http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, 2015; 26(1): 10–12 ! 2015 Informa UK Ltd. DOI: 10.3109/09537104.2014.880108
ORIGINAL ARTICLE
Pantoprazole-induced thrombocytopenia in patients with upper gastrointestinal bleeding Emine Binnetog˘lu1, Erdem Akbal2, Hacer S¸ en1, Fahri Gu¨ne¸s1, Go¨khan Erbag˘1, Mehmet A¸sık1, Neslihan Bozkurt1, Ay¸segu¨l Uludag˘3, Murat Tekin3, & Sati Zeynep Tekin4
Platelets Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 02/03/15 For personal use only.
1
Department of Internal Medicine, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey, 2Department of Gastroenterology, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey, 3Department of Family Medicine, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey, and 4Department of Microbiology, Faculty of Medicine, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey Abstract
Keywords
Proton pump inhibitors (PPIs) are highly effective drugs for patients suffering from peptic ulcer and gastro-esophageal reflux diseases, but recent studies have indicated possible risks with the long-term use of PPIs, such as osteoporosis, fractures, increased risk of pneumonia, diarrhea, iron and vitamin B12 deficiencies. There are publications written as a case study that indicate thrombocytopenia as side effects of PPIs, but there is no study on this subject. This study aimed to investigate the development of thrombocytopenia in patients with short-term use of PPIinfusion therapy. In this study, the records of the patients were evaluated retrospectively, for the period between January 2012 and January 2013. Thirty-five patients with upper gastrointestinal bleeding were enrolled. Platelet counts were analyzed before treatment, and on the first, second and third day of treatment, respectively. All patients were treated with intravenous pantoprazole. Hemogram values of patients were analyzed before and after PPI infusion treatment. Platelet counts were found to decrease from the first day to the third day of treatment (249 714.29/ml, 197 314.29/ml, 193 941.18/ml, 183 500/ml, respectively). The platelet count decrease was statistically significant (p50.001). After cessation of infusion therapy, platelet counts began to rise on the fourth day. Three patients had severe thrombocytopenia on the third day of the treatment. (69 000/ml, 97 000/ml and 49 000/ml respectively). Platelet counts recovered after discontinuation of treatment. In conclusion, this study demonstrates that PPIs may cause thrombocytopenia, and this result should not be ignored. In particular, patients with PPI infusion therapy should be monitored more closely.
Pantoprazole, proton pump inhibitors, thrombocytopenia
Introduction Peptic ulcer disease, gastroesophageal reflux disease (GERD) and functional dyspepsia are the most common diseases of the gastrointestinal system. The prevalence of GERD is reported to be approximately 10–30% [1, 2] and if untreated or inadequately treated, serious complications may arise [3]. Pharmacological treatment alleviates the symptoms in the majority of patients [4]. Proton pump inhibitors (PPIs) are highly effective drugs in patients suffering from gastrointestinal diseases such as GERD, peptic ulcer disease. They not only counter the disease, but also improve quality of life [5]. The reliability of these drugs is good, but recent studies have indicated possible risks with the long-term use of PPIs, such as osteoporosis, fractures, increased risk of pneumonia, diarrhea, and iron and vitamin B12 deficiencies. All studies on this subject to date have investigated the reliability of the long-term use of PPIs. Short-term side effects of PPIs have been reported in case reports in the literature. These reports have demonstrated that the short-term use of PPIs may be a cause of thrombocytopenia. In this study, we aimed to investigate the
Correspondence: Emine Binnetoglu, MD, Department of Internal Medicine, Faculty of Medicine, C¸anakkale Onsekiz Mart University, Kepez, C¸anakkale, Turkey. Tel(GSM): 90 533 8154947. Fax: 90 286 2635956. E-mail: [email protected]
History Received 13 December 2013 Revised 26 December 2013 Accepted 31 December 2013 Published online 10 February 2014
development of thrombocytopenia in patients being treated with the short-term use of PPI infusion therapy.
