal recipient, absence of any access for dialysis, etc.
The organs should be carefully assessed for poor flow during perfusion, which may suggest microthrombosis and may render organs unfit for use. Petechial hemorrhage on the surface of organs due to low platelet counts does not make an organ unsuitable. The risk of acquired VITT is the highest in the first 30 days.
Organ transplantation outcome from deceased donors with vaccine-induced thrombotic thrombocytopenia
The UK experience reported that 10 donors out of 13 consented deceased organ donors with VITT after the first dose of ChAdOx1 nCoV-19 vaccine proceeded to donate 27 allografts in 26 recipients. Many encountered thrombotic complications and also unfavorable graft outcomes, which raised concerns among organ procurement organizations (OPOs) across all parts of the world. There were seven major hematological complications (three bleeds and four venous or arterial allograft thromboses) in six recipients, resulting in the loss of three transplants within 9 days of transplantation. One recipient died within a day of transplantation from a presumed cardiac event. Early major hematological complications such as thrombosis or clinically significant bleeding, which may result from preexisting hemostatic and endothelial dysfunction in the allograft and possible transmission of pathogenic lymphocytes producing anti-PF4 are the potential risks of transplanting organs from donors with VITT. This raised concerns among OPO across all parts of the world. Nineteen brain-dead donors with VITT syndrome in the UK have had organs offered for transplantation, but only nine liver grafts (from eight donors) with the optimal patient and liver graft survival at 3 months follow-up. This signifies skepticism within the transplant community.,, There were 78% (21/27) of total allografts having a satisfactory function at a median follow-up of 19 days. However, there are a few reports,, with favorable outcomes as well. The first Indian study reported successful organ transplantation from an 18-year-old girl who presented with VITT following the first dose of the Covishield COVID-19 vaccine (Oxford/AstraZeneca formulation). All four recipients (31-year-old and 22-year-old kidneys recipients, 64-year-old liver recipient, and 26-year-old combined heart and lung recipient) had normal graft function without any thrombotic complication at 16 weeks of transplantation. India crossed the landmark of 100-crore COVID-19 vaccine doses. In India, the Oxford–AstraZeneca vaccine has been one of the major vaccines being used, hence, raising the alarm and theoretical concern of encountering more such cases. Transplantation societies across the world have shown concern about VITT and amended their guidelines. In the UK, the rise of VITT cases in the general population led to the formulation of VITT guidelines for solid organ transplantation (SOT). However, the International Society of Heart and Lung Transplantation recommended no specific protocol and insisted on following measures as in the general population. India too has recently updated its vaccine guidelines for SOT through the National Organ and Tissue Transplant Organization (NOTTO) and its transplant societies and stated a cautious approach for potential donors with VIIT.
This consensus statement is an attempt by the NOTTO apex technical committees to formulate guidelines for organ donation and transplantation in relation to VIIT to help in appropriate decision-making.
| Recommendations|| |
- A registry should be set up under NOTTO for monitoring prospective recipients undergoing transplants from VITT donors
- The National AEFI committee advisory for diagnosis, treatment, and reporting of thromboembolic events after COVID-19 vaccination should be followed
- There are other causes of thrombocytopenia and/or thrombosis that should be considered, especially in individuals with negative PF4 antibody testing
- Routine platelet count or D-dimer testing following COVID-19 vaccination is not advised
- We suggest not using aspirin before or following vaccination unless there is another indication
- Aspirin increases bleeding risk, and there is no evidence it reduces the risk of VITT
- At present, there is no evidence to suggest the use of organs from living donors with active VIIT.
