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Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis
Transfusion and Apheresis Science 45 (2011) 143–147
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis Mohammed Suhail Chaudhry a,⇑, Martin W.M. Saweirs b a b
Department of Haematology, Hammersmith Hospital, London, UK Department of General Surgery, Charing Cross Hospital, London, UK
a r t i c l e
i n f o
Keywords: Acute pancreatitis Thrombotic thrombocytopenic purpura Plasma exchange
a b s t r a c t A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare congenital or acquired systemic disorder defined classically by the pentad of thrombocytopenia, microangiopathic haemolytic anaemia, neurological symptoms, renal impairment and fever. Rapid diagnosis allows the early institution of potentially life saving therapy, and it is therefore important to recognise rare aetiological triggers of this condition. Herein, we describe the case of TTP occurring secondary to acute pancreatitis. We review the pathogenetic mechanisms which may link these two disorders, and provide support for the use of plasma exchange in this situation.
2. Case report A 20 year old woman was admitted with a 24 h history of severe epigastric pain radiating through to her back, associated with nausea and vomiting. She was previously fit and well, and there was nil else of note in the medical history. On examination, she appeared uncomfortable and dehydrated. She was not jaundiced. Her abdomen was soft but extremely tender in the epigastrium. Some intra-abdominal free fluid was also detectable upon examination. Her initial ⇑ Corresponding author. Tel.: +44 0 208 383 1000. E-mail address: [email protected] (M.S. Chaudhry). 1473-0502/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2011.07.009
bloods showed an elevated amylase of 1948 IU/L (0–50 IU/L normal level), but otherwise unremarkable baseline biochemistry, including normal lactate dehydrogenase (LDH, 213 IU/L) and normal renal function (urea 4.4 mmol/L, creatinine 65 lmol/L). Full blood count was also unremarkable (haemoglobin 14.4 g/dL, platelet count 206 109/L, white blood cell count 10.8 109/L). A clinical diagnosis of acute pancreatitis was made, and she was treated with analgesia and intravenous fluids, leading to an improvement in symptoms. Ultrasound and computed tomography of the abdomen confirmed the diagnosis, and a gallstone was seen to be impacted above the Ampulla of Vater. On day 2, her platelet count was noted to have fallen to 33 109/L, and this subsequently fell further to 23 109/L on day 3. Concurrently, by day 3 her haemoglobin had fallen to 8.8 g/dL. This was associated with an increase in bilirubin to 93 lmol/L (despite other liver function tests remaining normal) and a rise in the LDH level to 1002 IU/L, suggestive of haemolysis. Coombs test was negative. Blood film revealed marked schistocytes suggestive of microangiopathic haemolysis (Fig. 1). Disseminated intravascular coagulation was unlikely in view of a normal clotting profile (prothrombin time 12.7 s, activated partial thromboplastin time 29.0 s, thrombin time 22 s, fibrinogen 2.71 g/L). All other blood tests, including renal function, remained stable. Clinically the patient developed a mild pyrexia (38 °C) and reported an altered sense of smell, suggestive of mild neurological compromise. In the absence of any other cause, a diagnosis
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Fig. 1. Blood film displaying true thrombocytopenia and red cell anisopoikilocytosis. There are numerous schistocytes, consistent with microangiopathic haemolysis.
