Impaired Platelet Function Associated witn Parenteral Nafcillin*

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1 ANNALS O F CLIN ICAL AND LABORATORY SCIEN CE, Vol. 20, No. 1 Copyright 1990, Institute for Clinical Science, Inc. Impaired Platelet Function Associated witn Parenteral Nafcillin* ELAINE K. JETER, M.D., AMY SCOTT, M.D., JOETTE KIZER, M.L.T., and JOHN LAZARCHICK, M.D. Department of Pathology/Laboratory Medicine Medical University o f South Carolina, Charleston, SC ABSTRACT A 44-year-old Caucasian female was adm itted with a subarachnoid hem orrhage owing to a multilobular tubular anterior communicating artery aneurysm. Eleven days after the original craniotomy, an epidural h em a tom a was evacuated. The patient was placed on em piric nafcillin antim i crobial coverage (two g every six hours). W ithin 24 hours, the onset of epistaxis and oozing of blood from the endotracheal tube and craniotomy site was noted. Recurrent subdural and epidural hematomas necessitated a third em ergent craniotomy. The developm ent of an acquired qualitative platelet defect was suggested by the findings of a prolonged tem plate bleeding time and markedly abnormal platelet aggregation/ release studies despite a normal platelet count. Nafcillin therapy was immediately discontinued. Clinical bleeding resolved. Subsequent bleeding times and platelet aggregation studies confirmed the nafcillin-induced platelet dysfunction. Introduction Beta-lactam antibiotics, penicillins and cephalo sp o rin s, are com m only used pharmacologic agents which have a wide range of antimicrobial activity. A num ber of th e se m isy n th etic penicillins and cephalosporins have been reported to cause impaired hemostasis with bleeding diatheses in hospitalized patients as well as in healthy volunteers.7,8,9,13,16,17 In Send reprint requests to: Elaine K. Jeter, M.D., Medical University of South Carolina, Department of Pathology/Laboratory Medicine, Blood Bank Section, 171 Ashley Avenue, Charleston, South Carolina general, the mechanisms responsible for hematologic defects differ betw een the penicillins and cephalosporins, and, to date, have not b een com pletely elucidated. I t appears th at penicillin-m ediated hemostatic defects are produced by platelet dysfunction as dem onstrated by in vivo, as well as, in vitro platelet studies.9,14 A case is reported of nafcillin-induced platelet dysfunction with bleeding in a post-operative patient treated with pare n te ra l nafcillin. T em plate b leed in g tim es and platelet aggregation studies were performed during nafcillin therapy and twice after the antibiotic was discontinued /90/ $00.90 Institute for Clinical Science, Inc.

80 JETER, SCOTT, KIZER, AND LAZARCHICK Case Report A 44-year-old white female experienced sudden onset of global headache with nausea, vomiting, and urinary incontinence.