Materials and methods In this study, the records of the patients of the gastroenterology and internal medicine departments were evaluated retrospectively between January 2012 and January 2013. This study was approved by the local ethical committee of C¸anakkale Onsekiz Mart University. Demographic characteristics of the patients (age, gender, endoscopic results, medical therapy and hemogram results) were obtained from medical records. Patients whose baseline platelet counts were less than 150 000/mL, patients who received any drugs that may cause thrombocytopenia and patients with chronic hematologic, renal or hepatic diseases and infection diseases were excluded. Oral intake was completely stopped in patients with upper gastrointestinal bleeding and treated with PPI infusion for more than 3 days. After giving 80 mg intravenous bolus, an 8 mg per hour pantoprazole infusion was started and continued for 72 hours. After 72 hours, pantoprazole was given intravenously two times a day. Thirty-five patients with upper gastrointestinal bleeding were enrolled. Platelet counts were analyzed before treatment, at first day, second day and third day of treatment respectively. All patients were treated with intravenous pantoprazole, because only pantoprazole was available in the hospital.
Pantoprazole-induced thrombocytopenia
DOI: 10.3109/09537104.2014.880108
Statistical analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software version 13. The variables were investigated using visual (histograms, probability plots) and analytical methods (Kolmogorov–Smirnov/Shapiro’s–Wilk test) to determine whether or not they were normally distributed. Descriptive analyses were presented using means and standard deviations for normal distribution. When investigating the changes in platelet counts, the effects of treatment were adjusted using repeated measures of analysis of variance. The Greenhouse– Geisser correction was used when the sphericity assumption was violated.
Platelets Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 02/03/15 For personal use only.
Results The hemogram values of 35 patients (17 female and 18 male) were analyzed before and after PPI-infusion treatment. The demographic characteristics of the patients are summarized in Table I. Platelet counts were found to decrease from the first day to the third day of treatment (249 714.29/ml, 197 314.29/ml, 193 941.18/ml, 183 500/ml, respectively) (Table I). This decrease was statistically significant (p50.001) (Figure 1). After cessation of infusion therapy, platelet counts began to rise on the fourth day (Figure 1). Three patients had severe thrombocytopenia on the third day of the treatment (69 000/ml, 97 000/ml, 49 000/ml
Table I. The demographic characteristics of the patients.
Age Gender(M/F) Urea (mg/dl) AST (U/l) ALT (U/l) Platelets count at onset Platelets count at first day Platelet count at second day Platelet count at third day Platelet count at fourth day Abbreviations: ALT: aminotransferase.
alanine
Patients (n ¼ 35)
Standard deviation
61.34 18/17 64.32 20.29 14.53 249 714.29 197 314.29 193 941.18 183 500 184 592.59
±20.06
aminotransferase;
Figure 1. Platelet counts in patients before and after treatment and after cessation of treatment the increase in platelet count.(PLT: platelet count at onset; PLT-1: platelet count at first day; PLT-2: platelet count at second day; PLT-3: platelet count at third day; PLT-4: platelet count at fourth day).
±44.16 ±14.25 ±8.82 ±104 199.63 ±72 137.84 ±74 511.72 ±78 637.59 ±82 429.57 AST:
aspartate
11
respectively). Platelet counts recovered after discontinuation of treatment.
Discussion In this study we demonstrated that PPIs have thrombocytopenic effects in addition to well-known side effects. This study demonstrated a gradual decrease in platelet counts with PPI infusion therapy. Sometimes this decline can be very serious, and doctors may need to discontinue the treatment as was done with three of our patients. PPIs are important medications for the management of acidrelated disorders. Pantoprazole reduces gastric acid secretion by inhibiting proton pump (H+–K+ATP ase) in parietal cells [6]. Pantoprazole is a prodrug that is mostly activated in acidic environments, as with other PPIs. Pantoprazole binds to the proton pump irreversibly, resulting in a longer duration of action than that other PPIs. Pantoprazole is metabolized by the cytochrome P450 enzyme and is converted to an inactive form. Metabolites are eliminated primarily by the kidneys and less than 20% are excreted in feces. Although the plasma half-life is short (about 1 hour), it binds to the pump irreversibly and inhibition of acid is maintained for a long time [6]. Thrombocytopenia is not a common side effect of the proton pump inhibitors. Previous studies have mentioned many side effects such as headache, nausea and diarrhea, especially with omeprazole, pantoprazole and lansoprazole [7, 8]. But in the literature, there are cases of PPI-induced thrombocytopenia [9]. Ta¸s and Watson et al. have published similar cases with pantoprazol [10, 11]. Zlabek et al. published the case of a patient with thrombocytopenia after the administration of 60 mg of oral lansoprazole twice daily. On the second day of his treatment, thrombocytopenia occurred. After discontinuation of treatment, his platelet count was returned to normal limits [12]. Cases with esomeprazole and omeprazole-induced thrombocytopenia have also been reported in the literature [11, 13, 14]. There is only one study in the literature showing pantoprozoleinduced thrombocytopenia. Dotan et al. have shown that PPI treatment can cause thrombocytopenia in hospitalized patients [15]. However, some patients who were taking other drugs that may cause thrombocytopenia, such as heparin, were also included in their study group. Furthermore, in their studies, medication
Platelets Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 02/03/15 For personal use only.