of thrombotic thrombocytopenic purpura (TTP) was made. ADAMTS 13 activity was 101%, with no inhibitor detected. The patient was commenced on daily single volume plasma exchange using solvent detergent treated fresh frozen plasma for a total of eight days. This was well tolerated and a rapid response was noted. Pyrexia and the altered sense of smell resolved within 24 h of commencing plasma exchange. Platelet count and LDH normalized by day 9 following six daily plasma exchange procedures, and in accordance with national BCSH guidelines [1], plasma exchange was continued for two further days. Corticosteroid therapy was withheld in view of the lack of inhibitory autoantibody and association with pancreatitis. Adjunctive treatment with folic acid and low dose aspirin (upon platelet recovery) was administered as per national guidelines. The patient was discharged shortly after recovery of the blood counts. She is under regular haematology and surgical follow up. At the time of writing, her blood counts remain stable. Magnetic resonance cholangiopancreatography has revealed multiple stones in the gallbladder but no residual biliary obstruction, and she is awaiting an elective cholecystectomy. 3. Discussion Thrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz in 1924 [2]. It is defined classically by the pentad of thrombocytopenia, microangiopathic haemolytic anaemia, neurological symptoms, renal impairment and fever. There is deposition of platelet microvascular thrombi throughout the circulation, and in practice, ischaemic organ damage may be more widespread. TTP may be congenital or acquired. The majority of acquired cases are idiopathic, but several secondary causes have been identified, including collagen vascular diseases, malignancy, pregnancy, HIV infection, stem cell transplantation, and drugs such as oral contraceptives, cyclosporine and ticlopidine [1]. Von Willebrand factor (VWF) is a glycoprotein which mediates adhesion of platelets to subendothelial collagen exposed by vascular damage. It is normally secreted into the plasma from endothelial cells and platelets as ultra-
large (ULVWF) multimers which have a high degree of haemostatic activity. Subsequent cleavage of ULVWF multimers into smaller forms by the protease ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) limits platelet thrombus formation [3]. The central defect in TTP is persistence of these ULVWF multimers in the plasma, suggestive of a defect in this post secretory processing [4]. Indeed, deficiency of ADAMTS 13 has been characterized in both congenital TTP (caused by mutation in the ADAMTS 13 gene leading to a constitutional lack of the protease) [5] and many cases of acquired TTP (in which an autoantibody against the protease can often be detected) [6]. Deficiency of ADAMTS 13 provides the rationale for plasma exchange, the mainstay of treatment for TTP [7]. Plasma exchange replenishes ADAMTS 13 and provides a means to remove inhibitory autoantibody. It is less clear what role plasma exchange plays in cases of TTP with variable ADAMTS 13 and autoantibody levels. The ability of TTP to cause acute pancreatitis through ischaemic damage is well recognized [8]. The case presented provides further evidence for the much rarer converse phenomenon, in which acute pancreatitis is able to precipitate TTP. Evidence for the role of acute pancreatitis as an aetiological trigger (rather than effect) of TTP is provided by a normal full blood count at presentation, the improvement of the pancreatitis at the time of presentation of the TTP, and the fact that an alternative clear cause for pancreatitis in the form of gallstones was identified. In order to identify additional patients who had TTP following pancreatitis, a bibliographic search using Medline was performed, with the terms ‘thrombotic microangiopathy’, ‘thrombotic thrombocytopenic purpura’ and ‘pancreatitis. Patients in whom TTP was likely to be the primary event causing pancreatitis, and those patients who had alternative thrombotic microangiopathies such as haemolytic uraemic syndrome, were excluded. Twenty seven cases of TTP following pancreatitis were identified in the literature (Table 1) [9–23]. Of these 27 patients, 17 were men, consistent with the greater frequency of pancreatitis in men (but in contrast to the gender disparity observed in TTP in general). The most common aetiologies for the pancreatitis included biliary causes (eight patients), alcohol (nine patients) and idiopathic (10 patients), similar to that seen in pancreatitis in the general population. TTP was diagnosed 1–15 days (median 2 days) after the diagnosis of pancreatitis. The literature search identified 12 cases in which ADAMTS 13 level was measured [20,21,23]. Of these, only two patients had very severe ADAMTS 13 deficiency (less than 3%), and three patients had normal ADAMTS 13 levels. In the case described herein, we report the highest ADAMTS 13 level yet observed in TTP following pancreatitis (101%). This further highlights the ability of TTP to occur despite normal ADAMTS 13 activity and suggests a more complex model may underpin the pathological processes at work. This is substantiated by the observation in humans that a subset of TTP patients can attain remission after plasma exchange treatment despite ADAMTS 13 levels remaining less than 5% [24]. Further support comes from murine models of TTP, in which ADAMTS 13 deficient mice did not develop TTP [25]. In contrast, a baboon model
M.S. Chaudhry, M.W.M. Saweirs / Transfusion and Apheresis Science 45 (2011) 143–147
145
Table 1 Other cases of TTP following pancreatitis described in the literature. PEX – plasma exchange.
