Clin J Gastroenterol DOI 10.1007/s12328-016-0632-0
CASE REPORT
Acute pancreatitis-induced thrombotic thrombocytopenic purpura with recurrent acute pancreatitis Yasuhisa Fujino1 • Yoshihiro Inoue1 • Makoto Onodera1 • Satoshi Kikuchi1 Masayuki Sato1 • Masahiro Kojika1 • Hisaho Sato1 • Keijiro Suzuki2 • Masanori Matsumoto3
•
Received: 28 December 2015 / Accepted: 12 February 2016 Ó Japanese Society of Gastroenterology 2016
Abstract Recent successive reports on acute pancreatitisinduced thrombotic thrombocytopenic purpura (TTP) have revealed that TTP-related microvascular damage is an aggravating factor of acute pancreatitis. Here, we report the case of a 26-year-old man diagnosed with acute pancreatitis due to high alcohol consumption. The patient was unconscious as he had taken an overdose of medication, and presented with fever and renal failure due to acute pancreatitis on admission. Although the pancreatitis subsequently improved, the symptoms were still observed; on the next day, he exhibited hemoglobinuria, anemia, and thrombocytopenia. Moreover, general blood examinations indicated the presence of schistocytes and reduced activity of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13) to 47 %. Thus, the patient was diagnosed with TTP, and plasma exchange was performed. After the development of TTP, the acute pancreatitis recurred, but a severe pathogenesis was prevented by plasma exchange. Thus, ADAMTS13 activity may be useful for predicting a severe pathogenesis of acute pancreatitis. In ADAMTS13-deficient cases, plasma exchange may be an effective technique for preventing aggravation of acute pancreatitis. Keywords Pancreatitis TTP ADAMTS13 protein Plasma exchange & Yasuhisa Fujino [email protected] 1
Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan
2
Department of Laboratory Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan
3
Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijocho, Kashihara, Nara 634-8521, Japan
Introduction Although thrombotic thrombocytopenic purpura (TTP) is sometimes associated with acute pancreatitis [1, 2], successive reports on acute pancreatitis-induced TTP have recently been published [3–13], and the failure of pancreatic perfusion due to TTP has emerged as an aggravating factor of acute pancreatitis [4, 6, 7, 13–15]. In the present report, we describe a case of TTP that developed during the course of acute pancreatitis, which itself then induced recurrent pancreatitis. The findings of this case may suggest the mechanisms underlying the aggravation of acute pancreatitis.
Case report A 26-year-old man was admitted in an unconscious state after taking an overdose of medication (chlorpromazine hydrochloride, promethazine hydrochloride, and phenobarbital); the patient had a history of high alcohol consumption (500 mL of whiskey daily) and had consumed a considerable amount of alcohol just before admission. He had no fever or hematuria prior to admission. Upon admission, he was disoriented, and his vital signs were as follows: blood pressure, 147/90 mmHg; heart rate, 125 beats/min; and body temperature, 38.0 °C. An abdominal examination revealed tenderness of the upper abdomen. We also observed an inflammatory reaction, mild thrombocytopenia, liver dysfunction with mild jaundice, an elevated pancreatic enzyme level, and renal failure. No anemia was present (Table 1). Abdominal contrastenhanced computed tomography (CT) showed swelling of the pancreas and fluid collection around the pancreas and
123
Clin J Gastroenterol Table 1 Patient’s laboratory data on admission Blood WBC count
22,580/mm3
RBC count
385 9 104/mm3
Hb
14.9 g/dL
Ht
42.5 %
Plt count
14.0 9 104/mm3
Chemistry TP
5.6 g/dL
Alb
3.5 g/dL
Na
138 mEq/L
K
4.8 mEq/L
UN
25.5 mg/dL
Cr
2.1 mg/dL
AST
35 IU/L
ALT LDH
31 IU/L 543 IU/L
c-GTP