12
E. Binnetog˘lu et al.
methods (intravenous or oral use), causes of hospitalizations and the diagnosis of the diseases were not specified. In our study, only the patients with upper gastrointestinal bleeding and without any other medications were included. All patients were treated with intravenous pantoprazole. Erythrocyte suspensions were given to the patients in this study who needed blood transfusions. Therefore, dilutional thrombocytopenia is a confusing problem in these patients. In this study, more than half of our patients had received blood transfusions (average 1–2 units of erythrocyte suspension, maximum of 3 units). But we think that thrombocytopenia is not dilutional, because the decrease in platelet counts continued after the first day, until the third day. This decrease was found to be statistically significant. Counts et al. have determined that post-transfusional dilutional thrombocytopenia may occur after massive blood transfusions (at least 10 units). They have found a negative correlation between platelet counts and transfusion treatment [16]. In conclusion, PPIs may cause thrombocytopenia, and this should not be ignored. In particular, patients with PPI infusion therapy should be monitored more closely.
Declaration of interest No commercial party having a direct financial support, any conflicts interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated.
References 1. Holtmann G. Understanding GERD syptoms in the clinical setting. Drugs Today (Barc) 2005;41:S13–S17. 2. Holtmann G, Adam B, Liebregts T. The patient with gastroesophageal reflux disease-lifestyle advice and medication. Alim Pharmacol Ther 2004;20:24–27.
Platelets, 2015; 26(1): 10–12
3. Spechler SJ. Epidemiology and natural history of gastroesophageal reflux disease. Digestion 1992;51:S24–S29. 4. Kinoshita Y. Treatment for gastro-esophageal reflux disease-lifestyle advice and medication. Alim Pharmacol Ther 2004;20:S19–S23. 5. Donnellan C, Sharma N, Preston C, Moayyedi P. Medical treatment for the maintenance therapy of reflux esophagitis and endoscopic negative reflux disease. Cochrane Database Syst Rev 2005;2: CD003245. 6. Cheer SM, Prakash A, Aulds D, Lamb HM. Pantoprazole: An update of its pharmacological properties and therapeutic use in the management of acid-related disorders. Drugs 2003;63:101–133. 7. Benet LZ, Zech K. Pharmacokinetics—A relevant factor for the choice of a drug? Aliment Pharmacol Ther 1994;81:25–32. 8. Tucker GT. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther 1994;8:33–38. 9. Korkmaz U, Alcelik A, Eroglu M, Korkmaz AN, Aktas G. Pantoprazole-induced thrombocytopenia in a patient with upper gastrointestinal bleeding. Blood Coagul Fibrinolysis 2013;24: 352–353. 10. Ta¸s A. Thrombocytopenia as a side effect of pantoprazole. Turk J Gastroenterol 2013;24:295–296. 11. Watson TD, Stark JE, Vesta KS. Pantoprazole-induced thrombocytopenia. Ann Pharmacother 2006;40:758–761. 12. Zlabek JA, Anderson CG. Lansoprazole-induced thrombocytopenia. Ann Pharmacother 2002;36:809–811. 13. Ogoshi K, Kato T, Saito S. Clinical study of AG-1749 (lansoprazole): Effects on serum gastrin levels and gastric mucosal ECL cell density. Yakuri to Chiryo 1991;19:933–946. 14. Miller JL, Gormley AK, Johnson PN. Pantoprazole-induced thrombocytopenia. Indian J Pediatr 2009;76:1278–1279. 15. Dotan E, Katz R, Bratcher J, Wasserman C, Liebman M, Panagopoulos G, Spaccavento C. The prevalence of pantoprozole associated thrombocytopenia in a community hospital. Expert Opin Pharmacother 2007;8:2025–2028. 16. Counts RB, Haisch C, Simon TL, Maxwell NG, Heimbach DM, Carrico CJ. Hemostasis in massively transfused trauma patients. Ann Surg 1979;190:91–99.