2 80 JETER, SCOTT, KIZER, AND LAZARCHICK Case Report A 44-year-old white female experienced sudden onset of global headache with nausea, vomiting, and urinary incontinence. She presented to a local hospital on August 30, 1988 where a lumbar puncture was performed and grossly bloody cerebrospinal fluid (CSF) was obtained. A diagnosis of subarachnoid hemorrhage was made, and the patient was transferred to this Medical Center for further evaluation and treatment. Subarachnoid hemorrhage was confirmed by a computerized axial tomographic scan. Angiography revealed a large multilobular tubular anterior communicating artery aneurysm. There was no history of a bleeding tendency. Preoperative evaluation included hemoglobin of 13.3 g per dl, hematocrit of 40.0 percent, platelet count of 297 x 109 per L, prothrombin time (PT) of 11.9 seconds (normal reference range 11 to 13.2 seconds) and activated partial throm boplastin tim e (aptt) of 24.0 seconds (normal reference range 21 to 30 seconds). On the day after admission, a left temporal craniotomy was performed, and a complex anterior communicating artery aneurysm was dissected and clipped. Estimated blood loss was 800 cc. The patient received two units of packed red blood cells during surgery. During the first postoperative day (POD 1), the patient remained stable, alert, and was able to follow commands. However, during the next two weeks she experienced several complications. On POD 2, a small left anterior-medial basal ganglia infarct occurred. Neurologic status deteriorated but ultimately resolved by POD 9. During the postoperative course, hem atologic param eters remained within normal limits except for a gradual iatrogenically induced decline in the hemoglobin and hematocrit values. Medications during the postoperative period consisted of Decadron (Dexamethasone), Zantac (Ranitidine hydrochloride), mannitol, and morphine. On POD 11, a second intracranial bleed occurred into the left middle fossa as well as a subacute epidural hematoma in the left frontotemporal region. Re-entry of the craniotomy and evacuation of the extracerebral blood clot (100 cc) was performed. Intraoperative estimated blood loss was 100 cc, and two units of packed red blood cells were transfused intraoperatively. Postoperatively, nafcillin (two grams every six hours, intravenously) was added for empiric antimicrobial coverage for possible CSF leakage associated with surgical manipulation. Within 24 hours after the second surgery, epistaxis developed with onset of blood oozing from the craniotomy site and around the endotracheal tube. Petechia and ecchymosis were not present. A prolonged template bleeding time of 9.5 minutes (normal reference range 2 to 8 minutes) was obtained. The PT and PTT were normal. The platelet count had decreased from 284 X 109 per L the previous day to 175 x 10 per L. A third emergent craniotomy was performed and left frontotemporal subdural and epidural hemorrhages were evacuated. Oozing from the surgical site continued postoperatively. A repeat template bleeding time was 14.5 minutes with a platelet count of 142 x 109 per L. The patient had received a total of 16 grams of nafcillin during the previous 48 hours. The next day, platelet aggregation studies were performed and were abnormal. Nafcillin was discontinued and apheresis platelets w ere adm inistered. Within 24 hours of discontinuation of nafcillin, the template bleeding time normalized at 7.0 minutes and the patient was hemostatically stable without any source of bleeding. Materials and Methods Hemoglobin, hematocrit, and platelet counts were obtained from whole blood collected in ethylenediamine tetraacetic acid (EDTA) with an electronic particle co u n ter.* R leeding tim es w ere p e r formed by the tem plate m ethod.4 The prothrom bin tim e (PT) was determ ined using th ro m b o p lastin C.f A ctivated throm boplastin tim e was determ ined using A ctin.f Platelet aggregation studies were perform ed by a turbidim etric method. 10t Simultaneous measurement of adenosine trip h o sp h ate () was detected using the firefly luciferase-luciferin system with a highly sensitive photomultiplier tube.$ Values are expressed as am per 109 platelets. Results T hree in vitro platelet aggregation stu d ies w ere p erfo rm ed. T he initial p la te le t aggregation study was conducted while the patient was on nafcillin and had received a total cumulative dose of 16 grams. Platelet aggregation abnormalities w ere observed w ith all aggregating reagents and with all concentrations em ployed (table I). A bnorm alities in ADP-induced aggregation occurred with both high and low concentrations (1 X * Coulter Counter Model S plus STKR, Coulter Corp., Hialeah, FL. t Dade Division, Baxter Health Corp., Miami, FL. $ Lum inaggregom eter Model 400, Chronolog Corp., Havertown, PA.