364 IU/L
T-Bil
2.7 mg/dL
D-Bil
1.3 mg/dL
AMY
933 IU/L
Ca
9.4 mg/dL
CRP
19.3 mg/dL
Glucose
124 mg/dL
Arterial blood gas (room air) pH
7.442
pCO2
36.8 mmHg
pO2
69.3 mmHg
HCO3-
24.5 mmol/L
Base excess
0.7 mmol/L
Coagulation APTT PT
39.3 s 14.6 s
INR
1.17
Fibrinogen
313.0 mg/dL
FDP
38.4 lg/dL
AT III
77 %
AMY isozyme Total-S
10 %
Total-P
90 %
Pancreatic enzyme Trypsin
C900 ng/mL
Lipase
820 IU/L
WBC white blood cells, RBC red blood cells, Hb hemoglobin, Ht hematocrit, Plt platelets, TP total protein, Alb albumin, UN urea nitrogen, Cr creatinine, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, c-GTP c-glutamyl transpeptidase, T-Bil total bilirubin, D-Bil direct bilirubin, AMY amylase, Ca calcium, CRP C-reactive protein, APTT activated partial thromboplastin time, PT prothrombin time, INR international normalized ratio, FDP fibrinogen degradation products, AT III antithrombin III, Total-S, total salivary faction, Total-P total pancreatic faction
123
kidneys, but no contrast defect area of the pancreas (Fig. 1). Figure 2 illustrates the patient’s clinical course. Based on the presence of upper abdominal pain, an elevated pancreatic enzyme level, and the abdominal CT findings, the patient was diagnosed with acute pancreatitis. In addition, his APACHE II score [16] was 17, which further supported the diagnosis of severe acute pancreatitis. Hence, he was treated with a massive electrolytic infusion (8000 mL for the first 24 h) and administration of gabexate mesilate (2400 mg/24 h) and antibiotics (piperacillin sodium, 6 g/24 h). However, his urine volume did not increase, and renal function had continued to deteriorate by the next day. Therefore, hemodiafiltration was performed. Although the urine volume increased soon afterward, he exhibited hemoglobinuria. Despite the improvement in pancreatitis symptoms, an elevated lactate dehydrogenase (LDH) level was still noted (day 2, 2395 IU/L; day 3, 2835 IU/L), and progression of anemia (day 2, 9.6 g/dL; day 3, 7.5 g/dL) and thrombocytopenia (day 2, 1.2 9 104/ mm3) were observed. However, the prothrombin time/international normalized ratio (1.17) and fibrinogen levels (313.0 mg/dL) remained relatively constant. In addition to the persistent fever and prolonged disturbance of consciousness, general blood examinations also indicated the presence of schistocytes (6.4 %) at day 3 (Fig. 3); thus, he was diagnosed with TTP. On the same day, the activity of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13) was estimated to be 47 %, and no ADAMTS13 inhibitors were detected. Plasma exchange was performed daily for the treatment of TTP. Initially, the renal failure, thrombocytopenia, microangiopathic hemolytic anemia (an increase in LDH level), fever, and encephalopathy persisted. Pancreatitis was also found to have recurred at day 4, based on re-elevated levels of pancreatic enzymes (amylase, 291–633 IU/L; lipase, 1780 IU/L). Moreover, the patient experienced systemic convulsions beginning day 7, which progressed to epilepticus. Hence, he was intubated and mechanically ventilated, and was administered propofol at day 9. On day 9, abdominal plain CT showed swelling of the pancreas (Fig. 4). After daily plasma exchange, the LDH and amylase levels decreased at day 10, and the thrombocytopenia started to resolve at day 13. By day 16, the platelet count had recovered to a normal level, mechanical ventilation was discontinued, and the intubation tube was removed, as convulsions were not observed despite the cessation of propofol. By day 18, the ADAMTS13 activity had recovered to 76 %. Thereafter, the frequency of plasma exchange was gradually reduced and was finally discontinued at day 32 (a total of 20 plasma exchange sessions were conducted). On the same day, the patient was transferred to the psychiatric ward.