*
Patient/ reference
Age/ gender
Aetiology of pancreatitis
Days from pancreatitis to TTP diagnosis
ADAMTS 13 level (%)
Treatment
Outcome
1 2 3 4 5
[9] [10] [11] [12] [13]
18/M 55/F 55/M 18/M 50/F
4 2 3 3 2
– – – – –
Splenectomy, corticosteroids PEX PEX, corticosteroids PEX 6, corticosteroids FFP 8, haemodialysis
TTP TTP TTP TTP TTP
6a [14]
28/F
Idiopathic Idiopathic Biliary Alcohol Pancreatic divisum Idiopathic
2
–
PEX 5
6b [14] 7a [15]
30/F 37/M
Idiopathic Alcohol
2 2
– –
PEX 6 PEX 4, corticosteroids
7b [15] 8 [16] 9 [16] 10 [17] 11 [18]
38/M 24/M 37/F 70/M 38/M
Alcohol Alcohol Biliary Idiopathic Alcohol
3 2 2 15 2
– – – – –
PEX 4 PEX 5 PEX 2 PEX 9, corticosteroids, PEX, haemodialysis
12 [19] 13 [19]
33/M 38/M
2 2
– –
PEX 3, dipyridamole PEX 4
14 [20]
55/F
Alcohol Antiretroviral drugs for HIV Biliary
TTP resolved. Relapse after pancreatitis 2 years later (6b) TTP resolved TTP resolved. Relapse after pancreatitis 1 year later (7b) TTP resolved TTP resolved TTP resolved TTP resolved TTP resolved but further episodes of pancreatitis/TTP (treated with PEX, further details unknown) TTP resolved D15 TTP resolved D12
2
53
15 [21] 16 [21] 17 [21] 18 [21] 19a [21]
38/F 48/F 43/M 37/F 35/F
Biliary Alcohol Alcohol Sarcoid Biliary
6 4 2 1 13
– 90 <3 80 <3
PEX, corticosteroids, dipyridamole, vincristine, weekly rituximab 4 PEX 5 PEX 6, haemodialysis PEX 5, corticosteroids PEX 23, corticosteroids PEX
19b [21] 20 [22] 21 [23]
35/F 23/M 39
7 3 3
<3 – 49
PEX PEX 19, corticosteroids PEX
22 [23]
65
2
22
PEX
TTP resolved
23 [23]
24
2
87
PEX
TTP resolved
24 [23]
26
6
64
PEX
TTP resolved
25 [23]
34
5
65
PEX
TTP resolved
26 [23]
27
3
43
PEX
TTP resolved
27 [23]
22
Biliary Biliary Not specified* Not specified* Not specified* Not specified* Not specified* Not specified* Not specified*
TTP resolved TTP resolved TTP resolved TTP resolved TTP resolved. Relapse after pancreatitis on D101 (19b) TTP resolved TTP resolved TTP resolved
3
49
PEX
TTP resolved
resolved D16 resolved D10 resolved resolved resolved D21
Refractory TTP, only resolved following rituximab
Individual cases not specified but in total five cases idiopathic, one alcohol related, one biliary related.