ORIGINAL ARTICLE
Pantoprazole-induced thrombocytopenia in patients with upper gastrointestinal bleeding Emine Binnetog˘lu1, Erdem Akbal2, Hacer S¸ en1, Fahri Gu¨ne¸s1, Go¨khan Erbag˘1, Mehmet A¸sık1, Neslihan Bozkurt1, Ay¸segu¨l Uludag˘3, Murat Tekin3, & Sati Zeynep Tekin4
Platelets Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 02/03/15 For personal use only.
1
Department of Internal Medicine, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey, 2Department of Gastroenterology, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey, 3Department of Family Medicine, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey, and 4Department of Microbiology, Faculty of Medicine, C¸anakkale Onsekiz Mart University, C¸anakkale, Turkey Abstract
Keywords
Proton pump inhibitors (PPIs) are highly effective drugs for patients suffering from peptic ulcer and gastro-esophageal reflux diseases, but recent studies have indicated possible risks with the long-term use of PPIs, such as osteoporosis, fractures, increased risk of pneumonia, diarrhea, iron and vitamin B12 deficiencies. There are publications written as a case study that indicate thrombocytopenia as side effects of PPIs, but there is no study on this subject. This study aimed to investigate the development of thrombocytopenia in patients with short-term use of PPIinfusion therapy. In this study, the records of the patients were evaluated retrospectively, for the period between January 2012 and January 2013. Thirty-five patients with upper gastrointestinal bleeding were enrolled. Platelet counts were analyzed before treatment, and on the first, second and third day of treatment, respectively. All patients were treated with intravenous pantoprazole. Hemogram values of patients were analyzed before and after PPI infusion treatment. Platelet counts were found to decrease from the first day to the third day of treatment (249 714.29/ml, 197 314.29/ml, 193 941.18/ml, 183 500/ml, respectively). The platelet count decrease was statistically significant (p50.001). After cessation of infusion therapy, platelet counts began to rise on the fourth day. Three patients had severe thrombocytopenia on the third day of the treatment. (69 000/ml, 97 000/ml and 49 000/ml respectively). Platelet counts recovered after discontinuation of treatment. In conclusion, this study demonstrates that PPIs may cause thrombocytopenia, and this result should not be ignored. In particular, patients with PPI infusion therapy should be monitored more closely.
Pantoprazole, proton pump inhibitors, thrombocytopenia
Introduction Peptic ulcer disease, gastroesophageal reflux disease (GERD) and functional dyspepsia are the most common diseases of the gastrointestinal system. The prevalence of GERD is reported to be approximately 10–30% [1, 2] and if untreated or inadequately treated, serious complications may arise [3]. Pharmacological treatment alleviates the symptoms in the majority of patients [4]. Proton pump inhibitors (PPIs) are highly effective drugs in patients suffering from gastrointestinal diseases such as GERD, peptic ulcer disease. They not only counter the disease, but also improve quality of life [5]. The reliability of these drugs is good, but recent studies have indicated possible risks with the long-term use of PPIs, such as osteoporosis, fractures, increased risk of pneumonia, diarrhea, and iron and vitamin B12 deficiencies. All studies on this subject to date have investigated the reliability of the long-term use of PPIs. Short-term side effects of PPIs have been reported in case reports in the literature. These reports have demonstrated that the short-term use of PPIs may be a cause of thrombocytopenia. In this study, we aimed to investigate the
Correspondence: Emine Binnetoglu, MD, Department of Internal Medicine, Faculty of Medicine, C¸anakkale Onsekiz Mart University, Kepez, C¸anakkale, Turkey. Tel(GSM): 90 533 8154947. Fax: 90 286 2635956. E-mail: [email protected]
History Received 13 December 2013 Revised 26 December 2013 Accepted 31 December 2013 Published online 10 February 2014
development of thrombocytopenia in patients being treated with the short-term use of PPI infusion therapy.