3 PLATELET DYSFUNCTION WITH NAFCILLIN 81 T A B L E I Platelet Aggregation Studies - Daring Nafcillin Therapy (16 Grams Total) Control * Patient Aggregating Reagent Concentration Aggregation Releasef Percent Aggregation Release-j- ADP$ 5 x 1CT Disaggregation 0 1 x Disaggregation 0 Collagen Epinephrine$ 5 x x Arachidonic 7.5x acid Ristocetin *Control platelets were from a healthy donor with reproducible aggregation responses. fadenosine triphosphate () release is expressed in ym per 10^ platelets. ^Concentrations expressed in M. Concentrations expressed in g per L M and 5 X 10~6M). A ddition of adenise diphosphate (ADP) produced a primary wave of aggregation but failed to elicit the secondary irreversible wave (d isag g reg atio n p h en o m e n o n ). T he platelet response to high dose epinephrine (1 X 10-5 M) was characterized by diminished aggregation without release. Defects in high dose (9.5 g per L) collagen-induced aggregation consisted of the expected single wave of aggregation followed by a markedly depressed release response. High dose ristocetin produced a g g lu tin a tio n w ith o u t rele ase. There was no aggregation or release with low dose collagen (3.8 g per L), low dose epinephrine (5 X 10_6M), or arachidonic acid (7.5 X 10-4 M). The second platelet aggregation studies were performed six days after nafcillin had been discontinued. The patient was hem odynam ically stable. Norm al aggregation responses w ere observed with ADP, collagen, and arachidonic acid, but release was diminished or absent with each agonist. Both low and high concentrations of epinephrine produced diminished aggregation and failed to release. Ristocetin produced normal agglutination w ith abnorm al release (table II). The th ird and final p latelet aggregation study was performed approximately two weeks after nafcillin was discontinued (data not shown). Normal aggregation and release responses were elicited with all of the agonists tested (ADP, collagen, epinephrine, arachidonic acid, and ristocetin). The tem plate bleeding tim e was prolonged at 14.5 minutes during nafcillin therapy and normal on day 6 and 17. Discussion To date, there has been a single report of two cases of nafcillin-induced platelet dysfunction w ith associated bleeding diathesis.1 In one of their patients, Alexander and coworkers performed platelet aggregation studies during nafcillin th erapy and after nafcillin rechallenge. Studies perform ed at both tim es show ed abnormal platelet response to ADP, epi-

8 2 JETER, SCOTT, KIZER, AND LAZARCHICK A ggreg a tin g Reagent TABLE II Platelet Aggregation Studies - Six Days After Nafcillin Therapy Concentration Aggreg a tio n C ontrol* R e lea sef P a tie n t

4 8 2 JETER, SCOTT, KIZER, AND LAZARCHICK A ggreg a tin g Reagent TABLE II Platelet Aggregation Studies - Six Days After Nafcillin Therapy Concentration Aggreg a tio n C ontrol* R e lea sef P a tie n t P ercen t Aggreg a tio n R e le a s e f ADPj s x 10" x 10" NDf NDfi Collagen EpinephrineJ 5 x X 10" ArachidonicJ 7..5x acid Ristocetin *Control platelets were from a healthy donor with reproducible aggregation responses. fadenosine triphosphate () release is expressed in pm per 109 platelets. ^Concentrations expressed in M. ^Concentrations expressed in g per L. An d - not done. nephrine, and collagen. Three concentrations of ADP produced depression of the prim ary wave of aggregation and absence of the secondary wave w ith platelet disaggregation. Abnormal platelet aggregation was also produced with low doses of collagen and epinephrine. Bleeding times during both studies were m arkedly prolonged. In our in itial p la te le t aggregation study, severe defects in aggregation were noted with all agonists except ristocetin and high-dose collagen. Although p re viously unreported, the present authors have shown com plete absence of release with all agonists except high-dose collagen which had m arkedly im paired release. Additionally, at six days after nafcillin therapy, docum entation by us has shown that aggregation with all agonists was normal, and that release, a response to the irreversible second wave of a g g reg atio n, re m a in e d m ark ed ly abnormal. It has also been indicated that aggregation and release at 17 days post nafcillin therapy was normal. Our patient was not rechallenged with nafcillin, owing to h er poor clinical status. Defects in hemostasis may be caused by therapeutic doses of beta-lactam antib io tics and have b e e n o b se rv e d in patients treated with natural and semisynthetic penicillin or cephalosporin agents.3,9,17 The penicillins inhibit platelet aggregation by interfering with platele t m e m b ra n e re c e p to rs and th e ir responsiveness to physiologic agonists. In contrast, the cephalosporin antibiotics adversely effect vitam in K -dependent coagulation factors.5,6,9,16,17 Moxalactam, a cephalosporin, is unique in so far as it produces both platelet dysfunction and coagulopathy.5,20 The mechanism of penicillin-induced p latelet dysfunction has been investigated by in vitro platelet aggregation studies.6,7,14,18 Normal platelets exposed to physiologic concentrations of penicillin G and carb en icillin d e m o n stra te im pairm ent in the interaction of radiolabeled platelet agonists (epinephrine and ADP) w ith platelet surface receptors, inhibiting platelet aggregation and serotonin release. D ecreased ristocetininduced platelet agglutination was also o b s e rv e d.18 O th e r in v itro stu d ie s employing therapeutic doses of apalcillin,12 am picillin,6 m ethicillin,6 piperacillin,11 carbenicillin,7 and ticarcillin8,19 have p ro d u c e d sim ilar re s u lts w ith defective ADP, epinephrine, and collagen-induced primary aggregation. These studies suggest that penicillins produce platelet dysfunction by global interaction with m em brane surface receptors. It has been postulated that this may be due to the strong affinity of the penicillins for m em brane proteins and lipids.15 T he frequency and severity of penicillin-induced platelet abnorm alities are related to dose and duration of administration of the drug. Studies show that in volunteers, the longest bleeding times occurred in those individuals receiving th e la rg e s t dose o f tic a rc illin and returned to normal approximately four days after the drug was stopped.8 In