Clin J Gastroenterol
4000 3000
ADAMTS13 ( 10%)
5000
Gabexate mesilate Respirator HDF 12
HD PE ADAMTS13 LDH
10
Cr Hb
8
Plt AMY Urine volume
6
4 2000 1000
LDH (
0
103 mg/dL), Plt (
Urine volume (mL)
6000
105 mg/dL), Hb (
7000
10 g/dL), Cr (mg/dL), AMY (
102 mg/dL)
Fig. 1 Abdominal contrast-enhanced computed tomography shows swelling of the pancreas and fluid collection around the pancreas and kidneys, but no contrast defect area of the pancreas
2
0
5
10
15
20
25
30
35
Days after admission
Fig. 2 The clinical course of a 26-year-old man with thrombotic thrombocytopenic purpura (TTP) induced by acute pancreatitis. Despite the improvement in pancreatitis symptoms, an elevated lactate dehydrogenase (LDH) level was still noted, and the progression of anemia and thrombocytopenia was observed; hence, we
performed plasma exchange (PE; a total of 20 times) for the treatment of TTP and observed an improvement. HDF hemodiafiltration, HD hemodialysis, Hb hemoglobin, Plt platelets, Cr creatinine, AMY amylase, ADAMTS13 a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13 activity
Discussion
case, the initial onset of acute pancreatitis was the result of high alcohol consumption, and on admission, the patient had encephalopathy, fever, and renal failure—the classical pentad of TTP [17]. The encephalopathy was caused by the medication overdose, whereas the fever and renal failure had
In a study by Swisher et al. [6], the authors reported that acute pancreatitis preceded TTP or hemolytic uremic syndrome (HUS) in 21 of 356 patients (*5.9 %). In the current
123
Clin J Gastroenterol
Fig. 3 General blood examination shows the presence of schistocytes
developed due to the acute pancreatitis. Moreover, the thrombocytopenia was very mild, and there was no anemia or hemoglobinuria; hence, we assumed that TTP had not yet developed at this point. On the next day, the patient exhibited apparent hemoglobinuria, anemia, and thrombocytopenia; however, these symptoms were not consistent with a diagnosis of overt disseminated intravascular coagulation, given the unchanged prothrombin time and fibrinogen levels. In addition, the presence of schistocytes was confirmed on general blood examination. Hence the patient was diagnosed with acute pancreatitis-induced TTP, and plasma exchange [18, 19] was performed. The initial report of TTP was published by Moschcowitz [20] in 1925, but diagnosis of overt TTP on the basis of the classical pentad of symptoms [17] is very rare. Moreover, differentiation of TTP and HUS is often difficult. For this reason, the diagnosis of thrombotic microangiopathy (TMA) has been proposed [21].
Fig. 4 Abdominal plain CT shows swelling of the pancreas
123
Our patient had a mild ADAMTS13 deficiency, but no ADAMTS13 inhibitors were detected. To explain the cause of the ADAMTS13 deficiency, we considered gene mutations [22, 23], production of inhibitors [24, 25], consumption due to microvascular damage [15, 26], and the involvement of cytokines [27]. Among 14 patients with acute pancreatitis-induced TTP in which ADAMTS13 activity was measured, as reported previously [5–8], only eight had a deficiency of this enzyme (\50 %). Furthermore, ADAMTS13 activity decreased to less than 5 % in only four of these cases, including three of five cases reported by Swisher et al. [6] and the case reported by Bergmann et al. [7]. Only in these cases acute pancreatitisinduced TTP can be specifically considered, whereas the others can be considered as pancreatitis-induced TMA [21]. However, according to past reports [3–13], we considered that the current case without a significant decrease in ADAMTS13 activity had acute pancreatitis-induced TTP, by using a broad/non-specific definition of this condition. It has been suggested that TTP or associated morbidities contribute to the aggravation of acute pancreatitis [4, 6, 7, 13–15]. In acute pancreatitis, there are increased levels of cytokines and microvascular damage may have developed due to elevated pancreatic enzymes and the systemic inflammatory reaction syndrome [7, 14, 15, 28]. In some cases, including that of our patient, these mechanisms and ADAMTS13 deficiency result in the formation of microthrombi, which can aggravate acute pancreatitis. In acute pancreatitis-induced TTP, microvascular damage can contribute to a severe pathogenesis of acute pancreatitis through enhanced thrombogenesis [15], with or without an ADAMTS13 deficiency. In the current case, acute pancreatitis recurred after the development of TTP. Although the progression to severe acute pancreatitis is a
Clin J Gastroenterol
concern, the application of plasma exchange may lead to an improvement in TTP by the replacement of ADAMTS13 [21] and may prevent the aggravation of acute pancreatitis. Microvascular damage can deeply aggravate acute pancreatitis and ADAMTS13 deficiency, which is a concern in some cases. Morioka et al. [15] reported that in fatal cases of acute pancreatitis, ADAMTS13 activity was estimated at 10–15 % on admission or the next day. Thus, the measurement of ADAMTS13 activity soon after the onset of acute pancreatitis may be useful for predicting a severe pathogenesis of this condition. Moreover, in ADAMTS13deficient cases, plasma exchange may be an effective technique for preventing aggravation. Compliance with ethical standards Conflict of Interest: Yasuhisa Fujino, Yoshihiro Inoue, Makoto Onodera, Satoshi Kikuchi, Masayuki Sato, Masahiro Kojika, Hisaho Sato, Keijiro Suzuki, and Masanori Matsumoto declare that they have no conflict of interest. Human Rights: All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed Consent: Informed consent was obtained from all patients for inclusion in the study.
