Introduction:
Drug induced immune thrombocytopenia is a rare and potentially fatal cause of isolated thrombocytopenia with reported incidence of 10 in one million cases. It is supposed to be caused by formation of drug dependent platelet reactive antibodies leading to increased platelet consumption and destruction. DITP usually occurs within one week of initiation of offending drug and platelet nadir is typically less than 20,000/ul , with or without bleeding manifestations. Prompt discontinuation of inciting drug is the key to resolution and prevention of serious complication like gastrointestinal and intracranial bleeding.
Methods:
CASE REPORT: A 16 Year old female presented with loss of appetite, weight loss and stunted growth. On evaluation, she was found to have raised urea (212mg/dl) and creatitine ( 16mg/dl), serum electrolytes ( sodium 130 meq/l, potassium 5.9 meq/l) , hypocalcemia and low vitamin D levels. Her complete blood count revealed low hb level ( 6 g/dl), normal total leukocyte count (6500/ul) and normal platelet count ( 2,75,000/ul). Arterial blood gas analysis was suggestive of severe metabolic acidosis. She was admitted in the ICU , and family was counselled about the need of hemodialysis. Thereafter , right femoral HD catheter was inserted and patient was initiated on hemodialysis. Further investigations like ultrasound revealed bilateral small sized kidneys with thinning of cortex and indistinct corticomedullary differentiation – hence not feasible for renal biopsy. She was diagnosed with endstage renal disease and explained about need of long term renal replacement therapy as well as vascular access creation. She continued with regular hemodialysis sessions and also received 2 units prbc in subsequent sessions. However prior to fifth session of dialysis, the patient complained of fever in view of which blood cultures was sent ( central and peripheral) which was negative , serum procalcitonin was 1.05, dengue and malaria profile was done and found to be negative. Empirically she was on injectable ceftriaxone twice a day and she improved symptomatically. During the course of illness, she developed pain and swelling of right lower limb clinically suggestive of deep venous thrombosis which was further confirmed on ultrasound doppler of affected limb. Her complete blood count was done and was found to have thrombocytopenia (9000/ul) with no bleeding manifestations. Femoral HD catheter was removed from affected limb , new catheter was placed in left lower limb under platelet cover and subsequent sessions of hemodialysis was done with nil heparin. Her complete blood count was routinely monitored and was found to have continued thrombocytopenia despite receiving multiple platelet transfusions during dialysis sessions. The most pertinent question remained about the cause of persistently low platelet count . Work up was initiated to rule out sepsis, viral illness and also peripheral flood smear showed reduced number of platelets with normal morphology, with no schistocytes or platelet clumping. Immature platelet fraction was 30.7% , indicative of peripheral destruction with adequate marrow response. LDH was 184, liver function test did not reveal indirect hyperbilirubinemia( no evidence of hemolysis). Vitamin b12 levels was normal. The patient did not any rash , bleeding or splenomegaly on physical examination ( hence idiopathic thrombocytopenia was excluded) . Atypical Hemolytic uremic syndrome was also excluded with no schistocytes on pbs and normal complement levels. Heparin induced thrombocytopenia was also ruled out with HIT IgM antibody levels being negative. Finally after ruling out all the supposedly reversible causes of thrombocytopenia , her treatment course was reviewed again and ceftriaxone was discontinued considering it to be a likely drug inducing thrombocytopenia. She was followed up with sequential platelet count and was discharged with right ijv permacath in situ with platelet count of 50000/ul. She continued her maintenance hemodialysis sessions with nil heparin and hemogram, was followed up. We noted rise in platelet count almost her ten days of stopping ceftriaxone. Hence owing to temporal relationship between development and resolution of thrombocytopenia with initiation and withdrawal of ceftriaxone, a diagnosis of drug induced thrombocytopenia was done.
Results:
DISCUSSION : Ceftriaxone induced thrombocytopenia is a rare and potentially life threatening complication. Only seven cases of ceftriaxone-induced immune thrombocytopenia had been reported from 1991 to 2018 by the University of Oklahoma database. Grossjohann et al showed how antibodies with an affinity for epitopes on platelets led to platelet destruction and subsequent thrombocytopaenia in two separate cases, but what remains to be revealed is how ceftriaxone triggered the production of such antibodies.
What makes this case special is that it will be one of first cases of ceftriaxone induced thrombocytopenia to be reported in an end stage renal disease patient. The cause of thrombocytopenia in esrd is multifactorial including use of heparin during hemodialysis, uremia, sepsis, use of various dialyzer membranes and sterilization techniques , bone marrow disorders and use of certain medications. In our case all the relevant and reversible causes of low platelet count in end stage renal disease patient was excluded by doing extensive work up and evaluation. Finally ceftriaxone was found to be the inciting agent in this case. Ceftriaxone is a third generation cephalosporin , with molecular weight of 554.58 g/mol primarily eliminated in the urine (33-67%), remainder is eliminated through secretion in the bile and removed from the body via the feces. However ceftriaxone does not need dose adjustment in renal failure with dosages upto 2 g/d . The average elimination half life of ceftriaxone in normal healthy adults is 5.8 to 8.7 hours, but in case of renal impairement the average elimination half life becomes two fold (16 hours).
In our case probably altered excretion of the drug was proposed to be the cause. Due to laboratory limitations at the healthcare facility, we were unable to test for the presence of ceftriaxone-dependent platelet reactive IgG antibodies. This remains as a limitation of the case.
Laboratory studies with decreased platelet count and stable haemoglobin and white cell count after starting ceftriaxone should raise suspicion for cases of DITP which usually starts within a week of starting the drug and resolves within 7 to 10 days of stopping the drug. High clinical suspicion in formulating a diagnosis and management of unexplained thrombocytopaenia after starting ceftriaxone is imperative.
Conclusions:
CONCLUSION: Drug induced thrombocytopenia remains a diagnosis of exclusion and poses a significant therapeutic challenge. This case highlights the importance of altered drug metabolism and clearance in critically ill patients, especially those with renal dysfunction. Prompt cessation of offending drug remains the mainstay of therapy .
REFERENCES:
1. Sharma A , Mannuru D , Matta A, Kaushal A. Rare complication of ceftriaxone therapy: drug-induced thrombocytopenia ( DITP). BMJ Case Rep. 2021 Sep 6;14(9):e245228.
2. Jacquot C, Moayeri M, Kim B, Shugarts S, Lynch KL, Leavitt AD. Prolonged ceftriaxone-induced immune thrombocytopenia due to impaired drug clearance: a case report. Transfusion. 2013 Nov;53(11):2715-21.
3. Piedra Abusharar S, Shah N, Patel R, Jain R, Polimera HV. A Case of Confirmed Ceftriaxone-induced Immune Thrombocytopenia.Cureus.2019 May 17; 11(5):e4688.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.