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Sum m a r y
From the Departments of Hematology We report findings in five patients who presented with venous thrombosis and
(N.H.S., G.E.T., P.A.H.), Immunology thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19
(L.A.M., F.L.-J.), Neurosurgery (M.W.),
Neurology (A.-H.A.), and Radiology and adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients
Nuclear Medicine (T.H.S.), and the Re- were health care workers who were 32 to 54 years of age. All the patients had high
search Institute of Internal Medicine levels of antibodies to platelet factor 4–polyanion complexes; however, they had
(N.H.S., A.E.M., P.A.H.), Oslo University
Hospital, and the Faculty of Medicine had no previous exposure to heparin. Because the five cases occurred in a popula-
(A.E.M., G.E.T., P.A.H.), the KG Jebsen tion of more than 130,000 vaccinated persons, we propose that they represent a
Center for B Cell Malignancy (L.A.M., rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia
G.E.T.), Institute of Clinical Medicine,
and the ImmunoLingo Convergence Cen- that we refer to as vaccine-induced immune thrombotic thrombocytopenia.
ter (F.L.-J.), University of Oslo, the De-
partment of Hematology, Akershus Uni-
T
versity Hospital, Lørenskog (N.H.S.), and
the Norwegian National Unit for Platelet he European Medicines Agency has approved five vaccines
Immunology, Division of Diagnostics, against coronavirus disease 2019 (Covid-19), and more than 600 million
University Hospital of North Norway, doses have been administered globally.1 In Norway, older adults living in
Tromsø (I.H.S., M.T.A.) — all in Norway.
Address reprint requests to Dr. Holme at institutional settings and health care professionals who are in close contact with
the Department of Hematology, Oslo patients with Covid-19 have been prioritized to receive the BNT162b2 mRNA
University Hospital, Rikshospitalet, Post- Covid-19 vaccine (Pfizer–BioNTech). In addition, the ChAdOx1 nCoV-19 vaccine
box 4950, N-0424 Oslo, Norway, or at
pholme@ous-hf.no. (AstraZeneca) has been administered to health care professionals younger than 65
years of age who do not have close contact with patients with Covid-19. As of
This article was published on April 9,
2021, at NEJM.org. March 20, 2021, when administration of the vaccine was paused, a total of 132,686
persons in Norway had received the first dose of the ChAdOx1 nCoV-19 vaccine
N Engl J Med 2021;384:2124-30.
DOI: 10.1056/NEJMoa2104882 and none had received the second dose.2
Copyright © 2021 Massachusetts Medical Society. Within 10 days after receiving a first immunization with ChAdOx1 nCoV-19,
five health care workers 32 to 54 years of age presented with thrombosis in un-
usual sites and severe thrombocytopenia. Four of the patients had major cerebral
hemorrhage. Here we describe this vaccine-induced syndrome of severe thrombo-
sis and thrombocytopenia found among these five patients admitted to Oslo Uni-
versity Hospital.
C a se R ep or t s
Patient 1 was a 37-year-old woman with headaches that developed 1 week after
vaccination with ChAdOx1 nCoV-19. At presentation to the emergency department
the next day, she had fever and persistent headaches. She was found to have severe
thrombocytopenia (Table 1). Computed tomography (CT) of the head showed
Downloaded from nejm.org on June 29, 2021. For personal use only. No other uses without permission.
* The abbreviation aPTT denotes activated partial thromboplastin time, INR international normalized ratio, IVIG intravenous immune globulin, LMWH low-molecular-weight heparin, and
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.
† The reference range used for fibrinogen at Oslo University Hospital is 1.9 to 4.0 g per liter.
2125
The n e w e ng l a n d j o u r na l of m e dic i n e
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hemiazygos vein. Contrast-enhanced magnetic
M
M
resonance imaging (MRI) of the spine showed
Figure 1. Platelet Count Responses to Treatment.
areas of hypointensity in several thoracic verte-
The vertical dashed line indicates the time at which the results of platelet
factor 4 (PF4)–polyanion antibody tests were known. IVIG denotes intrave-
brae and basivertebral veins, indicating compro-
nous immune globulin. mised venous drainage. He was treated with in-
travenous immune globulin (1 g per kilogram
per day for 2 days) and prednisolone (1 mg per
thrombosis in the left transverse and sigmoid kilogram per day). Dalteparin was administered
sinuses. Because of the low platelet count, a re- at a dose of 5000 IU (one dose on the first day
duced dose of dalteparin (2500 IU daily) was and two doses on the second day), after which
given. The next day, her clinical condition dete- the platelet count returned to normal and the
riorated, and a new CT scan showed a massive dose was increased to 200 IU per kilogram per
cerebellar hemorrhage and edema in the poste- day (Fig. 1). An abdominal CT scan indicated
rior fossa. She was treated with platelet trans- partial resolution of thrombosis. He was dis-
fusions and decompressive craniectomy. During charged from the hospital on day 12 in good
surgery, massive and uncontrollable edema de- health with warfarin and tapering doses of pred-
veloped. The patient died on day 2 after surgery. nisolone.