References 1. Olsen H. Thrombotic thrombocytopenic purpura as a cause of pancreatitis. Report of a case and review of the literature. Am J Dig Dis. 1973;18:238–46. 2. Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. Arch Pathol Lab Med. 2003;127:834–9. 3. Jackson B, Files JC, Morrison FS, Scott-Conner CE. Thrombotic thrombocytopenic purpura and pancreatitis. Am J Gastroenterol. 1989;84:667–9. 4. Boyer A, Chadda K, Salah A, Bonmarchand G. Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis. Intensive Care Med. 2004;30:1235–9. 5. Ruiz J, Koduri PR, Valdivieso M, Shah PC. Refractory postpancreatitis thrombotic thrombocytopenic purpura: response to rituximab. Ann Hematol. 2005;84:267–8. 6. Swisher KK, Doan JT, Vesely SK, Kwaan HC, Kim B, Lammle B, et al. Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports. Haematologica. 2007;92:936–43. 7. Bergmann IP, Kremer Hovinga JA, Lammle B, Peter HJ, Schiemann U. Acute pancreatitis and thrombotic thrombocytopenic purpura. Eur J Med Res. 2008;13:481–2. 8. McDonald V, Laffan M, Benjamin S, Bevan D, Machin S, Scully MA. Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry. Br J Haematol. 2009;144:430–3. 9. Chaudhry MS, Saweirs MW. Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis. Transfus Apher Sci. 2011;45:143–7.
10. Jeliazkova P, Noe S, Jost P, Sarkar O, Ku¨chle C, Schmid RM, et al. Postendoscopic retrograde cholangiopancreatography pancreatitis: a rare cause of thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Eur J Gastroenterol Hepatol. 2011;23:825–7. 11. Arimoto M, Komiyama Y, Okamae F, Ichibe A, Teranishi S, Tokunaga H, et al. A case of thrombotic thrombocytopenic purpura induced by acute pancreatitis. Int J Gen Med. 2012;5:307–11. 12. Gurjar M, Saigal S, Azim A, Mohindra S, Prasad N, Srivastava G. Acute pancreatitis-induced thrombotic thrombocytopenic purpura. JOP. 2012;13:80–2. 13. Ali MA, Shaheen JSS, Khan MA. Acute pancreatitis induced thrombotic thrombocytopenic purpura. Indian J Crit Care Med. 2014;18:107. 14. Cuthbertson C, Christophi C. Disturbances of the microcirculation in acute pancreatitis. Br J Surg. 2006;93:518–30. 15. Morioka C, Uemura M, Matsuyama T, Matsumoto M, Kato S, Ishikawa M, et al. Plasma ADAMTS13 activity parallels the APACHE II score, reflecting an early prognostic indicator for patients with severe acute pancreatitis. Scand J Gastroenterol. 2008;43:1387–96. 16. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29. 17. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine. 1966;45:139–60. 18. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991;325:393–7. 19. George JN. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927–35. 20. Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. Arch Intern Med. 1925;36:89–93. 21. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589–600. 22. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA. 2002;99:11902–7. 23. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–94. 24. Steinhubl SR, Tan WA, Foody JM, Topol EJ, Investigators E. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA. 1999;281:806–10. 25. Tsai H-M, Rice L, Sarode R, Chow TW, Moake JL. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000;132:794–9. 26. Fujimura Y, Matsumoto M. Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during 1998–2008. Intern Med. 2009;49:7–15. 27. Bernardo A, Ball C, Nolasco L, Moake JF, Dong Jf. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell–derived ultralarge von Willebrand factor multimers under flow. Blood. 2004;104:100–6. 28. Kwaan HC, Anderson MC, Gramatica L. A study of pancreatic enzymes as a factor in the pathogenesis of disseminated intravascular coagulation during acute pancreatitis. Surgery. 1971;69:663–72.
