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REVIEW

Coagulation, Platelets, and Acute Pancreatitis


Anna Kakafika, MD(* Vasilios Papadopoulos, MD( Konstantinos Mimidis, MD(
and Dimitri P. Mikhailidis, MD, FACB, FFPM, FRCP, FRCPath*
Abstract: Acute pancreatitis generates a complex cascade of
immunological events that affect the pathogenesis and the progression
of this disease. Several inflammatory mediators seem to play a critical
role in the pathogenesis of pancreatitis and the subsequent inflammatory response. In turn, these mediators can influence hemostasis.
Coagulation abnormalities occur in acute pancreatitis and are related
to its severity. The contribution of blood platelets in the disturbed
hemostasis in acute pancreatitis, although extensively studied, remains
obscure. This article reviews the local and systemic implications of
hemostatic abnormalities during acute pancreatitis. Furthermore, we
discuss the prognostic value and the potential therapeutic implications
of platelet activation and other hemostatic variables.
Key Words: acute pancreatitis, platelet, coagulation, inflammatory
mediators, tissue factor
(Pancreas 2007;34:15Y20)

cute pancreatitis is an inflammatory disorder that


generates a complex cascade of immunological events
that affect the pathogenesis and the progression of this
disease.1 The most common and widely accepted theory is
that pancreatitis develops because of injury or disruption of
the pancreatic acini.1 The subsequent release of oxygen free
radicals by damaged pancreatic cells initiates the cascade of
digestive pancreatic enzymes, chemotaxis, and activation of
inflammatory cells.2 The activation of digestive enzymes
within pancreatic acinar cells is a critical initiating event that
leads to autodigestion of the pancreas.3 Furthermore,
activated proteases (trypsin and elastase) and lipase break
down tissue and cell membranes, causing edema, vascular
damage, hemorrhage, and necrosis.4 After the initial insult to
the pancreas and if this is sufficiently extensive, systemic
effects mediated by the immune system and consistent with
the systemic inflammatory response syndrome (SIRS) may
occur. SIRS can lead to distant organ damage and multiple
organ dysfunction syndrome (MODS).5 MODS associated
with acute pancreatitis is the primary cause of morbidity and

Received for publication February 20, 2006; accepted August 25, 2006.
From the *Department of Clinical Biochemistry, Royal Free Hospital, Royal
Free and University College School of Medicine, London, UK; and the
First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
Reprints: Dimitri P. Mikhailidis, MD, FACB, FFPM, FRCP, FRCPath,
Department of Clinical Biochemistry (Vascular Disease Prevention
Clinics), Royal Free Hospital Royal Free and University College School
of Medicine (University of London), Pond Street, London NW3 2QG, UK
(e-mail: mikhailidis@aol.com).
Copyright * 2007 by Lippincott Williams & Wilkins

Pancreas

mortality in this condition. Thus, inflammatory mediators


such as tumor necrosis factor (TNF) >, interleukin (IL) 1A,
IL-6, IL-8, intercellular adhesion molecule 1, platelet
activating factor (PAF), growth related oncogene >/cytokineinduced neutrophil chemoattractant (GRO->/CINC), monocyte chemoattractant protein 1, and substance P seem to play a
critical role in the pathogenesis of pancreatitis and more so
during the subsequent inflammatory response.6 On the other
hand, anti-inflammatory mediators that play an important role
in disease regression include IL-10, complement component
C5a, soluble TNF receptors, IL-1 receptor antagonist, and
neutral endopeptidase.7 The expression of several of these
mediators is regulated by transcription factors such as nuclear
factor (NF)-JB.8 Preclinical work has shown that some of
these mediators are markers for disease activity, whereas other
inflammatory components may actually Bdrive^ the disease
process. It follows that the interruption or blunting of an
inappropriate immune response may improve outcome.9

HEMOSTASIS AND ACUTE PANCREATITIS


Coagulation abnormalities occur in acute pancreatitis and
are related to its severity.10 These disorders range from
scattered intravascular thrombosis to disseminated intravascular
coagulation (DIC).11 Indeed, the ultrastructural changes in the
pancreas that accompany human acute pancreatitis involve the
infiltration of polymorphonuclear leukocytes, the accumulation
of platelets intravascularly and extravascularly, as well as fibrin
deposition in the connective tissue and intercellular spaces.12
Moreover, microthrombi occur in local blood vessels.12