Materials and methods In this study, the records of the patients of the gastroenterology and internal medicine departments were evaluated retrospectively between January 2012 and January 2013. This study was approved by the local ethical committee of C¸anakkale Onsekiz Mart University. Demographic characteristics of the patients (age, gender, endoscopic results, medical therapy and hemogram results) were obtained from medical records. Patients whose baseline platelet counts were less than 150 000/mL, patients who received any drugs that may cause thrombocytopenia and patients with chronic hematologic, renal or hepatic diseases and infection diseases were excluded. Oral intake was completely stopped in patients with upper gastrointestinal bleeding and treated with PPI infusion for more than 3 days. After giving 80 mg intravenous bolus, an 8 mg per hour pantoprazole infusion was started and continued for 72 hours. After 72 hours, pantoprazole was given intravenously two times a day. Thirty-five patients with upper gastrointestinal bleeding were enrolled. Platelet counts were analyzed before treatment, at first day, second day and third day of treatment respectively. All patients were treated with intravenous pantoprazole, because only pantoprazole was available in the hospital.
Pantoprazole-induced thrombocytopenia
DOI: 10.3109/09537104.2014.880108
Statistical analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software version 13. The variables were investigated using visual (histograms, probability plots) and analytical methods (Kolmogorov–Smirnov/Shapiro’s–Wilk test) to determine whether or not they were normally distributed. Descriptive analyses were presented using means and standard deviations for normal distribution. When investigating the changes in platelet counts, the effects of treatment were adjusted using repeated measures of analysis of variance. The Greenhouse– Geisser correction was used when the sphericity assumption was violated.
Platelets Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 02/03/15 For personal use only.
Results The hemogram values of 35 patients (17 female and 18 male) were analyzed before and after PPI-infusion treatment. The demographic characteristics of the patients are summarized in Table I. Platelet counts were found to decrease from the first day to the third day of treatment (249 714.29/ml, 197 314.29/ml, 193 941.18/ml, 183 500/ml, respectively) (Table I). This decrease was statistically significant (p50.001) (Figure 1). After cessation of infusion therapy, platelet counts began to rise on the fourth day (Figure 1). Three patients had severe thrombocytopenia on the third day of the treatment (69 000/ml, 97 000/ml, 49 000/ml
Table I. The demographic characteristics of the patients.
Age Gender(M/F) Urea (mg/dl) AST (U/l) ALT (U/l) Platelets count at onset Platelets count at first day Platelet count at second day Platelet count at third day Platelet count at fourth day Abbreviations: ALT: aminotransferase.
alanine
Patients (n ¼ 35)
Standard deviation
61.34 18/17 64.32 20.29 14.53 249 714.29 197 314.29 193 941.18 183 500 184 592.59
±20.06
aminotransferase;
Figure 1. Platelet counts in patients before and after treatment and after cessation of treatment the increase in platelet count.(PLT: platelet count at onset; PLT-1: platelet count at first day; PLT-2: platelet count at second day; PLT-3: platelet count at third day; PLT-4: platelet count at fourth day).
±44.16 ±14.25 ±8.82 ±104 199.63 ±72 137.84 ±74 511.72 ±78 637.59 ±82 429.57 AST:
aspartate
11
respectively). Platelet counts recovered after discontinuation of treatment.
Discussion In this study we demonstrated that PPIs have thrombocytopenic effects in addition to well-known side effects. This study demonstrated a gradual decrease in platelet counts with PPI infusion therapy. Sometimes this decline can be very serious, and doctors may need to discontinue the treatment as was done with three of our patients. PPIs are important medications for the management of acidrelated disorders. Pantoprazole reduces gastric acid secretion by inhibiting proton pump (H+–K+ATP ase) in parietal cells [6]. Pantoprazole is a prodrug that is mostly activated in acidic environments, as with other PPIs. Pantoprazole binds to the proton pump irreversibly, resulting in a longer duration of action than that other PPIs. Pantoprazole is metabolized by the cytochrome P450 enzyme and is converted to an inactive form. Metabolites are eliminated primarily by the kidneys and less than 20% are excreted in feces. Although the plasma half-life is short (about 1 hour), it binds to the pump irreversibly and inhibition of acid is maintained for a long time [6]. Thrombocytopenia is not a common side effect of the proton pump inhibitors. Previous studies have mentioned many side effects such as headache, nausea and diarrhea, especially with omeprazole, pantoprazole and lansoprazole [7, 8]. But in the literature, there are cases of PPI-induced thrombocytopenia [9]. Ta¸s and Watson et al. have published similar cases with pantoprazol [10, 11]. Zlabek et al. published the case of a patient with thrombocytopenia after the administration of 60 mg of oral lansoprazole twice daily. On the second day of his treatment, thrombocytopenia occurred. After discontinuation of treatment, his platelet count was returned to normal limits [12]. Cases with esomeprazole and omeprazole-induced thrombocytopenia have also been reported in the literature [11, 13, 14]. There is only one study in the literature showing pantoprozoleinduced thrombocytopenia. Dotan et al. have shown that PPI treatment can cause thrombocytopenia in hospitalized patients [15]. However, some patients who were taking other drugs that may cause thrombocytopenia, such as heparin, were also included in their study group. Furthermore, in their studies, medication
Platelets Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 02/03/15 For personal use only.