123
CASE REPORT
Acute pancreatitis-induced thrombotic thrombocytopenic purpura with recurrent acute pancreatitis Yasuhisa Fujino1 • Yoshihiro Inoue1 • Makoto Onodera1 • Satoshi Kikuchi1 Masayuki Sato1 • Masahiro Kojika1 • Hisaho Sato1 • Keijiro Suzuki2 • Masanori Matsumoto3
•
Received: 28 December 2015 / Accepted: 12 February 2016 Ó Japanese Society of Gastroenterology 2016
Abstract Recent successive reports on acute pancreatitisinduced thrombotic thrombocytopenic purpura (TTP) have revealed that TTP-related microvascular damage is an aggravating factor of acute pancreatitis. Here, we report the case of a 26-year-old man diagnosed with acute pancreatitis due to high alcohol consumption. The patient was unconscious as he had taken an overdose of medication, and presented with fever and renal failure due to acute pancreatitis on admission. Although the pancreatitis subsequently improved, the symptoms were still observed; on the next day, he exhibited hemoglobinuria, anemia, and thrombocytopenia. Moreover, general blood examinations indicated the presence of schistocytes and reduced activity of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13) to 47 %. Thus, the patient was diagnosed with TTP, and plasma exchange was performed. After the development of TTP, the acute pancreatitis recurred, but a severe pathogenesis was prevented by plasma exchange. Thus, ADAMTS13 activity may be useful for predicting a severe pathogenesis of acute pancreatitis. In ADAMTS13-deficient cases, plasma exchange may be an effective technique for preventing aggravation of acute pancreatitis. Keywords Pancreatitis TTP ADAMTS13 protein Plasma exchange & Yasuhisa Fujino [email protected] 1
Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan
2
Department of Laboratory Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan
3
Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijocho, Kashihara, Nara 634-8521, Japan
Introduction Although thrombotic thrombocytopenic purpura (TTP) is sometimes associated with acute pancreatitis [1, 2], successive reports on acute pancreatitis-induced TTP have recently been published [3–13], and the failure of pancreatic perfusion due to TTP has emerged as an aggravating factor of acute pancreatitis [4, 6, 7, 13–15]. In the present report, we describe a case of TTP that developed during the course of acute pancreatitis, which itself then induced recurrent pancreatitis. The findings of this case may suggest the mechanisms underlying the aggravation of acute pancreatitis.
Case report A 26-year-old man was admitted in an unconscious state after taking an overdose of medication (chlorpromazine hydrochloride, promethazine hydrochloride, and phenobarbital); the patient had a history of high alcohol consumption (500 mL of whiskey daily) and had consumed a considerable amount of alcohol just before admission. He had no fever or hematuria prior to admission. Upon admission, he was disoriented, and his vital signs were as follows: blood pressure, 147/90 mmHg; heart rate, 125 beats/min; and body temperature, 38.0 °C. An abdominal examination revealed tenderness of the upper abdomen. We also observed an inflammatory reaction, mild thrombocytopenia, liver dysfunction with mild jaundice, an elevated pancreatic enzyme level, and renal failure. No anemia was present (Table 1). Abdominal contrastenhanced computed tomography (CT) showed swelling of the pancreas and fluid collection around the pancreas and
123
Clin J Gastroenterol Table 1 Patient’s laboratory data on admission Blood WBC count
22,580/mm3
RBC count
385 9 104/mm3
Hb
14.9 g/dL
Ht
42.5 %
Plt count
14.0 9 104/mm3
Chemistry TP
5.6 g/dL
Alb
3.5 g/dL
Na
138 mEq/L
K
4.8 mEq/L
UN
25.5 mg/dL
Cr
2.1 mg/dL
AST
35 IU/L
ALT LDH
31 IU/L 543 IU/L
c-GTP
364 IU/L
T-Bil
2.7 mg/dL