has more recently shown that ADAMTS 13 deficiency alone is sufficient to cause TTP [26]. However, in this study, a non-fatal phenotype was observed, again raising the possibility that additional factors may be responsible for the life threatening picture seen in humans. Multiple other pathogenetic mechanisms have been proposed. Acute pancreatitis leads to a systemic inflammatory response syndrome characterized by dysregulated release of many cytokines, including TNF-a, IL-6 and IL-8 [27]. In addition to a non-immune mediated catabolic effect on ADAMTS 13 levels [28], it has been shown that these cytokines may increase the risk of TTP through enhanced secretion of ULVWF multimers, and rendering these ULVWF multimers
resistant to protease action [29]. Furthermore, the inflammatory state may augment the risk of TTP through the activation of complement system leading to microvascular damage and the loss of thromboresistance [30]. The role of nitric oxide (NO) may also be relevant to both the initiation and persistence of TTP following acute pancreatitis [31]. Endothelial NO has vasodilatory properties and can behave as a strong platelet anti-aggregatory agent, thus maintaining the patency of the vasculature [32]. There is evidence that pancreatic endothelial NO synthase is decreased in acute pancreatitis [33], and this may therefore predispose to the development of a thrombotic microangiopathy such as TTP. Moreover, free haemoglobin
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scavenges NO directly, and arginase (released from the haemolysed red cell) metabolises arginine, an essential precursor for NO synthesis. This is thought to be the basis for the thrombotic episodes seen in haemolytic disorders such as sickle cell disease and paroxysmal nocturnal haemoglobinuria.[34] Extending this model, the microangiopathic haemolysis observed in TTP may further deplete NO levels, thus propagating the disorder. In reality, it is likely that there is a complex interplay of factors at work, and the use of plasma exchange even in the absence of ADAMTS 13 deficiency would in theory allow some of these pathogenetic mechanisms to be reset. This is supported by the case presented, where plasma exchange was administered with good effect despite a normal ADAMTS 13 activity. Further evidence for the efficacy of plasma exchange can be found in our literature review, where of the 27 cases found, 25 patients were treated with plasma exchange, leading to resolution of the TTP in all but one case. Although there are reports in the literature of corticosteroids being used to treat TTP following pancreatitis, steroids were withheld in this case in view of the lack of inhibitory autoantibody, and also their association with acute pancreatitis. As our understanding of TTP increases, it is likely we will be able to further tailor therapy towards the individual pathogenetic processes at work. 4. Conclusion In conclusion, the case highlights the potential of acute pancreatitis to act as an aetiological factor in the pathogenesis of TTP. In such cases, various pathogenetic mechanisms may be at work and ADAMTS 13 level is not always decreased. A high clinical suspicion is required in order to make a rapid diagnosis and allow early institution of plasma exchange, which appears effective in treating this form of TTP. References [1] Allford SL, Hunt BJ, Rose P, Machin SJ. Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003;120:556–73. [2] Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc NY Pathol Soc 1924;24:21–4. [3] Hurskainen TL, Hirohata S, Seldin MF, Apte SS. ADAM-TS5, ADAMTS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases: general features and genomic distribution of the ADAM-TS family. J Biol Chem 1999;274:25555–63. [4] Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982;307:1432–5. [5] 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. [6] Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585–94. [7] 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: Canadian Apheresis Study Group. N Engl J Med 1991;325:393–7. [8] Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine 1981;60:413–28.
[9] Bone RC, Henry JE, Petterson J, Amare M. Respiratory dysfunction in thrombotic thrombocytopenic purpura. Am J Med 1978;65: 262–70. [10] Jackson B, Files JC, Morrison FS, Scott-Conner CEH. Thrombotic thrombocytopenic purpura and pancreatitis. Am J Gastroenterol 1989;84:667–9. [11] Garcia-Cano J, Vazquez Rodriguez de Alba J, Garcia Cabezas J, DiazRubio M. Pancreatitis aguda en el seno de la purpura thrombocitopenica thrombotica. A proposito de dos casos. An Med Interna 1992;9:551–3. [12] Silva VA. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome secondary to pancreatitis. Am J Hematol 1995;50:53–6. [13] Malka D, Levy P, Bernades P. Thrombotic thrombocytopenic purpura caused by acute pancreatitis in a woman with a pancreas divisum: a case report. Pancreas 1996;12:414–6. [14] Daryanani S, Wilde JT. Relapsing thrombotic thrombocytopenic purpura in association with recurrent pancreatitis. Clin Lab Haematol 1998;20:317–8. [15] Vergara M, Modolell I, Puig-Divi V, Guarner L, Malagelada JR. Acute pancreatitis as a triggering factor for thrombotic thrombocytopenic purpura. Am J Gastroenterol 1998;93:2215–8. [16] Blanco Jimenez J, Vargas Nunez JA, Garcia Gasalla M, Lopez Garcia E, Yebra Bango M. Pancreatitis aguda y purpura trombotica trombocitopenica. Revista clinica espamola 1998;198:47–8. [17] Varadarajula S, Ramsey WH, Israel RH. Thrombotic thrombocytopenic purpura in acute