PLATELET DYSFUNCTION WITH NAFCILLIN 8 3 vitro platelet aggregation with multiple agonists in these volunteers w ere all abnormal by day three of drug administration.

5 PLATELET DYSFUNCTION WITH NAFCILLIN 8 3 vitro platelet aggregation with multiple agonists in these volunteers w ere all abnormal by day three of drug administration. They reported abnormalities in ADP-induced aggregation, the most sensitive platelet agonist, within 24 hours after drug administration. Recovery of A D P-induced aggregation occurred in most volunteers by seven to 10 days after drug therapy was term inated. Platelet function, assessed by platelet aggregation, may remain abnormal for up to 21 days after cessation of therapy.2,6,7 The prolonged period to recovery of platelet aggregation studies after cessation of drug therapy may reflect drug-receptor inhibition on the megakaryocyte m em brane and may persist on the platelets despite absence of the drug in the circulation. In our study, the absent or diminished release at six days after nafcillin termination, despite recovery of the primary phase of aggregation, supports th e hypothesis for an additional m echanism of penicillin-induced platelet dysfunction. Risk factors that potentiate hemostatic p ro b le m s and b le e d in g in p a tie n ts receiving penicillins have b e e n id en tified. Significant co-variables associated with increased tem plate bleeding time and/or clinical bleeding include: throm bocytopenia, dose 5= 12 g p er day, primary bone marrow disorders affecting p late le t function, im paired renal function, postoperative status, chem otherapy, and age of 3=60 years.2,9,13 The only factor associated with increased risk of bleeding in our patient was the postoperative status. Since the incidence of beta-lactam - induced qualitative platelet defects is not known, acquired platelet dysfunction m ust be considered w ith the onset of clinically significant new bleeding (epistaxis, petechiae, mucosal hem orrhage or oozing around surgical, ostomy or IV sites) in patients receiving natural or sem isy n th etic penicillins. H em ostasis evaluation should include a tem plate bleeding tim e, platelet count and ro u tine coagulation studies. A prolonged tem plate bleeding tim e w ith norm al platelet count, PT and aptt (as was seen in our case) indicates a qualitative platelet defect, characteristic of the penicillins. In vitro platelet aggregation studies help to confirm the platelet dysfunction. The offending penicillin must be discontin u e d and an a lte rn a tiv e an tib io tic se le c te d for th erap y. T he te m p la te bleeding tim e will re tu rn to norm al within two to four days of drug discontinuation, although platelet aggregation studies may remain abnormal for more th a n 10 to 14 days as p re v io u s ly noted.2,6,7 Platelet transfusions may be indicated in patients at risk of significant b le e d in g or life -sa v in g in p a tie n ts actively bleeding. References 1. Alexander, D. P., Russo, M. E., F o hrm an, D. E., et al.: Nafcillin-induced platelet dysfunction and bleeding. Antimicrob. Agents Chemother. 23:59-62, Andrassy, K., W e is c h e d e l, E., Rit z, E., etal.: Bleeding in uremic patients after carbenicillin. Thromb. Haemos. 36: , Babiak, L. M. and Rybak, M. J.: Hematological effects associated with beta-lactam use. Drug Intell. Clin. Pharm. 20: , Ba bso n, S. R. and Ba bso n, A. L.: Development and evaluation of a disposable device for performing simultaneous duplicate bleeding time determinations. Am. J. Clin. Pathol. 70: , Bang, N. U., T e s s l e r, S. S., H e id e n r e ic h, R. O., et al.: Effects of moxalactam on blood coagulation and platelet function. Rev. Infect. Dis. 4 suppl.:s , B r o w n, C. H., Ill, Br a dsh a w, M. W., N a tel- SON, E. A., e t al.: D efectiv e p la te le t function fo llo w in g a d m in is tr a tio n o f p e n ic illin c o m pounds. Blood 47: , Brow n, C. H., Ill, N atelson, E. A., Bradshaw, W., et al.: The hemostatic defect produced by carbenicillin. New Engl. J. Med. 291: , Bro w n, C. H., Ill, N atelson, E. A., Bradsh a w, M. W., et al.: Study of the effects of ticarcillin on blood coagulation and platelet function. Antimicrob. Agents Chem other. 7: , 1975.