Animal Experimental Studies


The role of blood platelets in acute pancreatitis was
initially investigated in animal models. Studies in dogs with
acute experimental pancreatitis showed a significant decrease
in platelet count and a diminished sensitivity of platelet
aggregation to adenosine diphosphate (ADP), arachidonic
acid, PAF, and collagen.13 Furthermore, the release of
adenosine triphosphate from platelets was reduced in
collagen-stimulated aggregation.13 However, in another
study, experimental pancreatitis resulted in hyperaggregability of platelets after adding ADP and PAF.14 Furthermore,
when acute necrotizing (hemorrhagic) pancreatitis was
induced in dogs, there were decreases in antithrombin (AT)
III, blood platelets, and plasminogen after 24 and 48 hours.15
Additionally, raised plasma fibrinogen levels and prolongation of the prothrombin and activated partial thromboplastin
time were observed.15 The latter 2 changes together with
decreases in AT III, platelet numbers, and complement were
indicative of consumption coagulopathy.15 Furthermore,
studies in rats showed increased plasminogen activator

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15

Pancreas

Kakafika et al

inhibitor and decreased tissue (t)-PA activities, which might


explain the inhibited plasma fibrinolytic activity in the early
period of acute experimental pancreatitis.16 Finally, it is
worth noting that blocking blood perfusion in the splenic
portion of the pancreas by injection of polystyrene microspheres into the distal splenic artery of rats can induce acute
experimental pancreatitis. Thus, it seems that the vascular
component is important in pancreatic disease and altered
epithelial barriers allow interaction between bloodborne
material and pancreatic exocrine secretions.17

Human Studies
Similar results were obtained when coagulation disorders were investigated in humans. A study of 27 cases of
acute pancreatitis of differing severity showed decreased
platelet counts, decreased prothrombin values, and consumption of fibrinogen.18 Raised fibrinolysis was suggested by
decreased plasminogen values in severe attacks. Moreover,
fibrinogen degradation products were seen in 40% of the
patients in blood and in 100% of the patients in peritoneal
fluid.18 Another study in 14 patients (10 patients survived and
4 died) with acute pancreatitis showed, in both survivors and
fatal cases, a high frequency of reduced values of plasma
prekallikrein, functional AT III, and platelet count during the
first week after admission.19 In the fatal cases, these factors
were significantly more reduced than those in survivors, an
observation that suggests a prognostic value. Similarly, a
strong prognostic value of hemostatic parameters was
reported in severe necrotizing pancreatitis.20 In fact, changes
in protein C, AT III, D-dimer, and plasminogen activator
inhibitor 1 levels indicated exhaustion of fibrinolysis and
coagulation inhibitors and predicted a bad prognosis.
In this context, it is important to mention the role of
D-dimers as indicators of the severity of the inflammatory
process. There is evidence that the increase in D-dimer levels
reflects the activation of fibrinolysis that occurs in acute
pancreatitis.21 However, its extent is related to the degree of
severity of the disease and may gradually proceed from mild
activation (in uncomplicated pancreatitis) to a greater involvement of the coagulation system, with progression to a pre-DIC
state and finally to evident DIC and multiple organ failure.21
Two of our studies assessed platelet activation in mild
acute pancreatitis. The first study 22 consisted of 54 patients
with acute pancreatitis. Two successive end points were
considered: platelet activation during acute pancreatitis,
expressed as activated platelet ratio (APR), and alterations in
platelet number and indices (mean platelet volume, platelet
large cell ratio, and platelet distribution width) between onset
and remission of the disease. APR represents the percentage of
activated CD62 (+) platelets measured by flow cytometry using
an anti-CD62 monoclonal antibody. A significant difference
between onset and remission of the disease was documented in
APR, mean platelet volume, platelet large cell ratio, and
platelet distribution width, but not in platelet numbers. The
elevated APR at the onset, in combination with the elevation of
the platelet indices at later stages of acute pancreatitis, implies
a direct involvement of platelets in the systemic inflammatory
process of the disease, which leads to consumption compensated by an immediate bone marrow response.