pancreatitis. J Clin Gastroenterol 2000;31:243–5. [18] Talawalkar JA, Ruymann FW, Marcoux P, Farraye FA. Recurrent thrombotic thrombocytopenic purpura (TTP) as a complication of acute relapsing pancreatitis. Dig Dis Sci 2002;47:1096–9. [19] 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. [20] Ruiz J, Koduri PR, Valdivieso M, Shah PC. Refractory post-pancreatitis thrombotic thrombocytopenic purpura: response to rituximab. Ann Hematol 2005;84:267–8. [21] Swisher KK, Doan JT, Vesely SK, Kwaan HC, Kim B, Lämmle 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. [22] Anderson JA, Simpson PJ, Leber B, Warkentin TE. Acute pancreatitis preceding thrombotic thrombocytopenic purpura. Haematologica 2007;92:e94–5. [23] 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. [24] Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004;103:4043–9. [25] Banno F, Kokame K, Okuda T, Honda S, Miyata S, Kato H, et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 2006;107:3161–6. [26] Feys HB, Roodt J, Vandeputte N, Pareyn I, Lamprecht S, van Rensburg WJ, et al. Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus). Blood 2010;116:2005–10. [27] Bhatia M, Wong FL, Cao Y, Lau HY, Huang J, Puneet P, et al. Pathophysiology of acute pancreatitis. Pancreatology 2005;5:5132–44. [28] Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001;98:2730–5. [29] 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. [30] Ruiz-Torres MP, Casiraghi F, Galbusera M, Macconi D, Gastoldi S, Todeschini M, et al. Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies. J Thromb Haemost 2005;93: 443–52. [31] Thachill J. Lessons from acute pancreatitis-induced thrombotic thrombocytopenic purpura. Eur J Intern Med 2009;20:739–43.
M.S. Chaudhry, M.W.M. Saweirs / Transfusion and Apheresis Science 45 (2011) 143–147 [32] Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987;2:1057–8. [33] DiMagno MJ, Williams JA, Hao Y, Ernst SA, Owyang C. Endothelial nitric oxide synthase is protective in the initiation of caerulein-
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Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis Mohammed Suhail Chaudhry a,⇑, Martin W.M. Saweirs b a b
Department of Haematology, Hammersmith Hospital, London, UK Department of General Surgery, Charing Cross Hospital, London, UK
a r t i c l e
i n f o
Keywords: Acute pancreatitis Thrombotic thrombocytopenic purpura Plasma exchange
a b s t r a c t A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare congenital or acquired systemic disorder defined classically by the pentad of thrombocytopenia, microangiopathic haemolytic anaemia, neurological symptoms, renal impairment and fever. Rapid diagnosis allows the early institution of potentially life saving therapy, and it is therefore important to recognise rare aetiological triggers of this condition. Herein, we describe the case of TTP occurring secondary to acute pancreatitis. We review the pathogenetic mechanisms which may link these two disorders, and provide support for the use of plasma exchange in this situation.
2. Case report A 20 year old woman was admitted with a 24 h history of severe epigastric pain radiating through to her back, associated with nausea and vomiting. She was previously fit and well, and there was nil else of note in the medical history. On examination, she appeared uncomfortable and dehydrated. She was not jaundiced. Her abdomen was soft but extremely tender in the epigastrium. Some intra-abdominal free fluid was also detectable upon examination. Her initial ⇑ Corresponding author. Tel.: +44 0 208 383 1000. E-mail address: [email protected] (M.S. Chaudhry). 1473-0502/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2011.07.009
bloods showed an elevated amylase of 1948 IU/L (0–50 IU/L normal level), but otherwise unremarkable baseline biochemistry, including normal lactate dehydrogenase (LDH, 213 IU/L) and normal renal function (urea 4.4 mmol/L, creatinine 65 lmol/L). Full blood count was also unremarkable (haemoglobin 14.4 g/dL, platelet count 206 109/L, white blood cell count 10.8 109/L). A clinical diagnosis of acute pancreatitis was made, and she was treated with analgesia and intravenous fluids, leading to an improvement in symptoms. Ultrasound and computed tomography of the abdomen confirmed the diagnosis, and a gallstone was seen to be impacted above the Ampulla of Vater. On day 2, her platelet count was noted to have fallen to 33 109/L, and this subsequently fell further to 23 109/L on day 3. Concurrently, by day 3 her haemoglobin had fallen to 8.8 g/dL. This was associated with an increase in bilirubin to 93 lmol/L (despite other liver function tests remaining normal) and a rise in the LDH level to 1002 IU/L, suggestive of haemolysis. Coombs test was negative. Blood film revealed marked schistocytes suggestive of microangiopathic haemolysis (Fig. 1). Disseminated intravascular coagulation was unlikely in view of a normal clotting profile (prothrombin time 12.7 s, activated partial thromboplastin time 29.0 s, thrombin time 22 s, fibrinogen 2.71 g/L). All other blood tests, including renal function, remained stable. Clinically the patient developed a mild pyrexia (38 °C) and reported an altered sense of smell, suggestive of mild neurological compromise. In the absence of any other cause, a diagnosis
144
M.S. Chaudhry, M.W.M. Saweirs / Transfusion and Apheresis Science 45 (2011) 143–147
Fig. 1. Blood film displaying true thrombocytopenia and red cell anisopoikilocytosis. There are numerous schistocytes, consistent with microangiopathic haemolysis.