12
E. Binnetog˘lu et al.
methods (intravenous or oral use), causes of hospitalizations and the diagnosis of the diseases were not specified. In our study, only the patients with upper gastrointestinal bleeding and without any other medications were included. All patients were treated with intravenous pantoprazole. Erythrocyte suspensions were given to the patients in this study who needed blood transfusions. Therefore, dilutional thrombocytopenia is a confusing problem in these patients. In this study, more than half of our patients had received blood transfusions (average 1–2 units of erythrocyte suspension, maximum of 3 units). But we think that thrombocytopenia is not dilutional, because the decrease in platelet counts continued after the first day, until the third day. This decrease was found to be statistically significant. Counts et al. have determined that post-transfusional dilutional thrombocytopenia may occur after massive blood transfusions (at least 10 units). They have found a negative correlation between platelet counts and transfusion treatment [16]. In conclusion, PPIs may cause thrombocytopenia, and this should not be ignored. In particular, patients with PPI infusion therapy should be monitored more closely.
Declaration of interest No commercial party having a direct financial support, any conflicts interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated.
References 1. Holtmann G. Understanding GERD syptoms in the clinical setting. Drugs Today (Barc) 2005;41:S13–S17. 2. Holtmann G, Adam B, Liebregts T. The patient with gastroesophageal reflux disease-lifestyle advice and medication. Alim Pharmacol Ther 2004;20:24–27.
Platelets, 2015; 26(1): 10–12
3. Spechler SJ. Epidemiology and natural history of gastroesophageal reflux disease. Digestion 1992;51:S24–S29. 4. Kinoshita Y. Treatment for gastro-esophageal reflux disease-lifestyle advice and medication. Alim Pharmacol Ther 2004;20:S19–S23. 5. Donnellan C, Sharma N, Preston C, Moayyedi P. Medical treatment for the maintenance therapy of reflux esophagitis and endoscopic negative reflux disease. Cochrane Database Syst Rev 2005;2: CD003245. 6. Cheer SM, Prakash A, Aulds D, Lamb HM. Pantoprazole: An update of its pharmacological properties and therapeutic use in the management of acid-related disorders. Drugs 2003;63:101–133. 7. Benet LZ, Zech K. Pharmacokinetics—A relevant factor for the choice of a drug? Aliment Pharmacol Ther 1994;81:25–32. 8. Tucker GT. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther 1994;8:33–38. 9. Korkmaz U, Alcelik A, Eroglu M, Korkmaz AN, Aktas G. Pantoprazole-induced thrombocytopenia in a patient with upper gastrointestinal bleeding. Blood Coagul Fibrinolysis 2013;24: 352–353. 10. Ta¸s A. Thrombocytopenia as a side effect of pantoprazole. Turk J Gastroenterol 2013;24:295–296. 11. Watson TD, Stark JE, Vesta KS. Pantoprazole-induced thrombocytopenia. Ann Pharmacother 2006;40:758–761. 12. Zlabek JA, Anderson CG. Lansoprazole-induced thrombocytopenia. Ann Pharmacother 2002;36:809–811. 13. Ogoshi K, Kato T, Saito S. Clinical study of AG-1749 (lansoprazole): Effects on serum gastrin levels and gastric mucosal ECL cell density. Yakuri to Chiryo 1991;19:933–946. 14. Miller JL, Gormley AK, Johnson PN. Pantoprazole-induced thrombocytopenia. Indian J Pediatr 2009;76:1278–1279. 15. Dotan E, Katz R, Bratcher J, Wasserman C, Liebman M, Panagopoulos G, Spaccavento C. The prevalence of pantoprozole associated thrombocytopenia in a community hospital. Expert Opin Pharmacother 2007;8:2025–2028. 16. Counts RB, Haisch C, Simon TL, Maxwell NG, Heimbach DM, Carrico CJ. Hemostasis in massively transfused trauma patients. Ann Surg 1979;190:91–99.
