here , we describe a case of a hispanic male with thrombotic thrombocytopenic purpura induced by nonsteroidal anti - inflammatory drugs ( nsaids ) . the patient was a 21-year - old latino male who presented to the emergency department reporting a five day history of nausea , vomiting , and decreased urine output .
the patient reported that symptoms began shortly after a purposeful consumption of a large quantity of ibuprofen ( 600-mg pills ) in a suicide attempt .
the exact amount of ibuprofen is unclear , but it was predicted that he consumed approximately 18 grams of ibuprofen .
the past medical history was only notable for hypertension diagnosed three years prior , for which he was not receiving any medical therapy .
the patient noted a prior recreational use of alcohol , marijuana and cocaine use , but he denied any use in the past few months .
family history was unremarkable for blood disorders and heart or renal disease . on initial exam ,
the patient had a temperature of 35.8c , a heart rate of 56 beats per minute , a blood pressure of 122/70 mmhg , a respiratory rate of 18 breaths per minute and his oxygen saturation was 100% on room air . the patient was noted to be alert and oriented despite appearing drowsy . on physical exam ,
pertinent findings included jaundice , icteric sclera , dry mucous membranes , and generalized petechiae . heart and lung examination were unremarkable .
the abdomen was found to be soft but slightly tender to palpation at the right upper quadrant . no rebound or guarding was appreciated .
mmol / l , potassium of 5.1 mmol / l , chloride of 83 mmol / l , bicarbonate of 21 mmol / l , blood urea nitrogen of 184 md / dl and creatinine of 19.1 mg / dl , and glucose of 95 mg / dl .
serum osmolality was 323 mosm / kg , with an anion gap calculated at 26 .
white blood cell count 13.4 4 ( 10(3)/mcl ) , hemoglobin was 11.9 ( 10(6)/mcl ) with an mcv of 73 fl , hematocrit was 34% , and platelets were 31,000/mcl .
total bilirubin was 24.6 mg / dl ( direct bilirubin , 20 mg / dl ) , liver function tests were elevated with aspartate aminotransferase was 105 units / l , alanine aminotransferase was 167 units / l , and alkaline phosphatase was 464 units / l . international normalized ratio and prothrombin time were within normal limits .
lactate dehydrogenase ( ldh ) was 8747 units / l , and haptoglobin was less than 10 mg / dl . on the peripheral smear , schistocytes , helmet cells , and large platelets were noted .
ultrasound of the abdomen was unremarkable and hepatomegaly and atrophy of kidneys was not appreciated .
the patient immediately underwent plasma exchange for a total duration of 5 days and simultaneously started on oral glucocorticoids ( prednisone 1 mg / kg ) . following treatment , platelet count recovered and remained above 150,000 after 2 days .
the initiation of intermittent hemodialysis , creatinine and blood urea nitrogen improved significantly . additionally , the ldh returned to baseline .
psychiatry also evaluated the patient and concluded that the suicidal incident was rooted to an adjustment disorder .
a few weeks later , the patient was seen in the outpatient setting where he continued to report resolution of all symptoms and normal urination .
thrombotic thrombocytic purpura is a rare blood disorder characterized by clotting of small blood vessels and low blood platelet counts .
a pentad often characterizes ttp that includes neurological deficits ( often in the form of altered mental status ) , thrombocytopenia , fever , renal dysfunction , and evidence of microangiopathic hemolytic anemia .
not all features must be present for a diagnosis , but important primary criteria include thrombocytopenia and microangiopathy.3 the diagnosis of ttp is made after an exclusion of more prevalent multisystem diseases such as disseminated intravascular coagulation , sepsis , malignant hypertension , systemic lupus erythematosus , and hematologic malignancies.2 ttp is a rare disease with approximately 3.7 cases per million per year in the united states . in approximately 90% of patients , the cause of ttp is unknown.4,5 known conditions that are associated with ttp include a postpartum state , postinfection ( escherichia coli 0157:h7 , e. coli 0111 , e. coli 0104:h4 ) , pancreatitis , malignancy , post - surgical , hiv , post - pneumococcal infection , and drug - induced . for the association with drugs , quinine is the most commonly identified.6 other documented drugs include oral contraceptives , extended - release opioids , valacyclovir and chemotherapeutic agents such as mitomycin c , gemcitabine , cisplatin , oxaliplatin , pentostatin , bevacizumab , and sunitinib .
additionally , the chemotherapeutic agents are typically dose - dependent in their involvement with ttp , and therapies such plasma exchange have been found to be ineffective.4,6 other widely used medications such as the anti - platelet agents ticlopidine and clopidogrel have also been associated with development of ttp .
it is not clear if there is a direct effect of the drug or its metabolites on the vasculature or if a secondary immune response is responsible.3 however , the underlying mechanism for how platelet consumption occurs and the thrombotic microangiopathy that ensues is well - understood .
ttp is associated with a deficiency of a protein known as adamts13 ( a disintegrin and metalloprotease with a thrombospondin type 1 motif , member 13 ) .
the gene for the adamts13 protein is located on chromosome 9q34 . for the congenital form ,
this protein functions to cleave a large von willebrand factor ( ul - vwf ) multimer ( derived from endothelial cells ) into a smaller form.7 if the ul vwf - multimer can not be cleaved , it remains in circulation and activated platelets adhere to it .
platelets are then consumed in the process and the microvascular is further injured from the high shear stress.7 the platelet - uf vwf complexes , if large enough , can also thrombose in the microvasculature of multiple organs .
clinically , the adamts13 protein level is a useful tool in reaching the diagnosis of ttp .
it is important to recognize that levels of this protein can be variable and even normal in several of the drugs associated with ttp.8 in one study , the variability in ttp ranged from 1370%.9 therefore , a decrease in adamts13 activity and the presence of its antibody is more complementary to the diagnosis and overall clinical picture .
