Immune thrombocytopenic purpura following anti-rabies vaccines

To the editor

Rabies is a highly fatal disease with near 100% mortality. Immediate post-exposure prophylaxis is highly effective. Modern anti-rabies vaccines are very potent and safe. Side effects of these vaccines are mild and include pain and erythema at local site. Immune thrombocytopenia has not been reported with anti-rabies vaccines. We report here two cases of dog-bite who developed immune thrombocytopenia following anti-rabies vaccines.

The first case was a 12-year-old boy, who received minor scratches, without bleeding (category II wound) following dog-bite on right leg. He received three intramuscular injections of purified duck embryo vaccine (PDEV, Vaxirab®, Zydus Health Care Ltd.) on days 0, 3, and 7. On 8th day, he developed mild bleeding from gums and petechial spots over body. Patient was afebrile and had no lympadenopathy or hepatosplenomegaly. Hemogram revealed hemoglobin 11.2 g/dL, total leukocyte count 4.5 × 10⁹/L, and platelet count 16 × 10⁹/L. Prothrombin and active partial thromboplastin time were normal. Rheumatoid factor, antinuclear antibody, and antimitochondrial antibodies were absent. Serological assays for hepatitis C virus, hepatitis B virus, and human immunodeficiency virus were negative. Direct and indirect Coombs test were normal. Abdominal ultrasonography did not reveal any abnormality. Bone marrow biopsy revealed normal marrow cellularity with adequate megakaryocytes, suggestive of megakaryocytic thrombocytopenia. He was started on prednisolone 1 mg/kg/day (30 mg/day, tapered over 1 month) with increase in platelet counts to 75 × 10⁹/L. Eight months later he was maintaining platelet counts of 60 × 10⁹/L without any treatment. The second case was a 53-year-old male, who also had received category II injury following dog-bite, and presented with petechial spots over the body following the fifth intramuscular injection (days 0, 3, 7, 14, and 28) of purified chick embryo cell vaccine (PCEC, Rabipur®, Novartis, India). Clinical examination was unremarkable except for generalized petechial spots. Hemogram revealed hemoglobin of 11.6 g/dL, total leukocyte count 7.5 × 10⁹/L, and platelet count of 10 × 10⁹/L. Coagulation parameters (prothrombin and active partial thromboplastin time) were normal. Screening results for autoimmune (Rheumatoid arthritis factor, antinuclear antibody and viral markers human immunodeficiency virus, hepatitis B virus, and hepatitis C virus were negative. Bone marrow biopsy revealed normal marrow cellularity with adequate megakaryocytes. He was started on oral prednisolone (1 mg/kg/day, tapered over 1 month). Platelet counts increased to 80 × 10⁹/L, but fell to 20 × 10⁹/L 2 months after stopping prednisolone. After screening for G₆PD, he was started on dapsone 100 mg once daily. He is maintaining his platelet counts between 40 and 50 × 10⁹/L on dapsone for past 6 months.

Rabies is a highly fatal disease which can be easily prevented by immunization. As per the WHO estimate, about 50 000 people die of rabies worldwide each year, mostly in Asia, Africa, and South America [1]. Cell culture vaccines (e.g., PCEC) and PDEVs are currently recommended by WHO for postexposure prophylaxis. PDEV (Vaxirab) has safety and immunogenicity similar to PCEC (Rabipur) [2]. Neural vaccines are no longer used.

Immune thrombocytopenic purpura (ITP) is a disease characterized by decrease in platelets due to immune-mediated destruction. Most cases are idiopathic. The known common causes of ITP include infections and drugs. Among vaccines, MMR vaccine has been most commonly implicated as the cause of ITP [3], [4]. MMR vaccine is associated with an increased incidence of ITP of 1 case per 30–40 000 doses of MMR, defined as thrombocytopenia developing within 42 days of exposure [5], an incidence sixfold higher than acute ITP of childhood. Thrombocytopenia is often severe, but responsive to IVIG or corticosteroids. More than 80% recover within 2 months, typically within 2 to 3 weeks, with less than 10% evolving into chronic ITP [6]. The pathophysiology is unknown, although antibodies to GPIIb/IIIa have been identified in few patients, similar to primary ITP [7]. ITP has also been reported after hepatitis B [8], [9], and pneumococcal and influenza vaccination [10]. Side effects of anti-rabies vaccines include pain and erythema at local site in 9.6% of patients, and fever and myalgia in 2.1% [2], [11], with no evidence of increased frequency of autoimmune disorders. Bleeding manifestations due to immune thrombocytopenia by anti-rabies vaccines have never been reported in humans, though 2.3% of dogs receiving anti-rabies vaccines, which are derived from tissue-cultures, can develop thrombocytopenia [12]. Our patients developed thrombocytopenia when they were still on immunization schedule and required treatment with steroids for bleeding manifestations. Both patients had only partial recovery of platelet counts. The cause of thrombocytopenia is probably immune-mediated similar to that caused by other drugs and vaccines. These cases highlight that though anti-rabies vaccines, which are considered highly safe, may rarely be a cause of immune thrombocytopenia. Inspite of thrombocytopenia, the benefits of vaccination greatly exceed the significance of this possible side-effect.