of thrombotic thrombocytopenic purpura (TTP) was made. ADAMTS 13 activity was 101%, with no inhibitor detected. The patient was commenced on daily single volume plasma exchange using solvent detergent treated fresh frozen plasma for a total of eight days. This was well tolerated and a rapid response was noted. Pyrexia and the altered sense of smell resolved within 24 h of commencing plasma exchange. Platelet count and LDH normalized by day 9 following six daily plasma exchange procedures, and in accordance with national BCSH guidelines [1], plasma exchange was continued for two further days. Corticosteroid therapy was withheld in view of the lack of inhibitory autoantibody and association with pancreatitis. Adjunctive treatment with folic acid and low dose aspirin (upon platelet recovery) was administered as per national guidelines. The patient was discharged shortly after recovery of the blood counts. She is under regular haematology and surgical follow up. At the time of writing, her blood counts remain stable. Magnetic resonance cholangiopancreatography has revealed multiple stones in the gallbladder but no residual biliary obstruction, and she is awaiting an elective cholecystectomy. 3. Discussion Thrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz in 1924 [2]. It is defined classically by the pentad of thrombocytopenia, microangiopathic haemolytic anaemia, neurological symptoms, renal impairment and fever. There is deposition of platelet microvascular thrombi throughout the circulation, and in practice, ischaemic organ damage may be more widespread. TTP may be congenital or acquired. The majority of acquired cases are idiopathic, but several secondary causes have been identified, including collagen vascular diseases, malignancy, pregnancy, HIV infection, stem cell transplantation, and drugs such as oral contraceptives, cyclosporine and ticlopidine [1]. Von Willebrand factor (VWF) is a glycoprotein which mediates adhesion of platelets to subendothelial collagen exposed by vascular damage. It is normally secreted into the plasma from endothelial cells and platelets as ultra-
large (ULVWF) multimers which have a high degree of haemostatic activity. Subsequent cleavage of ULVWF multimers into smaller forms by the protease ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) limits platelet thrombus formation [3]. The central defect in TTP is persistence of these ULVWF multimers in the plasma, suggestive of a defect in this post secretory processing [4]. Indeed, deficiency of ADAMTS 13 has been characterized in both congenital TTP (caused by mutation in the ADAMTS 13 gene leading to a constitutional lack of the protease) [5] and many cases of acquired TTP (in which an autoantibody against the protease can often be detected) [6]. Deficiency of ADAMTS 13 provides the rationale for plasma exchange, the mainstay of treatment for TTP [7]. Plasma exchange replenishes ADAMTS 13 and provides a means to remove inhibitory autoantibody. It is less clear what role plasma exchange plays in cases of TTP with variable ADAMTS 13 and autoantibody levels. The ability of TTP to cause acute pancreatitis through ischaemic damage is well recognized [8]. The case presented provides further evidence for the much rarer converse phenomenon, in which acute pancreatitis is able to precipitate TTP. Evidence for the role of acute pancreatitis as an aetiological trigger (rather than effect) of TTP is provided by a normal full blood count at presentation, the improvement of the pancreatitis at the time of presentation of the TTP, and the fact that an alternative clear cause for pancreatitis in the form of gallstones was identified. In order to identify additional patients who had TTP following pancreatitis, a bibliographic search using Medline was performed, with the terms ‘thrombotic microangiopathy’, ‘thrombotic thrombocytopenic purpura’ and ‘pancreatitis. Patients in whom TTP was