6 84 JETER, SCOTT, KIZER, AND LAZARCHICK 9. F ass, R. J., C o pe l a n, E. A., B ra n d t, J. T., et al.: Platelet-mediated bleeding caused by broadspectrum penicillins. J. Infect. Dis. i 55: , F e in m a n, R. D., L ubow sky, J., and C h a r o, I. F.: The lumi-aggregometer: A new instrument for simultaneous measurement of secretion and aggregation. J. L ab. Clin. Med. 90: , G entry, L. O., J e m se k, J. G., and N a te lso n, E. A.: Effects of sodium pipericillin on platelet function in norm al volunteers. Antimicrob. Agents Chemother. 19: , G entry, L. O., W o o d, B. A., and N a te lso n, E. A.: Effects of apacillin on platelet function in normal volunteers. Antimicrob. Agents C hemother. 27: , H aburchak, D. R., H ea d, D. R., and E vere t t, E. D.: Postoperative hem orrhage associated with carbenicillin administration: Report of two cases and review of the literature. Am. J. Surg. 134: , J o h n s o n, G. J., Ra o, G. H. R., and W h it e, J. G.: Platelet dysfunction induced by parenteral carbenicillin and ticarcillin. Am. J. Path. 91:85 106, Pa d f ie l d, J. M. and Kellaw ay, I. W.: Rheological studies on mixed phospholipid sols and their interaction with penicillins: I. Continuous shear viscometry. Chem. Phys. Lipids 10: , Sattler, F. R., W eitekam p, M. R., and Balla r d, J. O. : Potential for bleeding with the new beta-lactam antibiotics. Ann. Int. Med. 105: , Sa ttler, F. R., W e it e k a m p, M. R., Sa y e g h, A., et al: Impaired hemostasis caused by betalactam antibiotics. Am. J. Surg. 155:30-39, S h a ttil, S. J., Be n n e t t, J. S., M c D o n o u g h, M., et al.: Carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of agonists with the platelet surface. J. Clin. Invest. 65: , So m a n i, P., S m it h, M. R., G o h a ra, A., et al.: The effects of mezlocillin, ticarcillin, and placebo on blood coagulation and bleeding time in normal volunteers. J. Antimicrob. Chemother. 11 suppl.:33-41, W e it e k a m p, M. R. and Ab er, R. C.: Prolonged bleeding times and bleeding diathesis associated with moxalactam administration. J. Am. Med. Assoc. 249:69-71, 1983.

Reemergence of the International Normalized Ratio for the Standardization of Prothrombin Time*

ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 23, No. 3 Copyright 1993, Institute for Clinical Science, Inc. Reemergence of the International Normalized Ratio for the Standardization of Prothrombin