Patient 2 was a 42-year-old woman who had Patient 4, a previously healthy 39-year-old
headaches 1 week after vaccination with woman who was vaccinated with ChAdOx1
ChAdOx1 nCoV-19. Her condition worsened rap- nCoV-19, presented to the emergency depart-
idly, and she presented with reduced conscious- ment with abdominal pain and headaches 8 days
ness at presentation to the emergency depart- after vaccination. A mild thrombocytopenia was
ment 3 days later. Her platelet count was 14,000 revealed. An abdominal ultrasound examination
per cubic millimeter. ADAMTS13 activity was was normal, and she was discharged. The head-
found to be normal. CT venography revealed aches increased in intensity, and she returned to
venous thrombosis with occlusion of the trans- the emergency department 2 days later. Cerebral
verse and sigmoid sinuses and hemorrhagic in- CT with venography showed massive thrombosis
farction in the left hemisphere. Hemicraniectomy in the deep and superficial cerebral veins and
was performed, and treatment with dalteparin at right cerebellar hemorrhagic infarction. The
a dose of 2500 IU daily was initiated. She re- platelet count was 70,000 per cubic millimeter.
ceived multiple platelet transfusions over the She was afebrile and had no signs of infection
following days. On day 8, methylprednisolone and no neurologic deficits. Treatment with
(1 mg per kilogram of body weight per day) and dalteparin (200 IU per kilogram per day), pred-
intravenous immune globulin (1 g per kilogram nisolone (1 mg per kilogram per day), and intra-
per day) were administered. The platelet count venous immune globulin (1 g per kilogram per
increased thereafter (Fig. 1). However, the pa- day for 2 days) was started. The platelet count
tient died after 2 weeks in the intensive care unit was normalized within 2 days (Fig. 1). Follow-up
CT venography showed recanalization in the af- PF4 IgG enzyme-linked immunosorbent assay
fected cerebral venous sinuses. When she was (ELISA) (Immucor) in accordance with the manu-
discharged after 10 days, the symptoms had re- facturer’s instructions (dilution, 1:50), including
solved. Her anticoagulation treatment was a confirmatory inhibition test with heparin in
changed from dalteparin to warfarin, and treat- high concentration. Serial dilution of serum in
ment with prednisolone was continued in taper- an ELISA was also performed.3 Patient serum
ing doses. was also evaluated in a functional test with the
Patient 5, a 54-year-old woman with a history use of heparin-induced multiple-electrode ag-
of hypertension who was receiving hormone- gregometry on a Multiplate analyzer (Dynabyte
replacement therapy, presented to the emergency Medical).4,5 Here, the ability of serum to aggre-
department with stroke symptoms that had been gate platelets was measured in the presence of
present when she woke up from sleep, including saline buffer and in the presence of unfraction-
hemiparesis on the left side of her body, 1 week ated heparin at high concentration (96 IU per
after vaccination with ChAdOx1 nCoV-19. The milliliter) and low concentration (0.96 IU per
platelet count was 19,000 per cubic millimeter, milliliter).
and CT of the head showed a right frontal hem- Serum antibodies to the spike and nucleocap-
orrhage. She received a platelet transfusion be- sid proteins of severe acute respiratory syndrome
fore she was transferred to our hospital, where coronavirus 2 (SARS-CoV-2) were measured with
treatment with methylprednisolone (1 mg per the Roche Elecsys platform and with an in-house
kilogram per day) and intravenous immune bead-based assay for IgG antibodies to full-
globulin (1 g per kilogram per day for 2 days) length recombinant proteins.6
was commenced. A CT scan with venography
showed a massive cerebral vein thrombosis with
R e sult s
global edema and growth of hematoma (Table 1,
and Fig. S1 in the Supplementary Appendix, Laboratory Testing
available with the full text of this article at Levels of d-dimer were elevated at the time of
NEJM.org). Venous recanalization was achieved admission in all patients. The international nor-
4 hours after admission by endovascular inter- malized ratio (INR) and activated partial throm-
vention with thrombectomy after administration boplastin time were within the normal range.
of 5000 IU of unfractionated heparin. During The fibrinogen level was lower than normal in
the procedure, a fully dilated right pupil was Patient 2 and was slightly lower than normal
observed, and decompressive hemicraniectomy in Patients 4 and 5 (Table 1). The C-reactive pro-
was performed immediately. Two days later, tein level was moderately elevated in Patients 1,
treatment was withdrawn because of an uncon- 3, and 5. Screening for thrombophilia with pro-
trollable increase in intracranial pressure. teins C and S and antithrombin was negative.
Antiphospholipid antibodies were detected only
in Patient 3, who had a slightly elevated anticar-
Me thods
diolipin IgG antibody level of 43 IgG phospho-
Ethical Considerations lipid (GPL) units. Levels of complement proteins
Written informed consent for publication was (C1q, C4, and C3) and activation products (sC5b-9)
obtained from all patients. In the event that the were within the normal range in all patients. No
patient was not able to provide consent, a rela- patients had signs of hemolysis, and ADAMTS13
tive of the patient provided written informed activity was normal in the one patient in whom
consent. The authors vouch for the accuracy and it was assessed.
completeness of the data in this report.