likely to be the primary event causing pancreatitis, and those patients who had alternative thrombotic microangiopathies such as haemolytic uraemic syndrome, were excluded. Twenty seven cases of TTP following pancreatitis were identified in the literature (Table 1) [9–23]. Of these 27 patients, 17 were men, consistent with the greater frequency of pancreatitis in men (but in contrast to the gender disparity observed in TTP in general). The most common aetiologies for the pancreatitis included biliary causes (eight patients), alcohol (nine patients) and idiopathic (10 patients), similar to that seen in pancreatitis in the general population. TTP was diagnosed 1–15 days (median 2 days) after the diagnosis of pancreatitis. The literature search identified 12 cases in which ADAMTS 13 level was measured [20,21,23]. Of these, only two patients had very severe ADAMTS 13 deficiency (less than 3%), and three patients had normal ADAMTS 13 levels. In the case described herein, we report the highest ADAMTS 13 level yet observed in TTP following pancreatitis (101%). This further highlights the ability of TTP to occur despite normal ADAMTS 13 activity and suggests a more complex model may underpin the pathological processes at work. This is substantiated by the observation in humans that a subset of TTP patients can attain remission after plasma exchange treatment despite ADAMTS 13 levels remaining less than 5% [24]. Further support comes from murine models of TTP, in which ADAMTS 13 deficient mice did not develop TTP [25]. In contrast, a baboon model
M.S. Chaudhry, M.W.M. Saweirs / Transfusion and Apheresis Science 45 (2011) 143–147
145
Table 1 Other cases of TTP following pancreatitis described in the literature. PEX – plasma exchange.
*
Patient/ reference
Age/ gender
Aetiology of pancreatitis
Days from pancreatitis to TTP diagnosis
ADAMTS 13 level (%)
Treatment
Outcome
1 2 3 4 5
[9] [10] [11] [12] [13]
18/M 55/F 55/M 18/M 50/F
4 2 3 3 2
– – – – –
Splenectomy, corticosteroids PEX PEX, corticosteroids PEX 6, corticosteroids FFP 8, haemodialysis
TTP TTP TTP TTP TTP
6a [14]
28/F
Idiopathic Idiopathic Biliary Alcohol Pancreatic divisum Idiopathic
2
–
PEX 5
6b [14] 7a [15]
30/F 37/M
Idiopathic Alcohol
2 2
– –
PEX 6 PEX 4, corticosteroids
7b [15] 8 [16] 9 [16] 10 [17] 11 [18]
38/M 24/M 37/F 70/M 38/M
Alcohol Alcohol Biliary Idiopathic Alcohol
3 2 2 15 2
– – – – –
PEX 4 PEX 5 PEX 2 PEX 9, corticosteroids, PEX, haemodialysis
12 [19] 13 [19]
33/M 38/M
2 2
– –
PEX 3, dipyridamole PEX 4
14 [20]
55/F
Alcohol Antiretroviral drugs for HIV Biliary
TTP resolved. Relapse after pancreatitis 2 years later (6b) TTP resolved TTP resolved. Relapse after pancreatitis 1 year later (7b) TTP resolved TTP resolved TTP resolved TTP resolved TTP resolved but further episodes of pancreatitis/TTP (treated with PEX, further details unknown) TTP resolved D15 TTP resolved D12
2
53
15 [21] 16 [21] 17 [21] 18 [21] 19a [21]
38/F 48/F 43/M 37/F 35/F
Biliary Alcohol Alcohol Sarcoid Biliary
6 4 2 1 13
– 90 <3 80 <3
PEX, corticosteroids, dipyridamole, vincristine, weekly rituximab 4 PEX 5 PEX 6, haemodialysis PEX 5, corticosteroids PEX 23, corticosteroids PEX
19b [21] 20 [22] 21 [23]
35/F 23/M 39
7 3 3
<3 – 49
PEX PEX 19, corticosteroids PEX
22 [23]
65
2
22
PEX
TTP resolved
23 [23]
24
2
87
PEX
TTP resolved
24 [23]
26
6
64
PEX
TTP resolved
25 [23]
34
5
65
PEX
TTP resolved
26 [23]
27
3
43
PEX
TTP resolved
27 [23]
22
Biliary Biliary Not specified* Not specified* Not specified* Not specified* Not specified* Not specified* Not specified*
TTP resolved TTP resolved TTP resolved TTP resolved TTP resolved. Relapse after pancreatitis on D101 (19b) TTP resolved TTP resolved TTP resolved
3
49
PEX
TTP resolved
resolved D16 resolved D10 resolved resolved resolved D21
Refractory TTP, only resolved following rituximab
Individual cases not specified but in total five cases idiopathic, one alcohol related, one biliary related.
