Transplantation Outcome in Recipients Engrafted With Organs Recovered From the First French Deceased Donor With a SARS-COV-2 Vaccine-induced Thrombotic Thrombocytopenia

The safety of organ donation from deceased donors with vaccine-induced thrombotic thrombocytopenia (VITT)^1-3 is unknown. First, the organs might be directly affected by VITT and never properly recover. Second, VITT is caused by strong autoantibodies targeting platelet-activating factor 4 (PF4) and passenger leukocytes could induce a similar thrombotic syndrome in the recipient (“passenger lymphocyte syndrome”).⁴

A woman in her 60s developed VITT 11 d after a first dose of ChAdOx1 nCov-19 vaccine (Oxford—Astra Zeneca). Onset was characterized by headache and behavioral disorders. Two days later, she was in a coma. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction of a nasopharyngeal swab was negative. MRI disclosed cerebral venous sinus thrombosis (thrombosis of the left internal jugular vein, the sigmoid sinus, and the superior sagittal sinus), plus bilateral frontal hemorrhage and brain herniation. In addition, a thorax CT scan revealed a segmentary pulmonary embolism. Blood analysis revealed disseminated intravascular coagulation with severe thrombocytopenia, increased D-Dimer, prolonged activated partial thromboplastin time ratio and low fibrinogen. Anti-PF4 antibodies were incriminated in the pathophysiology of VITT 2 d later¹: they were detected in our donor at a high titer using an enzyme-linked immunoassay, which detects the presence of anti-PF4/heparin antibodies (Stago Asserachrom Haem Polymerization Inhibitory Activity IgG): optical density was 2.17; n < 0.35. We confirmed their potency to activate platelets in a serotonin release assay, the gold standard functional method for heparin-induced thrombocytopenia diagnosis.⁵ The patient serum could activate normal platelets alone or with small amounts of heparin but not in the presence of high concentrations of heparin. A neurosurgical procedure was ruled out based on the patient’s poor neurological status at admission. She died within hours and was evaluated as an organ donor, under continuous hemodynamic noradrenaline support and with KDIGO stage 1 acute kidney injury.

The recipient of the heart and liver combined was a 63-y-old man with a restrictive cardiomyopathy and secondary cardiac cirrhosis. Cold ischemic times were 120 min for the heart and 510 min for the liver. Both organs were macroscopically normal before implantation. A standard unfractionated heparin anticoagulation was used during and after surgery. In addition to inotropic support, a temporary mechanical circulatory support by extracorporeal membrane oxygenation (ECMO) was required due to cardiac primary graft dysfunction. Echocardiographic monitoring showed a gradually recovering cardiac function, allowing the weaning of ECMO support at postoperative day (POD) 5 and of inotropic support at POD6. No postoperative bleeding or thrombotic complication occurred. At POD15, left ventricular ejection fraction was 60% and a protocol endomyocardial biopsy did not reveal any sign of acute allograft rejection or microvascular thrombosis. On the same day, liver biological tests were normal. A liver ultrasound showed a permeable hepatic artery and portal vein and no abnormality of the bile ducts.

The lung recipient was a 58-y-old woman with end-stage emphysema related to alpha-1 antitrypsin deficiency. A double lung transplantation was performed without extracorporeal circulatory support. The lungs were macroscopically normal. A thrombectomy was performed during the procedure. Ischemic time was 213 and 288 min for the left and right lungs, respectively. The recipient was extubated 4 h after surgery, required noninvasive ventilation until POD4, and was weaned off oxygen at POD6. Low-molecular-weight heparin anticoagulation was continued after ICU discharge at POD6. The first spirometry performed at POD15 showed normal lung function.

Kidneys were petechial before implantation. A biopsy of the right kidney performed before surgery revealed multiple thrombi within the glomerular capillaries of all 16 glomeruli except 2 devoid of thrombi (Figure 1). Arterioles were normal. The tubulointerstitial compartment displayed severe acute tubular injury. The recipient of the right kidney was a 70-y-old man with end-stage renal disease of undetermined origin. He was engrafted after 10 h of cold ischemia and recovered a renal function at POD4. Postoperative course was uneventful, and he was discharged at POD13. Platelet count remained stable, and anti-PF4 was undetectable. The nadir of serum creatinine was observed at POD14: estimated glomerular filtration rate 35 mL/min. Proteinuria was 42 mg/mmol. Recipient of the left kidney was a 52-y-old man with a history of coronary heart disease, hypertension, and end-stage renal disease. Cold ischemia time was 13 h. Patient was anuric during the first 12 PODs. Cortical necrosis was ruled out by a contrast ultrasound. A first graft biopsy was taken at POD8. The fragment was insufficient to score lesions but no thrombi remnants were seen (Figure 1). Instead, moderate inflammation within glomeruli and peritubular capillaries was observed, along with hemorrhagic suffusion. Capillaries stained negative for C4d. As acute cellular rejection was in doubt, the recipient received high pulse corticosteroids and thymoglobulin. On POD12, a second, sufficiently adequate kidney biopsy sample showed that capillary inflammation had resolved. However, a focal and segmental glomerulosclerosis [FSGS] lesion was present in 1 out of 9 glomeruli: in all probability, this lesion was not inherited from the donor since FSFGS was not seen in any of the 18 glomeruli counted in the preimplantation biopsy (Figure 1). From POD13, renal function finally started to recover. Platelet count remained stable, and anti-PF4 antibodies remained undetectable. The nadir of serum creatinine was observed at POD22, at 249 µmol/L (estimated glomerular filtration rate 25 mL/min). Proteinuria was 63 mg/mmol.

FIGURE 1.: Histological sequence of glomerular injury and scarring in kidneys from a donor with vaccine-induced thrombotic thrombocytopenia. Glomerular scarring from intracapillary extensive thrombi occluding capillary lumens (A, Masson’s trichrome stain; [B], Jones’ silver stain (original magnification ×400; preimplantation biopsy) was successively characterized by inflammation (C, segmental glomerulitis with complete occlusion of some capillary loops by leukocytes in 2 glomeruli; Periodic Acid Schiff, original magnification ×400; POD8) and then by focal and segmental glomerulosclerosis (D, diffuse acute tubular necrosis associated with red blood casts and on upper right the glomerulus with FSGS. Masson trichrome stain, original magnification ×200; POD12). FSGS, focal and segmental glomerulosclerosis; POD, postoperative day.

We conclude that organs retrieved from the first French deceased donor victim of brain death after a VITT eventually recovered function after engraftment in 4 different recipients. However, renal recovery was laborious, and there was attendant glomerular scarring. At present, French guidelines (issued 1 wk after this case) recommend against organ donation in the setting of VITT when 3 criteria are met in the donors: multiple organ failure, DICV, and presence of anti-PF4-heparin antibodies. In this initial case of transplantation, the donor had neurological, hemodynamic, and renal failure, disseminated intravascular coagulation was observed not only in blood but also in kidneys, and anti-PF4-heparin antibodies were present at a high titer. Therefore, we, to some extent, conclude that these guidelines are appropriate in this new contingency and that unspecific information about the risk of delayed graft function should be insisted on when approaching potential recipients.

ACKNOWLEDGMENTS

We thank the donor and the donor’s family, as well as the transplant program coordinators, Dr Jan Hayon, Eloïse Hervé, Mélanie Brandon, and Nathanaëlle Leroux.