Massive gingival bleed: a rare manifestation of cyclosporine toxicity

Abstract

A 12-year-old patient of thalassaemia major developed autoimmune cytopaenia after undergoing haematopoietic stem cell transplantation. She was started on cyclosporine (CsA) in view of poor response to steroids. She developed CsA toxicity manifesting as gum hyperplasia with multiple episodes of gum bleed. During endotracheal intubation for an elective splenectomy, she developed significant bleeding from gums requiring massive transfusion. Postoperatively the gum bleed persisted even after embolisation of facial artery and multiple transfusions. The catastrophic sequelae include transfusion-related lung injury, acute circulatory failure with subsequent cardiac arrest and death. Gum hyperplasia is a commonly reported toxic effect of CsA. Lethal presentations of this toxicity with such severity are limited in the medical literature. Evaluation of the patient’s medical and laboratory records, along with a review of literature, was very helpful in understanding more about the toxicity of CsA.

Background

Long-term treatment with cyclosporine (CsA) may cause various adverse reactions such as renal dysfunction, tremor, hirsutism, hypertension and gingival hyperplasia.¹ Children on CsA are more susceptible to CsA-induced gingival enlargement with a prevalence of >70%.^{2 3} Also, the prevalence of gingival overgrowth in children undergoing CsA treatment was higher (52%) than in adults.⁴ Gingival overgrowth appears to be linearly related to the dosage and plasma and salivary concentration of the drug.^5–7 Gingival hyperplasia can range from mild inflammation to spontaneous gingival bleeding. This has a paramount clinical significance in patients with underlying haematological disorders. The vigilance of healthcare providers about early detection of toxicity symptoms can decrease CsA-related morbidity and mortality in the future.

Case presentation

This case report describes the clinical course of a 12-year-old girl with thalassaemia major who underwent haematopoietic stem cell transplantation (HSCT). Post-HSCT, even after chimerism day 90 patient’s haemoglobin (Hb) was 47 g/L, white cell count 1.5×10⁹/L, neutrophils 0×10⁹/L, platelets 11×10⁹/L. She was suspected to have autoimmune cytopaenia affecting all the three cell lineages. However, direct Coombs test was negative. Bone marrow biopsy showed adequate number of megakaryocytes and erythroid hyperplasia; hence the thrombocytopaenia was attributed to autoimmune origin. However, she did not develop other related complications like thrombotic microangiopathy or sinusoidal obstruction syndrome. She was treated with steroids, granulocyte colony-stimulating factor, thrombopoietin receptor agonist (eltrombopag) and immunomodulators (rituximab). She was started on long term CsA therapy for maintenance of remission. She also received concomitant drug therapy with mycophenolate mofetil and tacrolimus. She developed grade III gingival hyperplasia with several episodes of gum bleed while on CsA therapy for a duration of 5 months. The episodes of bleeding were managed by transfusions with packed red cells and platelet-rich concentrates and local therapies like topical application of tranexamic acid. There was no significant improvement in pancytopaenia despite the dose titration of CsA. Repeat CsA HPLC levels were done till a target state trough level of 100 ng/mL was achieved. She developed transfusion-related haemosiderosis with calcineurin inhibitor-related toxicities like calcineurin inhibitor-induced pain syndrome (CIPS) and hypertension. Due to multiple adverse effects and failure of second-line immunosuppressive therapy, she was planned for an elective splenectomy operation.

During her assessment in the preanaesthetic clinic, her weight for age was less than the third percentile (according to Indian Academy of Pediatrics growth chart). She was pale, with no icterus, cyanosis, clubbing, pedal oedema, lymphadenopathy. Her pulse rate was 90 beats/minute with a blood pressure of 100/70 mm Hg. She had bilateral lower limb flexion deformity of 20°, secondary to CIPS. The liver was palpable 6 cm below the right costal margin, spleen was palpable 4 cm below the left costal margin. The examination of the cardiovascular and respiratory system was normal. Her higher mental functions were intact, she did not have cranial nerve palsy or focal neurological deficits. On airway assessment, the mouth opening was adequate with no features of thalassaemic facies. She had grade III gum hyperplasia, with no active gum bleed. Her laboratory investigations showed Hb of 83 g/L, total leucocyte count of 36×10⁹/L and platelet count of 20×10⁹/L. She had hypoalbuminaemia, other liver enzymes were within the normal reference ranges. Renal function tests, coagulation profile and serum electrolyte levels were within normal limits.

She was planned for an elective laparoscopic splenectomy, under general anaesthesia. Prophylactic platelet transfusion prior to splenectomy will simply result in infused platelets being entrapped in spleen with no clinical or haemostatic benefit. There will not be any increase in post transfusion platelet count in these patients. According to our institution protocol, in patients undergoing splenectomy, platelet transfusion is not initiated before ligation of splenic vessels. The preoperative platelet value was 20×10⁹/L, prophylactic platelet transfusion threshold in an HSCT patient is 10×10⁹/L.⁸

After intubation, while securing the endotracheal tube using adhesive tapes, generalised bleeding from the alveolar and buccal mucosa was noticed. The bleeding was refractory to local and systemic haemostatic measures such as application of pressure to the bleeding sites, administration of local and intravenous tranexamic acid, packing with adrenaline-soaked gauzes, suturing and cauterisation of gums, followed by application of surgical gel foam.