has more recently shown that ADAMTS 13 deficiency alone is sufficient to cause TTP [26]. However, in this study, a non-fatal phenotype was observed, again raising the possibility that additional factors may be responsible for the life threatening picture seen in humans. Multiple other pathogenetic mechanisms have been proposed. Acute pancreatitis leads to a systemic inflammatory response syndrome characterized by dysregulated release of many cytokines, including TNF-a, IL-6 and IL-8 [27]. In addition to a non-immune mediated catabolic effect on ADAMTS 13 levels [28], it has been shown that these cytokines may increase the risk of TTP through enhanced secretion of ULVWF multimers, and rendering these ULVWF multimers
resistant to protease action [29]. Furthermore, the inflammatory state may augment the risk of TTP through the activation of complement system leading to microvascular damage and the loss of thromboresistance [30]. The role of nitric oxide (NO) may also be relevant to both the initiation and persistence of TTP following acute pancreatitis [31]. Endothelial NO has vasodilatory properties and can behave as a strong platelet anti-aggregatory agent, thus maintaining the patency of the vasculature [32]. There is evidence that pancreatic endothelial NO synthase is decreased in acute pancreatitis [33], and this may therefore predispose to the development of a thrombotic microangiopathy such as TTP. Moreover, free haemoglobin
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scavenges NO directly, and arginase (released from the haemolysed red cell) metabolises arginine, an essential precursor for NO synthesis. This is thought to be the basis for the thrombotic episodes seen in haemolytic disorders such as sickle cell disease and paroxysmal nocturnal haemoglobinuria.[34] Extending this model, the microangiopathic haemolysis observed in TTP may further deplete NO levels, thus propagating the disorder. In reality, it is likely that there is a complex interplay of factors at work, and the use of plasma exchange even in the absence of ADAMTS 13 deficiency would in theory allow some of these pathogenetic mechanisms to be reset. This is supported by the case presented, where plasma exchange was administered with good effect despite a normal ADAMTS 13 activity. Further evidence for the efficacy of plasma exchange can be found in our literature review, where of the 27 cases found, 25 patients were treated with plasma exchange, leading to resolution of the TTP in all but one case. Although there are reports in the literature of corticosteroids being used to treat TTP following pancreatitis, steroids were withheld in this case in view of the lack of inhibitory autoantibody, and also their association with acute pancreatitis. As our understanding of TTP increases, it is likely we will be able to further tailor therapy towards the individual pathogenetic processes at work. 4. Conclusion In conclusion, the case highlights the potential of acute pancreatitis to act as an aetiological factor in the pathogenesis of TTP. In such cases, various pathogenetic mechanisms may be at work and ADAMTS 13 level is not always decreased. A high clinical suspicion is required in order to make a rapid diagnosis and allow early institution of plasma exchange, which appears effective in treating this form of TTP. References [1] Allford SL, Hunt BJ, Rose P, Machin SJ. Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003;120:556–73. [2] Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc NY Pathol Soc 1924;24:21–4. [3] Hurskainen TL, Hirohata S, Seldin MF, Apte SS. ADAM-TS5, ADAMTS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases: general features and genomic distribution of the ADAM-TS family. J Biol Chem 1999;274:25555–63. [4] Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982;307:1432–5. [5] 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. [6] Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585–94. [7] 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: Canadian Apheresis Study Group. N Engl J Med 1991;325:393–7. [8] Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine 1981;60:413–28.
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