Management of donor
- Ensure adherence to government guidelines for conducting postmortem examination, which is now allowed 24 × 7,
- VITT is a rare entity, but a meticulous approach should be taken by the OPO team in screening such cases, and all such cases must be strictly notified to the national authorities as a resource for data collection and ensuring compliance of protocols in the management of AEFI,
- A complete history of vaccination, including the type of vaccine and interval from last dose to the occurrence of any such event, should be an integral part of history in all potential donors
- A complete physical examination should be done to find out any evidence of vascular thrombosis. Basic hematological tests should be performed to screen any evidence of platelet activation and/or consumption. Any abnormal physical examination or screening tests should be followed with radiological assessment for detecting the multiorgan impact of VITT in the donor
- In case of suspected/confirmed VITT, the decision to proceed for transplant must be assessed by weighing the risk‒benefit ratio and informed consent in respect to this condition must be taken
- Organs should be assessed for the presence of thrombi (including biopsy if required)
- The threshold for preimplantation biopsy must be low
- The viability of the organs must be thoroughly checked by the OPO, and the final decision in relation to organ use should be decided by the expert committee of the OPO team consisting of a virologist, a hematologist, and a treating team
- Organ donation should be canceled in the case of severe disseminated intravascular coagulation, and organs should be discarded if thrombi were extensive
- Preferably avoid transplanting the organs to the recipients with previous thrombotic complications
- Preferably avoid platelet transfusion in VITT donors.
Management of recipient
- Considering the organ shortage, both clinicians and patients should consider the risk‒benefit equation based on limited experience, and an appropriate written informed consent of potential recipients and family members should be obtained before transplantation of organs from suspected or proven VITT donors
- No change in immunosuppression of the recipient receiving organs from VITT donors is required. Organ transplant recipients of VITT donors should have serial monitoring of thrombotic/hemorrhagic events, hemostasis, and graft dysfunction and undergo regular testing with PF-4 antibodies, platelet counts, D-dimer, fibrinogen, prothrombin time-international normalized ratio, and Fibrin degradation product(FDP) for early detection of the possibility of transmission. Surveillance of the recipient and reporting of graft dysfunction/thromboembolic events should preferably be mandatory
- There is no evidence for protocol biopsy in VITT recipients
- There are no specific prophylactic therapy recommendations currently. However, prophylactic anticoagulation for the recipient is an individualized decision based on the risk of bleeding
- In the case of a thromboembolic event in a recipient, there is no specific management protocol that is at variance from the general population with VITT. If the recipient is partially vaccinated/unvaccinated, the scheduled dose of vaccine should be avoided.
With the continued global administration of the COVID-19 vaccine, donors with VITT syndrome are likely to continue and more research and longer-term recipient follow-up are needed to guide the optimal approach for organ transplantation from deceased donors with VITT. All individuals with VITT and thrombosis and even without thrombosis should receive full (therapeutic) dose anticoagulation. We suggest a nonheparin anticoagulant rather than heparin, especially if heparin-induced thrombocytopenia remains in the differential. If the suspicion for VITT is high, anticoagulation should not be delayed while awaiting confirmatory testing. Novel anticoagulation such as argatroban can be used for preserving the viability of organs. For adult patients, the recommended argatroban dose is 2 mcg/kg/min administered as a continuous intravenous infusion.
Monitoring: Obtain baseline activated partial thromboplastin time (aPTT). The aPTT should also be obtained 2 h after the initiation of therapy and after any change in dosage. The target range for steady-state aPTT is 1.5-3.0 times the initial baseline value, but not exceeding 100 seconds. The appropriate duration of anticoagulation is unknown. A reasonable approach for VITT with thrombosis would be to continue anticoagulation for 3 months after normalization of the platelet count, as long as no further thrombosis occurs. For VITT without thrombosis, anticoagulation until platelet count recovery and perhaps longer if tolerated (4–6 weeks after platelet count recovery) appears prudent.
For further updates, visit https://www.mohfw.gov.in
The COVID-19 pandemic is evolving in a dynamic manner; therefore, this guideline is a live and dynamic document and will be updated as per the evolving situation. This article is submitted simultaneously in the Indian Journal of Nephrology and Indian Journal of Transplantation.
The authors wish to thank members of the apex technical committee, NOTTO, for helpful comments and support in reviewing this manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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