Potential complications of diabetic ketoacidosis include dehydration, cerebral venous thrombosis, mucormycosis, pancreatitis, sepsis and electrolyte imbalance like hypokalemia and hypophosphatemia [1]. Acute kidney injury is fatal complication of diabetic ketoacidosis and development of renal failure in DKA is associated with high mortality in pediatric age group [1,2]. Thrombotic complications like thrombotic thrombocytopenic purpura (TTP) secondary to DKA are under-reported. Recently, a new thrombotic microangiopathic syndrome, called thrombocytopenia associated multi organ failure (TAMOF), has been described in literature. TTP is now considered to be a part of this syndrome. This syndrome is defined by presence of various clinical and laboratory markers including multi-organ dysfunction, new onset thrombocytopenia and elevated lactate dehydrogenase (LDH) levels [3]. Untreated TAMOF/TTP is associated with high mortality. Early diagnosis is the most important step for prompt intervention like plasmapharesis, which can be lifesaving. Therefore, pediatricians must be aware of microangiopathic complication of DKA. We report the development of this fatal syndrome in two girls presenting with diabetic ketoacidosis.

Case 1: A 14-year old girl presented with one day history of fever, vomiting, respiratory difficulty and altered state of consciousness. This was preceded by a 2-3 weeks history of polyuria, polydipsia, increased appetite and undocumented weight loss. On examination, she had tachycardia, hypotension, and altered sensorium with Glasgow Coma Scale of 4/15. She had evidence of severe dehydration, gasping respiratory efforts with oxygen saturation of 85-90% on room air. Initial investigations revealed hyperglycemia (random blood sugar=947 mg/dL), severe metabolic acidosis (pH of 7.00, bicarbonate 5.0), glycosuria and ketonuria. Blood counts were normal. She was intubated and started on insulin infusion along with fluid resuscitation. She was mechanically ventilated. The ketoacidosis resolved within 48 hours and she was switched to subcutaneous insulin. She was extubated on 3rd day of admission. Subsequently, she developed evidence of renal insufficiency (serum creatinine 4.4 mg/dL). Ultrasound kidneys, ureters, bladder (KUB) was reported normal. Continuous renal replacement therapy (CRRT) was started. Subsequently, she developed paraparesis along with low hemoglobin, low platelet count with evidence of microangiopathy on peripheral smear. A, clinical diagnosis of thrombotic thrombocytopenic purpura (TTP) was made. Plasmapharesis and hemodialysis were started. 5 cycles of plasmapharesis were done. She gradually improved, microangiopathy resolved and her platelet count returned to normal. She was discharged in stable condition on insulin.

Case 2: A 13-year-old girl presented with short history of vomiting and loss of consciousness few hours prior to presentation. There was history of polyuria, polydipsia and weight loss for last 4 weeks. On examination, she was tachycardiac, afebrile and drowsy with GCS of 7/15. She had deep acidotic breathing and moderate to severe dehydration. She was also intubated in emergency room and shifted to PICU for further management. Investigation revealed blood sugar level of 289 mg/dL, severe metabolic acidosis with pH. of 6.98 and bicarbonate level of 5.8. Fluid resuscitation was started along with insulin infusion. Inotropic support was started. She developed thrombocytopenia (45,000 per mm), high LDH of 1439 and renal insufficiency (serum creatinine 3.5 mg/dL). Peripheral smear also showed evidence of microangiopathy. These findings were consistent with thrombocytopenia associated multi-organ failure. The patient underwent CRRT and 3 cycles of plasmapharesis. The clinical condition gradually improved. She was extubated and finally discharged on subcutaneous insulin in stable clinical condition.

Laboratory findings of both patients at the time of admission and development of microangiopathic syndrome are summarized in Table I.

TABLE I Laboratory Findings of Two Patients on Admission, before and after Plasmapharesis

Thrombotic thrombocytopenic purpura characterized by sudden onset of formation of platelet rich thrombi in blood vessels, leading to thrombocytopenia and dramatic response to plasma infusion. Since the identification of this disorder, cases of TTP are gradually increasing with reported incidence of 2-7 per million person-years [4]. Despite rarity, it is considered to be a fatal disorder with mortality rate of >90% in untreated patients [5].

In intensive care settings, thrombocytopenia has been identified as an important risk factor for the development of multi-organ failure and a predictor of guarded outcome in critically ill children [6]. Thrombocytopenia associated multiple organ dysfunction (TAMOF) includes a spectrum of pathologic disorders. In addition to thrombotic thrombocytopenic purpura (TTP), thrombotic microangiopathy (TMA) and disseminated intravascular coagulation (DIC) are also considered to be a part of this syndrome [3]. At times, some overlap may be evident in these clinical phenotypes. Deficiency of von Willebrand factor cleaving protease (i.e. ADAMTS13) has been linked to be associated with platelets aggregation and formation of microthrombi in the circulation which lead to thrombotic microangiopathy and clinical manifestations of TAMOF and TTP [7]. Various secondary conditions like exposure to toxins/radiation, systemic infections, malignancies, vasculitis, chemotherapy, immunosuppressive drugs like cyclosporine A, organ transplantation and cardiopulmonary bypass have also been associated with TAMOF/TTP but endocrine causes are rarely reported.

Renal failure alone is not sufficient to establish the diagnosis of TTP or TAMOF. Clinically, thrombotic thrombocytopenic purpura is defined by the presence of pentad of symptoms. These include thrombocytopenia, renal failure, seizure/abnormal CNS condition, microangiopathic anemia along with fever [8]. Evidence of microangiopathy may be evident on peripheral blood smear or elevated lactate dehydrogenase. Both of our patients developed these clinical symptoms and relevant laboratory findings during the course of hospitalization.

In adults, sufficient data is available highlighting the association of TAMOF with various conditions but TTP associated with DKA has been reported in one case only [9]. Only one case of TAMOF has been recently reported in a child with diabetic ketoacidosis but in that case, there was also associated pancreatitis which may have contributed to the development of microangiopathy and TAMOF [10]. No other risk factor except diabetic ketoacidosis was identified in our case series which may have led to the development of TAMOF/TTP.

Contributors: All the authors prepared the case-report, and approved the study.

Funding: None; Competing interest: None stated.

1. Al-matrafi J, Vethamuthu J, Feber J. Severe acute renal failure in a patient with diabetic ketoacidosis. Saudi J Kidney Dis Transpl. 2009;20:831-4.

2. Woodrow G, Brownjohn AM, Turney AH. Acute renal failure in patients with type 1 diabetes mellitus. Postgrad Med J. 1994;70:192-4.

3. Nquyen TC, Carcillo JA. Bench-to-bedside review: Thrombocytopenia-associated multiple organ failure —a newly appreciated syndrome in the critically ill. Crit Care. 2006;10:235.

4. Adil SN, Karim F. Thrombotic microangiopathies: role of ADAMTS-13. J Pak Med Assoc. 2012;62:91-2.

5. Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 2003;14:1072-81.

6. Agarwal S, Sachdev A, Gupta D, Chugh K. Platelet counts and outcome in the pediatric intensive care unit. Indian J Crit Care Med. 2008;12:102-8.

7. Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwkura Y, Ishiwata A, et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood. 2006;107:528-34.

8. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589-600.

9. Dandona P, Beckett AG. Diabetic ketoacidosis associated with thrombotic thrombocytopenic purpura. Diabetes Res. 1986;3:433-5.