agranulocytosis is defined as an absolute neutrophil count ( anc ) less than 100/mm in association with infectious disease .
the risk of agranulocytosis is 0.38% of all clozapine treated cases and there is a relatively lesser incidence in indian population .
the risk of clozapine - induced agranulocytosis and neutropenia is highest in the first 6 months and higher in the initial 18 months after the onset of treatment .
the reports of clozapine induced agranulocytosis in co - morbid multiple sclerosis and delayed onset neutropenia and 2 reports of early treatment phase clozapine induced agranulocytosis have been reported from india , so far no reports of late onset clozapine induced agranulocytosis has been reported from india .
a 44-year - old female patient with a diagnosis of paranoid schizophrenia , on clozapine treatment and regular follow - up presented in psychiatry outpatient department with fever , rigor , swelling of the right hand and sore throat .
she has a 22 year history of fear suspicion and hearing voices with history of treatment with typical and atypical antipsychotics and poor treatment response .
she was started on clozapine around 5 years back and subsequently given risperidone and trihexyphenidyl . at the time of presentation , she was on 150 mg of clozapine , 6 mg of risperidone and 4 mg of trihexyphenidyl .
a total count done 1 week back showed 6,700/mm with 70% neutrophils , 26% lymphocytes and 4% eosinophils .
she was on examination , conscious , oriented , febrile , had a pulse rate of 96/min , her blood pressure was 110/60 mm of hg , diffuse swelling of right upper limb , her systemic examination was normal and had on mental status examination persecutory delusions and third person auditory hallucinations .
she was admitted under the department of internal medicine and worked up . on admission ,
her hemoglobin level was 8.1 g / dl , total count was 700 , her differential count was n4p95e1 , packed cell volume ( pcv ) was 25.3% , erythrocyte sedimentation rate - 140 mm/1 h , platelet count was 6.8 lakhs / dl , random blood sugar was 100 mg / dl , urea - 14 mg / dl , creatinine - 1.1 mg / dl , total bilirubin - 0.8 mg / dl , serum glutamic oxaloacetic transaminase - 103 iu / l , serum glutamic - pyruvic transaminase - 102 iu / l , serum alkaline phosphatase ( sap ) - 125iu / l , total protein - 8 g / dl , a : g ratio was 1:2 , human immunodeficiency virus and hepatitis b surface antigens were negative , chest x - ray was normal , electrocardiogram was normal , computed tomography head was normal , ultrasonography abdomen was normal , but doppler of right upper limb showed dilatation of cephalic vein ( 4.2 mm ) with echogenic content and thrombus extending up to axillary vein with non - compressibility and no internal flow .
she was diagnosed as having - drug induced agranulocytosis and deep vein thrombosis of right upper limb .
she was started on antibiotics ( cefoperazone + sulbactum ) , warfarin , analgesics , proton pump inhibitors , supportive measures , barrier nursing and was given granulocyte - colony stimulating factor 300 g for 7 days .
the bone marrow examination and biopsy carried out post - treatment showed lymphocytosis with 6% blasts .
she however was at request referred to a specialized hematology unit and was treated there with antibiotics ( amoxicillin + clavulanic acid ) warfarin , analgesics , proton pump inhibitors , supportive measures and barrier nursing .
improvement of blood picture patient in the meantime had an exacerbation of psychotic symptoms and was given risperidone , chlorpromazine and trihexiphenidyl .
the patient on improvement of blood picture was discharged on oral antibiotics , warfarin , mupirocin ointment , glycerine mag sulfate thrombocytophobe dressing , risperidone 3 mg , chlorpromazine 150 mg and trihexyphenidyl 2 mg .
the patient had an asymptomatic course and was reviewed by both medicine and psychiatry . at 6 months post event follow - up
she is currently on 8 mg of risperidone , 50 mg of chlorpromazine and 4 mg of trihexiphenidyl and is in partial symptom remission and not on any other medication .
the mechanism of clozapine - induced of agranulocytosis is unclear especially as neither clozapine nor its major stable metabolites , n - desmethylclozapine at therapeutic drug concentrations ( 1 - 3 m ) , have been found to be directly cytotoxic to neutrophils or interfere with the turnover of bone marrow precursor cells .
a strong possibility is for an immune - mediated mechanism or at least an immunological background for clozapine - induced agranulocytosis , as on re - exposure to the drug , the course is more severe and the time interval to recurrence of toxicity is shorter . of the known risk factors of agranulocytosis such as female sex and
increased age or age less than 21 of which this case had one risk factor .
there is also an association between eosinophilia and neutropenia , which was not seen in this case .
the report of delayed onset agranulocytosis is very rare and this is the first reported from india on a patient without co - morbidity .
it is hypothesized modest growth - inhibiting effects of clozapine on bone marrow may be amplified in patients undergoing long - term therapy with clozapine .
dose and serum levels of clozapine may not be directly associated with clozapine - induced agranulocytosis , although some reports suggest a dose - related aspect of this phenomenon .
the phenomenon of late onset agranulocytosis should therefore be considered with care and all clinicians should insist to regular guideline based monitoring of white cell count , even in patients who have been on clozapine for years .
 agranulocytosis is defined as an absolute neutrophil count less than 100/mm3 in association with infectious disease . 
 the risk of agranulocytosis is 0.38% of all clozapine treated cases and there is a relatively lesser incidence in indian population . 
 the risk of clozapine - induced agranulocytosis and neutropenia is highest in the first 6 months and higher in the initial 18 months after the onset of treatment . 
 there have been very few reports of neutropenia and agranulocytosis after this period . 
 there have so far been no reports of late onset clozapine induced agranulocytosis has been reported from india . a case of late onset 
 clozapine induced agranulocytosis with possible mechanism of the same is reported . 
INTRODUCTION
CASE REPORT
DISCUSSION