D-Bil
1.3 mg/dL
AMY
933 IU/L
Ca
9.4 mg/dL
CRP
19.3 mg/dL
Glucose
124 mg/dL
Arterial blood gas (room air) pH
7.442
pCO2
36.8 mmHg
pO2
69.3 mmHg
HCO3-
24.5 mmol/L
Base excess
0.7 mmol/L
Coagulation APTT PT
39.3 s 14.6 s
INR
1.17
Fibrinogen
313.0 mg/dL
FDP
38.4 lg/dL
AT III
77 %
AMY isozyme Total-S
10 %
Total-P
90 %
Pancreatic enzyme Trypsin
C900 ng/mL
Lipase
820 IU/L
WBC white blood cells, RBC red blood cells, Hb hemoglobin, Ht hematocrit, Plt platelets, TP total protein, Alb albumin, UN urea nitrogen, Cr creatinine, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, c-GTP c-glutamyl transpeptidase, T-Bil total bilirubin, D-Bil direct bilirubin, AMY amylase, Ca calcium, CRP C-reactive protein, APTT activated partial thromboplastin time, PT prothrombin time, INR international normalized ratio, FDP fibrinogen degradation products, AT III antithrombin III, Total-S, total salivary faction, Total-P total pancreatic faction
123
kidneys, but no contrast defect area of the pancreas (Fig. 1). Figure 2 illustrates the patient’s clinical course. Based on the presence of upper abdominal pain, an elevated pancreatic enzyme level, and the abdominal CT findings, the patient was diagnosed with acute pancreatitis. In addition, his APACHE II score [16] was 17, which further supported the diagnosis of severe acute pancreatitis. Hence, he was treated with a massive electrolytic infusion (8000 mL for the first 24 h) and administration of gabexate mesilate (2400 mg/24 h) and antibiotics (piperacillin sodium, 6 g/24 h). However, his urine volume did not increase, and renal function had continued to deteriorate by the next day. Therefore, hemodiafiltration was performed. Although the urine volume increased soon afterward, he exhibited hemoglobinuria. Despite the improvement in pancreatitis symptoms, an elevated lactate dehydrogenase (LDH) level was still noted (day 2, 2395 IU/L; day 3, 2835 IU/L), and progression of anemia (day 2, 9.6 g/dL; day 3, 7.5 g/dL) and thrombocytopenia (day 2, 1.2 9 104/ mm3) were observed. However, the prothrombin time/international normalized ratio (1.17) and fibrinogen levels (313.0 mg/dL) remained relatively constant. In addition to the persistent fever and prolonged disturbance of consciousness, general blood examinations also indicated the presence of schistocytes (6.4 %) at day 3 (Fig. 3); thus, he was diagnosed with TTP. On the same day, the activity of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13) was estimated to be 47 %, and no ADAMTS13 inhibitors were detected. Plasma exchange was performed daily for the treatment of TTP. Initially, the renal failure, thrombocytopenia, microangiopathic hemolytic anemia (an increase in LDH level), fever, and encephalopathy persisted. Pancreatitis was also found to have recurred at day 4, based on re-elevated levels of pancreatic enzymes (amylase, 291–633 IU/L; lipase, 1780 IU/L). Moreover, the patient experienced systemic convulsions beginning day 7, which progressed to epilepticus. Hence, he was intubated and mechanically ventilated, and was administered propofol at day 9. On day 9, abdominal plain CT showed swelling of the pancreas (Fig. 4). After daily plasma exchange, the LDH and amylase levels decreased at day 10, and the thrombocytopenia started to resolve at day 13. By day 16, the platelet count had recovered to a normal level, mechanical ventilation was discontinued, and the intubation tube was removed, as convulsions were not observed despite the cessation of propofol. By day 18, the ADAMTS13 activity had recovered to 76 %. Thereafter, the frequency of plasma exchange was gradually reduced and was finally discontinued at day 32 (a total of 20 plasma exchange sessions were conducted). On the same day, the patient was transferred to the psychiatric ward.