a decrease in activity can be associated with ttp if less than 510% ( detection range 0.5100% ) .
the overall consensus is that the presence of an adamts13 deficiency is a critical underlying risk factor , but requires a secondary trigger to develop ttp.4 in clinical practice , if a diagnosis is even suspected , it is imperative to consider initiating plasma exchange ( plasmapheresis with infusions of fresh frozen plasma ) immediately.3 plasma exchange therapy for acquired ttp is effective because it removes adamts13 autoantibodies and ul - vwf multimers , as well as prevents further supply of adamts13.7 disease activity can then be tracked by monitoring ldh and platelets .
notably , prior to the availability of plasma exchange , patient survival was about 10% . with the advent of plasma exchange technology , the overall response rate
is now estimated at 8090%.3,4 the therapy options include plasma exchange , and recent studies have also shown a benefit in using rituximab as a first line therapy of acute acquired ttp.7,10 the rituximab was used in conjunction with plasma exchange and corticosteroids and administered at 375 mg / m intravenously within the first three days of admission and diagnosis with shown clinical benefit.10 the chemical compound 2-(4-isobutylphenyl ) propionic acid , also known as ibuprofen , is a nonsteroidal anti - inflammatory agent used in the management of pain , inflammation , fever , etc . in the the us alone about 30 billion doses
are utilized each year.11 the drug inhibits both cyclooxygenase 1 and 2 that prevents the production of thromboxanes and prostaglandins upon inhibition induce an anti - inflammatory , analgesic , and antipyretic effect .
it is well characterized that the inhibition of the cox-1 pathway is responsible for most of the unwanted side effects.12 these commonly include nausea , dyspepsia , gastrointestinal bleeding , transaminitis , and , less likely , jaundice , fatal fulminant hepatitis , liver necrosis , and renal papillary necrosis and occasionally hepatic failure .
ibuprofen is plasma protein bound with a large volume of distribution ( 0.110.19 l / kg ) .
a single 400-mg dose in adults produces a peak plasma level at 12 hours after ingestion and is eliminated via the kidneys within the next 8 h and then is practically undetectable by 12 h. its maximum recommended daily dose is 12003200 mg.1214 anemia is the only known hematological effect.15 more serious effects associated with long - term use and can manifest as esophageal ulceration and chronic renal failure and can worsen heart failure.16 nsaid overdose is generally a benign process . in 2010 , the annual report of the american association of poison control centers national poison data system ( npds ) : 28th annual report reported 65,699 cases of overdose with 9,169 of those characterized as intentional .
forty - seven cases were classified as a serious toxicity that manifested as status epilepticus , respiratory failure , ventricular arrhythmias , or cardiac arrest .
no deaths due to ibuprofen were reported in 2010 . the high index of safety centers around ibuprofen s inability to accumulate in the body regardless of subsequent doses.17
there have been no recent cases attributing the development of ttp to patients exposed to nsaids .
one case report from 1974 described a 55-year - old italian female who developed ttp after ingesting 900 mg of ibuprofen .
no other alternative etiologies could be accounted for and the patient eventually expired as no plasma exchange therapy was available at that time.2 however , there have been some reports of nsaids causing hemolytic uremic syndrome ( hus ) , a disease process very similar to ttp.18 paradoxically , antiplatelet therapy was at one point considered as potential treatment for ttp .
the theory stipulated that by preventing platelet aggregation with antiplatelet agents , further endothelial injury and thrombosis could be prevented .
data from this study demonstrated that at least in certain cases , antiplatelet drugs probably play only a limited role in the treatment of patients with ttp.19 in another trial , prostacyclin ( pgi2 ) infusion , again with the same principle , failed to reverse platelet aggregation caused by ttp.20
our patient presented with clinical symptoms that included altered mental status , acute renal dysfunction , thrombocytopenia , and evidence of red blood cell fragmentation .
all symptoms evolved a few hours after ingesting a large amount of ibuprofen . in our assessment ,
other possible disease entities were considered but excluded such as hemolytic uremic syndrome ( no history of diarrhea and negative e. coli 0157h7 study ) , autoimmune hemolytic anemia ( coombs test was negative ) , disseminated intravascular coagulation ( coagulation factors were normal ) , hiv , and absence of other known drugs .
adamts13 activity was less than 10% and solidified our assessment that ttp was the clear diagnosis .
ibuprofen , its metabolites or even components of the drug formula may have caused this condition .
nonetheless , because of the widespread use of nsaids and the high mortality associated with undiagnosed ttp , we present this case - report to shed light into a possible , unknown association between ibuprofen and ttp .
 a 21-year - old male presented to the emergency department after a 5-day history of recurrent vomiting and decreased urine output . 
 history revealed ingestion of ibuprofen . during the diagnostic workup , 
 the following was identified : white blood cell count 13.4 ( 10(3)/mcl ) , hemoglobin 11.9 ( 10(6)/mcl ) with an mcv of 73 fl , hematocrit 34% and platelets were 31,000/mcl , sodium of 130 mmol / l , potassium of 5.1 mmol / l , chloride of 83 mmol / l , bicarbonate of 21 mmol / l , blood urea nitrogen of 184 mg / dl and creatinine of 19.1 mg / dl . 
 he was later diagnosed with thrombotic thrombocytopenic purpura ( ttp ) based on the fact that he presented with most components of the ttp pentad ( except for fever ) , which included altered mental status , acute kidney injury , thrombocytopenia , and evidence of red cell fragmentation and his adamts13 level was found to be less than 10% prior to therapy . 
 the patient then received plasma exchange , oral corticosteroids , and hemodialysis , which led to a full recovery of platelet count and renal function . 