Platelet Immunologic Testing
Immunoassays and Functional and Serologic All five patients had high levels of IgG antibod-
Testing ies to PF4–polyanion complexes, as indicated by
Antibodies to platelet factor 4 (PF4) in complex strikingly high optical density values — in the
with poly(vinyl sulfonate) (heparin analogue) in range of 2.9 to 3.8 — measured by ELISA. The
patient serum were tested with a LIFECODES reactivity was efficiently inhibited by heparin in
Discussion
Patient serum Patient serum+heparin
4.0
We present five cases of severe venous thrombo-
3.5 embolism in unusual sites and concomitant
3.0
thrombocytopenia that occurred 7 to 10 days
after vaccination for Covid-19. Four of the pa-
Optical Density
2.5
tients had severe cerebral venous thrombosis
2.0 with intracranial hemorrhage, and the outcome
1.5
was fatal in three. Thrombotic thrombocytope-
nic purpura and immune thrombocytopenic
1.0
purpura were not suspected because of the ab-
0.5 Cutoff sence of hemolysis and because of the good
0.0 response to platelet transfusions, respectively. A
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 common denominator in all five patients was a
high level of antibodies to PF4–polyanion com-
Figure 2. IgG PF4–Polyanion Detection in Serum.
plexes. We therefore propose that these cases
IgG PF4–polyanion antibodies in serum from the patients were measured by
represent a vaccine-related variant of spontane-
enzyme-linked immunosorbent assay. Serum from all the patients showed
strong reactivity that was efficiently inhibited (>97%) by the addition of a ous heparin-induced thrombocytopenia that we
saturating dose of heparin (100 IU per milliliter). Samples were run in du- refer to as vaccine-induced immune thrombotic
plicate. A mean optical density of 0.4 or higher indicates the presence of thrombocytopenia (VITT).
antibodies. All the patients had strikingly high levels of
antibodies to PF4–polyanion complexes. Although
the optical density values may not be directly
all samples (Fig. 2). Functional activity of serum comparable between studies, it is worth noting
from a patient with typical heparin-induced that 5 to 7% of blood donors have detectable
thrombocytopenia was compared with that of PF4–heparin antibodies; however, typical blood
serum from our patients. Platelets from the pa- donors rarely have levels yielding an optical den-
tient with heparin-induced thrombocytopenia sity higher than 1.6.7 Moreover, in patients with
were not activated unless low levels of heparin typical heparin-induced thrombocytopenia, opti-
were added, and platelet aggregation was effi- cal density values higher than 2 are unusual.8
ciently reduced by high heparin levels (Fig. 3). Nearly all healthy adults have a reservoir of
Platelets in serum from Patients 1, 3, 4, and 5 were B cells specific for PF4–heparin complexes; pro-
clearly activated in the absence of added heparin. duction of “heparin-induced thrombocytopenia–
The platelet aggregation curve for Patient 2 was like” antibodies by these B cells is kept in check
not a sigmoid curve and was considered to be by immune regulatory mechanisms.9,10
inconclusive. Platelet aggregation was inhibited In contrast to platelet aggregation in patients
efficiently by high-dose heparin in Patients 3 and with typical heparin-induced thrombocytopenia,
4 but was inhibited less efficiently in Patients 1 platelet aggregation in our patients was less de-
and 5. pendent on physiological levels of heparin and
was less sensitive to inhibition with high-dose
Covid-19 Serologic Testing heparin. Since Patients 1, 2, 3, and 4 had re-
All five patients were negative for antibodies to ceived low-molecular-weight heparin before blood
SARS-CoV-2 nucleocapsid protein. Thus, previous samples were obtained, we cannot rule out the
infection with SARS-CoV-2 was highly unlikely. presence of circulating complexes containing
The levels of antibodies to spike protein varied antibodies bound to PF4 and low-molecular-
with the assay, but anti-spike binding was de- weight heparin. Such complexes are generally
tected in at least one assay in all five patients. disrupted in the presence of a high concentra-
The variation most likely reflects the fact that tion of unfractionated heparin (96 IU per milli-
the anti-spike vaccine response was in an early liter), but this was not observed in all cases.
phase. Moreover, Patient 5 had not received heparin.
for requesting ELISA testing for PF4–polyanion found in previous studies in which the safety of
antibodies, including confirmatory functional the ChAdOx1 nCoV-19 vaccine has been investi-
testing, in patients who have unexpected symp- gated.12
toms after vaccination. Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
Although rare, VITT is a new phenomenon A data sharing statement provided by the authors is available
with devastating effects for otherwise healthy with the full text of this article at NEJM.org.
young adults and requires a thorough risk–bene We thank Siw Leiknes Ernstsen, M.D., of the Norwegian Na-
tional Unit for Platelet Immunology at University Hospital of
fit analysis. The findings of our study indicate North Norway for important contributions to laboratory inves-
that VITT may be more frequent than has been tigations of the cases.
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