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Case Reports
Post-mortem findings in vaccine-induced
thrombotic thombocytopenia
Greinacher et al.1 and Schultz et al.2 were the first to independently report the main clinical and laboratory features of 11 and five respective patients from Germany, Austria and Norway who developed life-threatening thrombohemorrhagic complications 5 to 16 days after the administration of the first dose of the chimpanzee adenoviral vector vaccine ChAdOx1nCoV-19 against SARS-CoV-2 and COVID-19. Subsequently Scully et al.3 reported similar findings in 23 patients treated with the same vaccine in the United Kingdom. More recently, See et al.4 reported a case series of 12 patients from the USA with cerebral venous sinus thrombosis following the vac- cination with Ad26.CoV2.S employing a human adenovi- ral vector. The main post-vaccination features common to the case series were the occurrence of venous throm- boembolism mainly in unusual sites (cerebral and abdominal veins) and the concomitant presence of bleed- ing symptoms associated with severe thrombocytopenia, often accompanied by laboratory signs of consumption coagulopathy with low plasma fibrinogen and hugely increased levels of D-dimer. The majority of reported patients reacted positively for serum immunoglobulin G (IgG) antibodies to the platelet factor 4 PF4/heparin com- plex.1-4 Another common feature was the high mortality rate. The mechanism of this very rare thrombohemor- rhagic syndrome was postulated to be a vaccine-triggered autoimmune reaction, with the development of antibod- ies against a still ill-defined PF4/polyanion complex that causes platelet activation as in heparin-induced thrombo- cytopenia (HIT),1-4 notwithstanding the fact that no cases were exposed to heparin before the onset of thrombosis and thrombocytopenia. We report herewith the detailed post-mortem macroscopic and microscopic findings in two similar cases that occurred in the Italian region of Sicily.
Case Reports. Patient 1 was a 50-year-old man (body weight 90 kg) with abdominal pain that developed 10 days after vaccination with ChAdOx1 nCoV-19. He had neither a history for thrombosis risk factors nor had he any intake of drugs increasing this risk. At the emergency room he presented with severe thrombocytopenia, low plasma fibrinogen and very high D-dimer (Table 1). The results of other blood tests were normal except for mod- erately elevated white blood cells and inflammatory serum markers. Computed tomography (CT) showed portal vein thrombosis with smaller thrombi in the splenic and upper mesenteric veins. During the next 4 days after admission platelets and fibrinogen remained low and D-dimer very high with no substantial changes. An initial dose of the low molecular weight heparin nadroparin was given subcutaneously at a dosage of 5,700 IU followed by a second dose after 8 hours. Clinical conditions deteriorated and a new CT scan showed massive intracerebral hemorrhage. Treated with multiple transfusions of platelet concentrates that failed to control bleeding the patient died 4 days after the onset of symptoms and 16 days after vaccination. A serum sample obtained before nadroparin showed the presence of anti PF4/polyanion complex IgG antibodies by enzyme-linked immunosorbent assay (ELISA) (Lifecodes PF4 IgG assay, Immucor, USA).
Patient 2, a 37-year old previously healthy woman (61 kg) with a negative history for significant disease and drug intake developed 10 days after the administration of the same vaccine first low back pain and then a strong
Table 1. Clinical and laboratory characteristics. Case 1
Case 2
37
Female
None of significance
10
Low back pain, headache
Superior sagittal sinus
9,000
290
0.34 Negative Positive for IgG None
Fatal
Age, years
Sex
Pre-existing conditions
Time from vaccination
to admission, days Presenting symptoms
Thrombosis location
Platelet count nadir, per mm3 D-dimer peak, mg/dL
Fibrinogen nadir, g/L
Sars-CoV-2 molecular test Anti-PF4/polyanion complex testing Anticoagulation
Outcome
50
Male
None of significance
10
Abdominal pain
Portal, splenic and superior mesenteric veins
7,000
52
0.66 Negative Positive for IgG Nadroparin Fatal
The reference ranges for platelet count are 130.000-400.000 per mm3, for D-dimer less than 0.5 mg/dL for fibrinogen 1.7-4.0 g/L. Ig: immunoglobulin.
headache. She became progressively drowsy and ulti- mately unconscious, and was, therefore, admitted to the emergency room of her local hospital. With laboratory tests similar of those of patient 1 (Table 1), a CT scan showed an occlusive thrombus in the superior sagittal venous sinus and a very large hemorrhage in the frontal cerebral lobe. Transported comatose by helicopter to a larger hub hospital she underwent craniotomy in order to control intracranial hypertension and remove the frontal lobe hemorrhage. She survived the operation but remained comatose and died 10 days after the first hos- pital admission and 23 days after vaccination. Anti- PF4/polyanion complex antibody reactivity was detected by ELISA and confirmed in a stored serum sample (Table 1).
Autopsy findings. The anatomic dissection showed a multi-district catastrophic picture of venous thrombosis, but neither entrapment or nutcracker nor any compres- sion which may produce blood stasis and facilitate venous thrombosis. In both cases the sites of venous thrombosis identified by imaging were confirmed, cou- pled with dramatic pictures of cerebral hemorrhages. While case 1 was confirmed to have had portal and mesenteric thrombosis with extension into the splenic vein, case 2 showed besides cerebral sinus thrombosis a massive thrombosis of the whole venous tree of the left upper limb extending from the hand to the axillary vein, with symmetric lesions in the veins of the right hand and the right axillary vein. In addition, the superficial veins of both feet appeared to be thrombosed. The histological evaluation revealed the presence of vascular thrombi associated with hemorrhagic phenomena localized in the meningeal space and focally involving the brain. The thrombotic phenomena also involved small- and medi- um-sized vessels. The immunohistochemical findings detailed in Figure 1 suggested endothelial activation asso- ciated with the dense recruitment of inflammatory myeloid cells, presumably sustaining procoagulant condi- tions and thrombus formation.
From a clinical and laboratory standpoint these two fatal cases of venous thrombosis located in unusual sites
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