Epistaxis and gross haematuria with severe thrombocytopaenia associated with influenza vaccination

Abstract

Epistaxis may be attributed to many causes during the winter including dry mucous membranes from low indoor humidity from heating. However, epistaxis may also be due to thrombocytopaenia. Immune thrombocytopaenia purpura (ITP) is an autoimmune disorder causing thrombocytopaenia. Viral infections sometimes lead to ITP. Vaccines, predominantly the measles-mumps-rubella vaccine, have been associated with the development of ITP. There are several published case reports regarding influenza vaccine induced ITP. However, an association between ITP and influenza vaccination has not been firmly proven yet. We report the case of an adult with three episodes of epistaxis, each within 1 week of receiving a yearly influenza trivalent inactivated vaccine, the last episode being more severe and also featuring gross haematuria.

Background

A cornerstone of primary care is offering the influenza vaccination annually. Influenza has manifold benefits. For example, it is even associated with reduced cardiovascular events.¹

Yet, there is anti-vaccination lay literature and some patients are thus fearful from side effects. As a result of skipping vaccinations, these patients receive substandard care.

Therefore, it is important to identify true possible adverse effects of influenza vaccination and to separate them from fiction (such as that vaccines cause autism). Thus equipped, physicians can encourage more widespread vaccination and improved individual and public health.

Case presentation

A 68-year-old man presented to the urgent care with epistaxis lasting 1 day, gross haematuria, and bleeding gums. When they saw his bloody urine, urgent care personnel forwarded him to the emergency department. He had received the influenza and pneumococcal conjugate vaccine 13 2 days prior. He stated that he consistently had epistaxis after obtaining the influenza vaccine for the last 3 years. However, this time was unusual in that while the epistaxis would usually last for a couple of hours and then resolve spontaneously, it was more prolonged this time. In addition, this time he developed gross haematuria as well as bleeding oral ulcers.

Review of systems was negative for fever, night sweats, recent infections, diarrhoea. The patient also denied having epistaxis throughout other times in the year.

• Medical history: hepatitis C (diagnosed 4 years prior, treatment with ledispavir/sofosbuvir having been completed 2 months prior), pre-diabetes, hypertriglyceridaemia, chronic back pain and anxiety.

• Surgical history: cholecystectomy and tonsillectomy.

• Social history: smoking half a pack of cigarettes daily as well as occasional marijuana use, with no use of alcohol or other drugs.

• Home medications included tamsulosin 0.4 mg daily, fenofibrate 145 mg daily and fluticasone 50 mg actuation to each nostril daily. The patient did take aspirin once 2 days prior for an episode of chest pain (no chest pain currently).

Physical exam was significant for non-tender sores over the buccal mucosa, blood in the oropharynx and blood clots in bilateral nares with no active bleeding. The nasal mucosa was otherwise unremarkable. The patient also had a petechial rash scattered over bilateral lower extremities and his trunk.

Investigations

• Complete blood count: thrombocytes 0/µL (reference range 150 000–400 000), compared with 210 000–267 000/µL in the past; leucocytes 11.1×10⁹/L/ (reference 4.0–12.0×10⁹/L); haemoglobin 132 g/L (reference 126–165) were within normal limits.

• Peripheral blood smear confirmed severe thrombocytopaenia with no thrombocyte clumping. Rare small, lightly granulated thrombocytes were present. There were no other significant abnormalities.

• Serum chemistry had a creatinine of 0.99 mg/dL (reference 0.60–1.40), glucose 104 mg/dL (reference 65–99), with other lab values normal.

• Urine microscopy showed >100 erythrocytes (reference 0–3) with 0–5 leucocytes and no squamous cells or bacteria.

• Prothrombin time: 10.1 s (reference 9.0–11.5).

• Activated partial thromboplastin time: 23.5 s (reference 21.0–31.0).

• Fibrinogen: 378 mg/dL (reference 150–450).