She weighed 19.7 kg with a calculated blood volume of 1477.5 mL and allowable blood loss of 253 mL. The patient had lost 1600 mL of blood in 6 hours with a drop in haemoglobin to 50 g/L. The patient developed hypovolemic shock and required inotropic support for maintaining adequate blood pressure. Immediate resuscitation was achieved by transfusing 5 units of packed red cell units (250 mL each), 16 units of platelet-rich concentrates (50 mL each), 1 unit of fresh frozen plasma (250 mL) and 2 units of cryoprecipitates (30 mL each) with simultaneous administration of 2000 mL of crystalloids and 150 mL of colloids. Eptacog (Factor VII) 1 mg was administered as a part of the massive transfusion protocol. The operation was abandoned due to haemodynamic instability. The patient was transferred to the intensive care unit (ICU) for stabilisation and elective ventilation because of ongoing gingival bleeding. Laboratory investigations after transfusion showed haemoglobin of 119 g/L, platelet count of 30×10⁹/L, prothrombin time of 11.6 s with an International Normalised Ratio (INR) 1.07, activated partial thromboplastin time of 35.3 s with serum levels of fibrinogen and D-dimer of 216 mg/dL and 707 ng/mL, respectively. Emergent embolisation of bilateral facial arteries and left inferior alveolar artery was performed with the continuation of intensive care after the procedure.

After 3 days, following adequate haemodynamic resuscitation, she was taken up for a splenectomy operation. On the day of the rescheduled operation, she was empirically transfused one unit of fresh frozen plasma and 6 units of platelet-rich concentrate. Open splenectomy operation was completed within 2 hours with a blood loss of 350 mL (allowable blood loss: 360 mL). Postoperatively the patient was shifted back to ICU. She was not extubated because of the chance of rebleeding from the gingiva.

Outcome and follow-up

Throughout her course in ICU, she had persistent bleeding from the gums refractory to haemostatic measures, even after normalising the platelet counts with multiple transfusions. She acquired ventilator associated pneumonia caused by human metapneumovirus. On postoperative day 15, she deteriorated with the onset of hypotensive shock refractory to fluids and vasopressors leading to cardiac arrest and death.

Discussion

The 12-year-old HSCT recipient presented here developed CsA-induced severe gum bleeding resulting in death. Numerous cases of CsA-induced gum hyperplasia have been reported so far but there are no reports with such severe manifestations resulting in mortality.

The relationship between CsA therapy and gingival overgrowth was first described by Rateitschak-Plüss et al and Daley et al.^{9 10} The strong correlation between the use of CsA and gingival hyperplasia can be understood with the regression or complete reduction of the disease on cessation of CsA therapy as early as 3–6 months.^{11 12} Pathogenesis of gingival hypertrophy is multifactorial.^13–18 Factors that impact on this iatrogenic effect include age, genetic predisposition, pharmacokinetic variables, plaque-induced inflammatory and immunological changes and activation of growth factors.⁴ Recurrent gum bleeding secondary to gingival hyperplasia can adversely affect the patient’s quality of life or can even lead to a life threatening event as seen in our case.

Early detection of the overdose is important. Therefore, it is necessary to evaluate the toxic level of the drug when indicated. Dose reduction or cessation or changing over to other drugs should be considered on recognising the signs of CsA toxicity. Prophylactic antimicrobials or antiviral treatment for gum hyperplasia should be considered. Systemic antibiotics proven to reduce gingival hyperplasia include metronidazole and azithromycin.^19–22

Surgical management is definitive and scalpel gingivectomy remains the treatment of choice, the main disadvantage being perioperative haemorrhage which is significant in patients with vascularised gums and underlying bleeding diathesis.²³ Non-surgical management includes the change of drug to new immunosuppressant alternatives, vigorous oral hygiene programme.²⁴ Continuing treatment of autoimmune thrombocytopaenia with second-line drugs such as dapsone, anti-D immunoglobulin, eltrombopag, steroids should have been considered even after splenectomy. Immunosuppressed state and general malnourishment (hypoalbuminaemia) impairs healing of the inflamed bleeding gums. The underlying autoimmune thrombocytopaenia is the other major factor that could have played a significant role in the catastrophic bleeding.

Learning points.

• Effect of cyclosporine (CsA) on the gingival tissues can range from hyperplasia to severe gum bleeding, especially when associated with an underlying haematological disorder.

• In the advent of increase in the usage of CsA, knowledge about the prevalence of this particular toxic effect and the risk factors leading to this condition is a must.

• Dose reduction or cessation or change of drug should be considered on recognising the signs of CsA toxicity.