Clin J Gastroenterol
4000 3000
ADAMTS13 ( 10%)
5000
Gabexate mesilate Respirator HDF 12
HD PE ADAMTS13 LDH
10
Cr Hb
8
Plt AMY Urine volume
6
4 2000 1000
LDH (
0
103 mg/dL), Plt (
Urine volume (mL)
6000
105 mg/dL), Hb (
7000
10 g/dL), Cr (mg/dL), AMY (
102 mg/dL)
Fig. 1 Abdominal contrast-enhanced computed tomography shows swelling of the pancreas and fluid collection around the pancreas and kidneys, but no contrast defect area of the pancreas
2
0
5
10
15
20
25
30
35
Days after admission
Fig. 2 The clinical course of a 26-year-old man with thrombotic thrombocytopenic purpura (TTP) induced by acute pancreatitis. Despite the improvement in pancreatitis symptoms, an elevated lactate dehydrogenase (LDH) level was still noted, and the progression of anemia and thrombocytopenia was observed; hence, we
performed plasma exchange (PE; a total of 20 times) for the treatment of TTP and observed an improvement. HDF hemodiafiltration, HD hemodialysis, Hb hemoglobin, Plt platelets, Cr creatinine, AMY amylase, ADAMTS13 a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13 activity
Discussion
case, the initial onset of acute pancreatitis was the result of high alcohol consumption, and on admission, the patient had encephalopathy, fever, and renal failure—the classical pentad of TTP [17]. The encephalopathy was caused by the medication overdose, whereas the fever and renal failure had
In a study by Swisher et al. [6], the authors reported that acute pancreatitis preceded TTP or hemolytic uremic syndrome (HUS) in 21 of 356 patients (*5.9 %). In the current
123
Clin J Gastroenterol
Fig. 3 General blood examination shows the presence of schistocytes
developed due to the acute pancreatitis. Moreover, the thrombocytopenia was very mild, and there was no anemia or hemoglobinuria; hence, we assumed that TTP had not yet developed at this point. On the next day, the patient exhibited apparent hemoglobinuria, anemia, and thrombocytopenia; however, these symptoms were not consistent with a diagnosis of overt disseminated intravascular coagulation, given the unchanged prothrombin time and fibrinogen levels. In addition, the presence of schistocytes was confirmed on general blood examination. Hence the patient was diagnosed with acute pancreatitis-induced TTP, and plasma exchange [18, 19] was performed. The initial report of TTP was published by Moschcowitz [20] in 1925, but diagnosis of overt TTP on the basis of the classical pentad of symptoms [17] is very rare. Moreover, differentiation of TTP and HUS is often difficult. For this reason, the diagnosis of thrombotic microangiopathy (TMA) has been proposed [21].
Fig. 4 Abdominal plain CT shows swelling of the pancreas
123
Our patient had a mild ADAMTS13 deficiency, but no ADAMTS13 inhibitors were detected. To explain the cause of the ADAMTS13 deficiency, we considered gene mutations [22, 23], production of inhibitors [24, 25], consumption due to microvascular damage [15, 26], and the involvement of cytokines [27]. Among 14 patients with acute pancreatitis-induced TTP in which ADAMTS13 activity was measured, as reported previously [5–8], only eight had a deficiency of this enzyme (\50 %). Furthermore, ADAMTS13 activity decreased to less than 5 % in only four of these cases, including three of five cases reported by Swisher et al. [6] and the case reported by Bergmann et al. [7]. Only in these cases acute pancreatitisinduced TTP can be specifically considered, whereas the others can be considered as pancreatitis-induced TMA [21]. However, according to past reports [3–13], we considered that the current case without a significant decrease in ADAMTS13 activity had acute pancreatitis-induced TTP, by using a broad/non-specific definition of this condition. It has been suggested that TTP or associated morbidities contribute to the aggravation of acute pancreatitis [4, 6, 7, 13–15]. In acute pancreatitis, there are increased levels of cytokines and microvascular damage may have developed due to elevated pancreatic enzymes and the systemic inflammatory reaction syndrome [7, 14, 15, 28]. In some cases, including that of our patient, these mechanisms and ADAMTS13 deficiency result in the formation of microthrombi, which can aggravate acute pancreatitis. In acute pancreatitis-induced TTP, microvascular damage can contribute to a severe pathogenesis of acute pancreatitis through enhanced thrombogenesis [15], with or without an ADAMTS13 deficiency. In the current case, acute pancreatitis recurred after the development of TTP. Although the progression to severe acute pancreatitis is a
Clin J Gastroenterol
concern, the application of plasma exchange may lead to an improvement in TTP by the replacement of ADAMTS13 [21] and may prevent the aggravation of acute pancreatitis. Microvascular damage can deeply aggravate acute pancreatitis and ADAMTS13 deficiency, which is a concern in some cases. Morioka et al. [15] reported that in fatal cases of acute pancreatitis, ADAMTS13 activity was estimated at 10–15 % on admission or the next day. Thus, the measurement of ADAMTS13 activity soon after the onset of acute pancreatitis may be useful for predicting a severe pathogenesis of this condition. Moreover, in ADAMTS13deficient cases, plasma exchange may be an effective technique for preventing aggravation. Compliance with ethical standards Conflict of Interest: Yasuhisa Fujino, Yoshihiro Inoue, Makoto Onodera, Satoshi Kikuchi, Masayuki Sato, Masahiro Kojika, Hisaho Sato, Keijiro Suzuki, and Masanori Matsumoto declare that they have no conflict of interest. Human Rights: All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed Consent: Informed consent was obtained from all patients for inclusion in the study.