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It is of interest to mention that platelet serotonin


(hydroxytryptamine; p-5HT) is an index of platelet activation.23,24 Furthermore, the administration of human pancreatic fluid caused the release of 5HT in parallel with platelet
activation.25 Studies showed that the production of 5HT can
induce further platelet aggregation and 5HT release,26,27 a
positive feedback that may lead to thrombus formation.28
Furthermore, 5HT is also a potent vasoconstrictor.24 Thus,
these proprieties may mean that this bioamine is an
aggravating factor for acute pancreatitis. The latter suggestion was further supported by showing that selective 5HT2
receptor antagonists (ketanserin, ritanserin, and R-96544) in
experimental acute pancreatitis reduced serum amylase and
lipase concentrations as well as pancreatic lesions.29Y31
Finally, early 5HT receptor antagonist administration in
patients with acute respiratory failure associated with
pancreatitis may have a beneficial effect.32
Apart from 5HT, disturbed protein C homeostasis
seems to contribute to the development of MODS in acute
pancreatitis. Indeed, a recent study showed that protein C
deficiency and decreased activated protein C generation in
acute pancreatitis may contribute to an attenuated anticoagulant and anti-inflammatory defense.33
In our second study,34 we evaluated the alterations of
platelet function by using a platelet function analyser (PFA100TM). Patients (n = 16) with acute edematous pancreatitis
were studied along with 32 healthy controls. The hemostatic
capacity of platelets was tested in citrated blood and standard
cartridges containing collagen-ADP or collagen-epinephrine.
A statistically significant shortening of the collagen-ADP
closure time but not of collagen-epinephrine time was
noted.34 These findings confirmed the increased platelet
adhesiveness and aggregation in the early stages of acute
pancreatitis. These findings underline the prothrombotic
potential of the disease.

PATHOPHYSIOLOGY OF HEMOSTATIC
DISORDERS IN ACUTE PANCREATITIS:
POTENTIAL OPTIONS FOR TREATMENT?
The release of inflammatory mediators in the early
stages of pancreatitis plays a key role in the evolution of the
disease. PAF is a proinflammatory mediator (produced
largely from vascular endothelium) that, in addition to
activating platelets, can also activate neutrophils and cause
increased capillary permeability leading to hypovolemia and
edema.35 Acute pancreatitis induces increased levels of
phospholipase A2 that promotes the synthesis of PAF.36
Once produced, PAF activates circulating platelets and mast
cells, causing degranulation and systemic histamine release.
PAF also primes and amplifies the production of cytokines
such as IL-1, IL-6, and TNF-> and interacts with phospholipase A2, thrombin, and other adhesion molecules, which
produce toxic free radicals and leukotrienes.37 Moreover,
several experimental studies showed that PAF induces a
significant increase in serum amylase and lipase levels and
that a PAF antagonist (lexipafant) reduces the amount of
hemorrhage and tissue damage.38 There is also evidence that
PAF receptor antagonists (recombinant PAF-acetylhydrolase
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Pancreas

& Volume 34, Number 1, January 2007

and BN 52021) can reduce experimental pancreatitis-induced


bacterial translocation to distant sites, which is responsible
for the high incidence of infections occurring after acute
pancreatitis.39 In addition, experiments in rats showed that
amelioration of pancreatitis and prevention of pancreatitisassociated lung injury can be achieved with recombinant
PAF-acetylhydrolase even if treatment is begun after pancreatitis is established.40
Lexipafant (BB-882) is a potent PAF antagonist
because it has much greater affinity than PAF itself for
binding to human platelet PAF receptors.41 Clinical phase II42
and III43 trials showed that the intravenous administration of
lexipafant in patients with acute pancreatitis led to a
significant reduction in the incidence of organ failure and
also suppression of the inflammatory response. However, a
recent double-blind, randomized, placebo-controlled study in
the treatment and prevention of organ failure using lexipafant
in 290 patients with acute pancreatitis and an Acute
Physiology and Chronic Health Evaluation II score greater
than 6 failed to demonstrate a reduction in the frequency of
new organ failure.44 Thus, a critical appraisal of the clinical
trials with lexipafant shows that the drug failed to reduce
mortality in severe acute pancreatitis.45
Another important aspect of the pathogenesis of acute
pancreatitis is the microcirculatory dysfunction that includes
increased vascular permeability, reduced blood flow, ischemia/reperfusion injury, intravascular thrombus formation,
and hypercoagulation.46 Indeed, experimental data showed
that the pancreatic microcirculation in a mild pancreatitis
model (caused by warm ischaemia for 1 hour followed by
reperfusion for 24 hours) was characterized by pronounced
platelet-endothelium interaction in capillaries and venules.47
Similarly, ischaemia/reperfusion injury plays a key role in the
progression of disease from mild edematous to severe
necrotizing form.48
The pancreatic circulation during acute experimental
edematous pancreatitis may also be influenced by the
expression of platelet endothelial cell adhesion molecule
(PECAM) 1 on polymorphonuclear leukocytes. Indeed,
PECAM-1 expression was upregulated in the peripheral
circulation and downregulated in the pancreatic microcirculation, suggesting that inhibition of PECAM-1 expression
may improve the pathological changes associated with acute
edematous pancreatitis.49,50
There has been considerable scientific interest regarding the role of the potent vasoconstrictor endothelin (ET) 1 in
acute pancreatitis. In fact, during the acute phase, cytokines
and activated thrombin and trypsin stimulate the production
of ET-1 by endothelial cells.51 Studies in rats showed that the
use of ET antagonists improved histological and ultrastructural alterations in the pancreas and decreased trypsinogen
activation in severe pancreatitis.52 However, the effect of ET-1
on platelets is still controversial.53
Resveratrol, a natural polyphenolic compound extracted from plants, seems to inhibit platelet aggregation
and change platelet reactivity in inflammatory processes including acute pancreatitis.54,55 There is also some evidence
that resveratrol prevents leukocyte recruitment and endothelial barrier disruption in ischemic/reperfusion injury56 and

