Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been
strongly associated with immune-mediated reactions, including the development of autoimmune
disorders.[1] It is theorized that the spike protein S1 of SARS-CoV-2 may be responsible for this
phenomenon by means of molecular mimicry.[2] Emerging data also suggest a link between coronavirus disease 2019 (COVID-19) vaccination
and development of various autoimmune conditions ranging from autoimmune hepatitis
to immune thrombocytopenia (ITP).[3]
[4] This is not a new phenomenon as other vaccines are also associated with immunologic
adverse effects, such as Guillain–Barre syndrome, ITP, or vasculitis.[5]
We present a case of acquired hemophilia A (AHA) after application of Pfizer-BioNTech
SARS-CoV-2 vaccine. The patient, a 67-year-old African American male with a history
of hypertension and asymptomatic pulmonary sarcoidosis not receiving any pharmacological
treatment, began to experience left thigh tightness and cramping pain at day +19 after
his second dose of the Pfizer-BioNTech COVID-19 vaccine. He originally presented to
the emergency department (ED), where an ultrasound was performed, which was negative
for deep venous thrombosis. He was instructed to follow up with his sarcoidosis clinic
and was discharged from the ED. However, two days later, he presented to another ED
for worsening pain and persistent swelling of his left thigh. He was found to have
a large hematoma of his left posterior leg extending from his buttock to below his
left knee. A smaller area of ecchymosis was also noted on his right arm proximal to
the medial epicondyle. Physical exam was otherwise unremarkable. His activated partial
thromboplastin time (aPTT) was 72 seconds (normal 25–35 seconds). Review of prior
medical records showed normal aPTT in 2013 and 2014, but no more recent coagulation
laboratories. He was transferred to University of Alabama at Birmingham Hospital for
further evaluation. His hemoglobin level was 10.2 g/dL (from 11.4 g/dL 2 days prior
and down from a baseline of 15.5 g/dL in September 2020). A 1:1 mixing study combining
the patient's plasma (aPTT of 78 seconds) with a normal control plasma (aPTT of 28 seconds)
showed no significant correction of the aPTT (i.e., 60 seconds), suggesting the presence
of an inhibitor other than factor deficiency. Factor VIII activity was undetectable
(i.e., <1%) and an inhibitor assay confirmed the presence of a factor VIII inhibitor
at 110 Bethesda Units/mL. Other laboratories were significant for: platelets 207,000/mm3, white blood cells 9,740/mm3, prothrombin time 13 seconds (international normalized ratio: 0.99), creatinine 1.27 mg/dL
(estimated glomerular filtration rate > 60 mL/min), blood urea nitrogen 19 mg/dL,
aspartate aminotransferase 16 U/L, alanine aminotransferase 19 U/L, total bilirubin
0.6 mg/dL. A computed tomography with intravenous contrast of the chest/abdomen/pelvis
from 7 months before presentation showed stable calcified mediastinal and bilateral
hilar lymph nodes, without any signs of malignancy. Patient had a colonoscopy in 2017
without any signs of malignancy. Last prostate specific antigen was 0.44 ng/mL and
patient did not report any urinary symptoms. We also obtained antinuclear antibodies,
ds-DNA antibodies, and rheumatoid factor, which were negative.
The patient was started on factor eight inhibitor bypass activity (FEIBA) 4,500 u/kg
every 8 hours, oral prednisone 1 mg/kg daily (i.e., 90 mg daily), and rituximab therapy
(375 mg/m2 weekly for 4 doses). Due to continued hemoglobin drop over the first few days of
hospitalization (see [Fig. 1]), recombinant factor VIIa was also initiated. Seven days after the first dose of
rituximab, factor VIII inhibitor decreased to 59 Bethesda Units/mL, but aPTT persisted
in the 70s. Finally, after another 7 days and before the third dose of rituximab,
factor VIII inhibitor was 8 Bethesda Units/mL and FEIBA was stopped (see [Fig. 1]). Patient completed four doses of rituximab and a 28-day taper of prednisone after
discharge. Factor VIII activity was at 171% with undetectable factor VIII inhibitor
at day +34 after admission. No new signs of bleeding have been observed after completion
of all treatments.
Fig. 1 Changes over time in platelets, hemoglobin, and aPTT. Treatments received as well
as factor VIII activity and inhibitor levels were also plotted in the graph. aPTT,
activated partial thromboplastin time.
AHA is a rare autoimmune disorder characterized by autoantibody formation against
clotting factor VIII, resulting in disruption of secondary hemostasis. Most cases
of AHA in nonpregnant and nonpostpartum patients are associated with pre-existing
autoimmune conditions or malignancy.[6] However, this patient had no evidence of malignancy and no pre-existing autoimmune
disorders, except for sarcoidosis. No reports of an association between pulmonary
sarcoidosis and AHA were found on literature review. While certain medications can
be associated with AHA, the patient's medications included only amlodipine, benazepril,
pantoprazole, and rizatriptan, none of which have been associated with AHA.[7] The only identified risk factor for the development of AHA, based on the suspicious
timing, was the Pfizer-BioNTech SARS-CoV-2 vaccine. While the causal relationship
cannot be proven, we still felt compelled to report this case to increase awareness
among health care providers about potential adverse events after COVID-19 vaccination.
Whether the course of AHA after COVID-19 vaccine is similar to regular AHA is also
unknown. Unlike prior reports of post-COVID-19 vaccine AHA,[8]
[9] our patient had persistence of aPTT elevation with significant hemoglobin drop,
requiring a multi-strategy approach with FEIBA, recombinant factor VIIa, glucocorticoids,
and rituximab. As we learn more about COVID-19 and the effects of its vaccine, there
is an urgent need to report cases like this one, to share our experiences, and help
us battle this pandemic.
While SARS-CoV-2 infection has been more frequently associated with a proinflammatory
response and prothrombotic complications,[10] a higher risk of bleeding has also been reported in a subset of patients.[11] Different immune-mediated conditions that predispose to bleeding have also been
reported during or after COVID-19, such as ITP[12] and AHA.[13]
[14] While the exact mechanisms responsible for these immunohematologic complications
are unknown, there is increasing concern that antibodies against SARS-CoV-2 spike
protein S1 could be responsible for autoimmunity.[2] In support of this, similar presentations have been reported after COVID-19 vaccination,
such as postvaccine ITP[4] and postvaccine AHA.[8] Therefore, as COVID-19 infection and current available vaccines only share the S1
spike protein in common, it is suspected that an immune response against this protein
is responsible for autoimmune conditions observed.
We have presented a case of AHA that developed after Pfizer-BioNTech SARS-CoV-2 vaccination.
This case adds to the increasing reports of immune-mediated conditions that develop
after COVID-19 infection or its vaccine. However, establishing a causal relationship
between these vaccines and autoimmune disorders can be challenging due to variable
latency periods and diverse presentation of autoimmune processes.[9] Until more epidemiological and pharmacovigilance information is available, case
reports will be crucial to keep health care providers well-informed and on the lookout
for these postvaccine complications. Of note, these associations should not discourage
patients and physicians from receiving and/or prescribing COVID-19 vaccines, as the
potential harm of COVID-19 infection outweighs potential side effects of its vaccines.