References 1. Olsen H. Thrombotic thrombocytopenic purpura as a cause of pancreatitis. Report of a case and review of the literature. Am J Dig Dis. 1973;18:238–46. 2. Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. Arch Pathol Lab Med. 2003;127:834–9. 3. Jackson B, Files JC, Morrison FS, Scott-Conner CE. Thrombotic thrombocytopenic purpura and pancreatitis. Am J Gastroenterol. 1989;84:667–9. 4. Boyer A, Chadda K, Salah A, Bonmarchand G. Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis. Intensive Care Med. 2004;30:1235–9. 5. Ruiz J, Koduri PR, Valdivieso M, Shah PC. Refractory postpancreatitis thrombotic thrombocytopenic purpura: response to rituximab. Ann Hematol. 2005;84:267–8. 6. Swisher KK, Doan JT, Vesely SK, Kwaan HC, Kim B, Lammle B, et al. Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports. Haematologica. 2007;92:936–43. 7. Bergmann IP, Kremer Hovinga JA, Lammle B, Peter HJ, Schiemann U. Acute pancreatitis and thrombotic thrombocytopenic purpura. Eur J Med Res. 2008;13:481–2. 8. McDonald V, Laffan M, Benjamin S, Bevan D, Machin S, Scully MA. Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry. Br J Haematol. 2009;144:430–3. 9. Chaudhry MS, Saweirs MW. Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis. Transfus Apher Sci. 2011;45:143–7.
10. Jeliazkova P, Noe S, Jost P, Sarkar O, Ku¨chle C, Schmid RM, et al. Postendoscopic retrograde cholangiopancreatography pancreatitis: a rare cause of thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Eur J Gastroenterol Hepatol. 2011;23:825–7. 11. Arimoto M, Komiyama Y, Okamae F, Ichibe A, Teranishi S, Tokunaga H, et al. A case of thrombotic thrombocytopenic purpura induced by acute pancreatitis. Int J Gen Med. 2012;5:307–11. 12. Gurjar M, Saigal S, Azim A, Mohindra S, Prasad N, Srivastava G. Acute pancreatitis-induced thrombotic thrombocytopenic purpura. JOP. 2012;13:80–2. 13. Ali MA, Shaheen JSS, Khan MA. Acute pancreatitis induced thrombotic thrombocytopenic purpura. Indian J Crit Care Med. 2014;18:107. 14. Cuthbertson C, Christophi C. Disturbances of the microcirculation in acute pancreatitis. Br J Surg. 2006;93:518–30. 15. Morioka C, Uemura M, Matsuyama T, Matsumoto M, Kato S, Ishikawa M, et al. Plasma ADAMTS13 activity parallels the APACHE II score, reflecting an early prognostic indicator for patients with severe acute pancreatitis. Scand J Gastroenterol. 2008;43:1387–96. 16. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29. 17. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine. 1966;45:139–60. 18. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991;325:393–7. 19. George JN. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927–35. 20. Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. Arch Intern Med. 1925;36:89–93. 21. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589–600. 22. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA. 2002;99:11902–7. 23. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–94. 24. Steinhubl SR, Tan WA, Foody JM, Topol EJ, Investigators E. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA. 1999;281:806–10. 25. Tsai H-M, Rice L, Sarode R, Chow TW, Moake JL. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000;132:794–9. 26. Fujimura Y, Matsumoto M. Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during 1998–2008. Intern Med. 2009;49:7–15. 27. Bernardo A, Ball C, Nolasco L, Moake JF, Dong Jf. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell–derived ultralarge von Willebrand factor multimers under flow. Blood. 2004;104:100–6. 28. Kwaan HC, Anderson MC, Gramatica L. A study of pancreatic enzymes as a factor in the pathogenesis of disseminated intravascular coagulation during acute pancreatitis. Surgery. 1971;69:663–72.
123
