This presentation deals with bicytopenia induced by proton pump inhibitors, that were reported and published as a Case Report by researchers from China. References have been provided as a separate textbox under each slide, for extensive referencing into the same.

1. PRESENTED BY:
VISHNU.R.NAIR, DIVYA SEBASTIAN,
PHARM.D INTERNS,
NATIONAL COLLEGE OF PHARMACY.

2. TITLE “Neutropenia and Thrombocytopenia
induced by Proton Pump Inhibitors: A Case
Report”
AUTHORS Zheng Yu, Jing Hu, Yaojun Hu
DATE OF PUBLICATION 23.11.2018
JOURNAL INVOLVED Drug Safety-Case Reports(Springer)

3.  Proton pump inhibitors(PPIs)  widely used medications for treatment of gastrointestinal
disorders
 With ever-increasing use of PPIs  complications & adverse effects have come up!
 Although cases of “cytopenia” have been attributed to PPI therapy
Bi-cytopenia has not been documented before
Makes this case rare, yet alarming !
1. Turner T. Proton pump inhibitors. 2018. Available at https: //www.drugwatch.com/proton-pump-inhibitors /. Last accessed on 10 Oct 2018. [Crossref]
2. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroentrology. 2017;152:706–
15. [Crossref]
3. Malfertheiner P, Kandulski A, Venerito M. Proton-pump inhibitors: understanding the complications and risks. Nat Rev Gastroenterol Hepatol. 2017;14:697–710. [Crossref]
4. Dury S, Nardi J, Gozalo C, Lebargy F, Deslee G. Agranulocytosis induced by proton pump inhibitors. J Clin Gastroenterol. 2012;46:859. [Crossref]

4.  85 year old Chinese man  admitted to hospital with C/O dysphagia in 2017
 Past medical history details:
MEDICAL HISTORY TREATMENT INITIATED
BPH(2012) Transurethral resection of prostate
Lumbar vertebral compression fracture(2015) Percutaneous vertebroplasty
Early squamous cell carcinoma of
esophagus(21 months before existing case)
Endoscopic multi-band mucosectomy
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

5. Diagnosis of squamous cell carcinoma of esophagus(in another hospital)
Mucosectomy was performed
Patient developed progressive dysphagia
Patient received 4 endoscopic dilations
Dysphagia recurred after each episode of dilation
 Severity of dysphagia  rendered patient to be able to swallow only liquids!
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

6.  BMI: 18.4
 Vital signs were stable
 CBC  revealed mild anemia, with slightly reduced serum iron & ferritin concentrations:
WBC 5.6 * 109 cells/L
Neutrophil count 4.46 * 109 cells/L
RBC count 2.97 * 1012 cells/L
Hb 104 g/L
Platelet count 135 * 109 cells/L
Serum iron 5.70 µmol/L
Transferin saturation 16.72%
TIBC 34.10 µmol/L
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

7. Iron deficiency anemia owing to malnutrition suspected
Iron sucrose was administered intravenously, intermittently(100 mg, thrice weekly)
Esophagoscopy & esophagogram
Revealed 2 mm-long benign scar stricture
Stent was placed after dilation
After dislodgement of stent
Dysphagia recurred!
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

8.  With each dilation  dysphagia improved, but again recurred!!
Finally
Pantoprazole sodium(80 mg, i.v infusion, BD) was administered in hospital
Esomeprazole (20 mg/day, orally) was administered intermittently at home
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

9. On admission to hospital for next dilation
Pantoprazole was given again from hospital
The following abnormalities were found :
HEMATOLOGICAL PARAMETER INITIAL VALUE(AFTER 1ST
HOSPITAL ADMISSION)
FINAL VALUE(AFTER PPI
INITIATION)
Platelet count 135 * 109 cells/L 83 * 109 cells/L
WBC 5.6 * 109 cells/L 2.67 * 109 cells/L
Neutrophils 4.46 * 109 cells/L 0.88 * 109 cells/L
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

10. Bone marrow aspiration smear
Revealed “hypoplastic hematopoiesis”
Pantoprazole was immediately discontinued
Values returned to normal within 8 days!!!
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

11. Drastic changes in
levels of WBC,
neutrophils and
platelets after
administration of
pantoprazole.
With drug
discontinuation
Values tend to
normalize!
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

12. Although package inserts of both pantoprazole & esomeprazole indicate risk for neutropenia
Occurrence of the same is a rarity!
 In this case PPI usage led to bone-marrow suppression
Led to thrombocytopenia & neutropenia
Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

13. Cross-reactivity between esomeprazole & pantoprazole
May have resulted in cytopenia
However
Neutropenia & thrombocytopenia were directly associated with pantoprazole(evident from
Naranjo scale of 5)
1. Gouraud A, Vochelle V, Descotes J, Vial T. Proton pump inhibitor-induced neutropenia: possible cross-reactivity between omeprazole and pantoprazole. Clin Drug Investig. 2010;30:559–63.
2. Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

14. Mechanisms of PPI-induced cytopenia include:
A. IMMUNE-MEDIATED MECHANISM:
- In this  drug-induced antibodies  act against circulating hemocytes
B. TOXIC MECHANISM:
- Involves direct, dose-mediated toxicity to hematopoietic cells.
1. Heimpel H. When should the clinician suspect a drug- induced blood dyscrasia, and how should he proceed? Eur J Haematol Suppl. 1996;60:11–5. [Crossref]
2. Yu Z, Hu J, Hu Y. Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. Drug safety-case reports. 2018 Dec 1;5(1):28.

15.  Proton pump inhibitors  widely used agents for management of gastrointestinal disorders
 Widespread use of PPIs  increase risk of long-term complications and adverse effects
 PPIs  might cause leukopenia & thrombocytopenia
 Neutrophil & platelet counts may normalize days within cessation of PPI administration
Since PPI-induced bicytopenia is a rare incident
Occurrence of the same may be overlooked in clinical practice
Mandates monitoring of hematological parameters during PPI therapy!

16. THANK YOU!!