Coagulation, Platelets, and Acute Pancreatitis

that it upregulates nitric oxide synthase mRNA expression in


endothelial cells.57
Another aspect in the pathogenesis of acute pancreatitis is the hypercoagulable state generated in hypothermic conditions.58 Hypothermia impairs the synthesis and
increases (indirectly) the rate of decay of prostacyclin
(PGI2) and may also activate platelets.59,60 These changes
result in a predisposition to thrombosis.60 Furthermore,
platelet hyperaggregability is enhanced by increased free
fatty acid levels and decreased serum albumin levels often
observed in acute pancreatitis.60 Indeed, free fatty acids
inhibit vascular PGI2 synthesis,61 whereas albumin inhibits
platelet aggregation possibly by decreasing the conversion
of arachidonic acid to thromboxane and by increasing
the conversion of endoperoxides (PGH2) to prostaglandin
(PGD2).62
There is interest in the role of tissue factor (TF,
thromboplastin) released from damaged tissues in the
generation of coagulative disorders during pancreatic disease.63 TF favors thrombin formation, which serves to induce
coagulopathy and many other aspects of inflammation.64
Diagnostic patterns for these disorders include decreased
platelet count, fibrinogen, and AT III levels and raised
thrombin-AT III activity, prothrombin fragment 1 + 2, and
D-dimer level. There is also a bleeding diathesis together with
a hypercoagulable state.65 It is worth noting that abnormal TF
expression is a major mechanism initiating DIC.64 This key
role of TF in the pathogenesis of hemostatic disorders during
pancreatic disease was shown in a study that evaluated
coagulation activation after islet transplantation and the
subsequent release of insulin.66 Even in the absence of signs
of intraportal thrombosis, the investigators concluded that the
endocrine, but not the exocrine, cells of the pancreas
synthesize and secrete active TF. The clotting reaction
triggered by pancreatic islets in vitro could be abrogated by
blocking the active site of TF with specific antibodies or siteinactivated factor VIIa, a candidate drug for inhibition of TF
activity in vivo. Thus, blockade of TF could represent a new
therapeutic approach that might increase the success of islet
transplantation in patients with type 1 diabetes in terms of
both reducing the risk of intraportal thrombosis and the need
for islets from more than 1 donor.66 These results were
supported by the observation that pancreatic duct cells can
produce TF. The latter phenomenon may possibly explain
graft rejection after islet transplantation when islet preparations are not 100% devoid of epithelial cells.67
Even minimal pancreatic tissue damage, including
epithelial components, may trigger TF-dependent coagulation. This may not be limited to local thrombotic events, but
could initiate SIRS involving upregulation of adhesion
molecule expression and chemokine production.68
However, the question is whether SIRS, which can
accompany acute pancreatitis, is a result of TF interlinking
between coagulation and inflammation. In fact, TF is
produced in 2 forms: the first represents a cell-bound
molecule having a transmembrane region and the second a
soluble molecule lacking this transmembrane domain as a
result of alternative splicing (as-HTF).69 Although TF has
been shown to act as an adhesion molecule, cytokine receptor,