• D-dimer: 2.09 mg/L (reference 0.00–0.50).

• Nasopharyngeal influenza A, influenza B and respiratory syncytial virus PCR: negative.

• HIV antigen/antibody: negative.

• Hepatitis C quantitative viral load: none detected.

• Flow cytometry: negative.

Differential diagnosis

• Thrombocytopaenia secondary to influenza vaccination.

• Thrombocytopaenia due to asymptomatic infection.

• Thrombocytopaenia secondary to lymphoproliferative disorder.

• Severe thrombocytopaenia due to primary immune thrombocytopaenia purpura (ITP).

• Hepatitis C.

Treatment

The epistaxis had resolved with some external pressure prior to arrival to the emergency department and the patient was no longer bleeding. Patient received a platelet transfusion. He was initiated on both intravenous immunoglobulin (IVIG) therapy and dexamethasone 40 mg daily for 3 days. He was then switched to oral prednisone 60 mg daily. All told, the patient received four transfusions of platelets during the admission given his platelet count of 0/µL and bleeding from both the nose and the urinary tract (platelet transfusion is recommended with platelet counts of <10 000/µL or when a clinician feels there is severe bleeding).² The day after initial treatment, his platelet count improved to 39 000 and on the fourth day, it improved to 101 000. By the 10th day, the platelet count was normal at 342 000/µL. The patient was discharged on 60 mg of prednisone as well as a proton pump inhibitor and advised not to receive any further influenza vaccinations.

Outcome and follow-up

The patient continues to follow-up. It has now been one and a half years. He has never had another abnormal platelet count or any episodes of bleeding.

Discussion

It is highly likely that the severe thrombocytopaenia in our patient was due to the influenza vaccination due to the temporal association of the vaccination with the thrombocytopaenia and the ruling out of other diagnoses (hepatitis C RNA count was zero and there was no evidence of an infection or lymphoproliferative disorder). He always had normal platelet counts. Only on this occasion of epistaxis when the blood count was checked did he have an abnormal platelet count, which was immensely low at 0/µL. Furthermore, the patient noted that he only had epistaxis after influenza vaccination, and that this was happened consistently after three influenza vaccinations.

ITP is linked with different kinds of vaccinations. Prior retrospective studies showed that there is a risk of developing ITP after receiving measles-mumps-rubella, hepatitis A, varicella and diphtheria-tetanus-pertussis vaccines in children and adolescents.³ A number of case-control studies and case reports regarding post-influenza vaccination ITP have been published.^4–8 Vaccine-associated ITP may be caused by molecular mimicry, which demands the activation of autoreactive B or T cells by peptides in the vaccine that display structural parallel to antigens found on platelets.³ In previously reported cases of post-influenza vaccination ITP, patients made a full recovery after treatment. Our patient also achieved platelet recovery and was stable after treatment. Therefore, post-influenza vaccination ITP in elderly patients may respond to steroid and IVIG treatment.⁹

The time frame of development of ITP in relation to the epistaxis is notable in this case. At least one case report has had a child develop three occurrences of ITP, each within 1 week of receiving the influenza trivalent vaccine.⁷ It is possible that with first exposure, there is a prolonged period of time before symptoms and that repeat exposures produce an anamnestic, symptomatic response which is both more brisk and more severe. This may explain our patient’s gross haematuria and oral ulcers with his latest presentation.

Learning points.

• Influenza vaccination is recommended annually for most persons and is generally safe and effective.

• Even in egg allergy, influenza vaccination can be given under supervision if there is no anaphylaxis.

• Influenza vaccination rarely causes unusual adverse effects such as Guillain-Barre syndrome or as in our patient, thrombocytopaenia with epistaxis (which on repeat exposure, evolved into presenting with concurrent epistaxis and oral ulcers). In cases of thrombocytopaenia associated with influenza vaccination, patients should avoid the influenza vaccine.