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17

Pancreas

Kakafika et al

and signal transduction molecule, enhancing the inflammatory process, its splice variant as-HTF probably lacks these
attributes, serving only as propagator of coagulation.70
A recent clinical study of ours71 was designed to
elucidate the clinical significance of these 2 splice variants in
SIRS and sepsis by investigating the pattern of F3 gene
expression in intensive care unit patients with sepsis in
comparison with healthy individuals. Nine consecutive
nonsurgical intensive care unit patients with sepsis and 7
healthy individuals were compared. Tissue-bound TF and
circulating as-HTF F3 splice variants were quantitatively
determined at the c-DNA level; 18S was used as a housekeeping gene. The whole tissue-bound F3 transcript (TF) is
elevated in patients with sepsis, in contrast with its circulating
splice variant (as-HTF). Given the multitask effect of the TF
molecule (hemostasis triggering, cytokine release, mediation
of reverse transmigration through adhesion, signal transduction, protease-activated receptors activation, etc) but not of
the as-HTF splice variant, the TF/as-HTF ratio could
represent a balance between thrombosis and inflammation.
Moreover, these preliminary findings suggest that the most
effective site of extrinsic pathway inhibition in sepsis could be
the specific blockade at the level of unspliced F3 m-RNA.71
Another molecule, tissue factor pathway inhibitor
(TFPI), impedes TF function.72 Thus, the ratio (TF + asHTF)/TFPI might indicate thrombotic potential. The TF/asHTF ratio may reflect the regulation of crosstalk between
thrombotic and inflammatory pathways. Therefore, defining
TF/as-HTF in the early stages of acute pancreatitis would
show if this interlinkage is impaired and suggest potential
clinical implications.70,73 Concerning clinical practice, the
prevention of further complications remains a major treatment goal for patients with acute pancreatitis. Therefore, the
role of antithrombotic agents should not be underestimated.
Indeed, studies in rats showed that heparin administration in
experimental acute pancreatitis improved both pancreatic
microcirculation and the inflammatory response (reduction in
leukocyte-endothelium interaction).74,75 Moreover, anticoagulant treatment with heparin seems to reduce platelet
entrapment in the lungs during acute pancreatitis.76 On the
other hand, the role of heparin in postYendoscopic retrograde
cholangiopancreatography (ERCP) pancreatitis is still
unclear.77,78 There is also evidence that the use of diclofenac
(a nonsteroidal anti-inflammatory drug) is beneficial postERCP.79 Until now, the effect of prostaglandins on the
pathogenesis of acute pancreatitis seems to be undefined.
Prostaglandins can protect the pancreas from acute damage,80
but they can also increase the incidence of hemorrhagic
pancreatitis through increased vascular permeability.81 Thus,
the role of cyclooxygenase inhibitors, which reduce the
synthesis of prostaglandins, remains controversial. Aspirin
therapy seems to reduce the deposition of fibrinogen in the
lungs but not that of platelets after acute pancreatitis.76
However, aspirin may also increase calcium secretion,
inducing pancreatic damage.82 An anti-TF monoclonal antibody, having been clinically tested in sepsis with not much
success, still remains to be evaluated in acute pancreatitis.83
Moreover, tifacogin (recombinant TFPI), which was suggested to be beneficial in treating patients with sepsis and low

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international normalized ratio, might prove useful in controlling the rapid extrapancreatic tissue damage associated with
acute pancreatitis.66,84 Finally, resveratrol has been shown to
inhibit the induction of TF expression in endothelial and
mononuclear cells.85

CONCLUSIONS
Coagulation abnormalities are related to the severity of
acute pancreatitis. Hemostatic disorders may range from
scattered intravascular thrombosis to DIC. Pancreatic
enzymes and inflammatory mediators released from the
damaged pancreas may convert a single-organ disease to a
multiple-organ disease. Platelet count and activity, D-dimer
and fibrinogen levels, and prothrombin time may prove useful
in the evaluation of disease progression. Modulating
hemostasis may provide a therapeutic target for the prevention or treatment of acute pancreatitis. This option deserves
further research.
REFERENCES
1. Bhatia M, Wong FL, Cao Y, et al. Pathophysiology of acute pancreatitis.
Pancreatology. 2005;5:132Y144.
2. Dominguez-Munoz JE, Viedma JA, Perez-Mateo M, et al. Inflammatory
response in the initial phase of acute pancreatitis: relationship to the
onset and severity of the disease. Rev Esp Enferm Dig. 1995;87:225Y246.
3. McKay CJ, Buter A. Natural history of organ failure in acute pancreatitis.
Pancreatology. 2003;3:111Y114.
4. Imrie CW. Acute pancreatitis: overview. Eur J Gastroenterol Hepatol.
1997;9:103Y105.
5. Bhatia M. Novel therapeutic targets for acute pancreatitis and associated
multiple organ dysfunction syndrome. Curr Drug Targets Inflamm
Allergy. 2002;1:343Y351.
6. Rinderknecht H. Fatal pancreatitis, a consequence of excessive leukocyte
stimulation? Int J Pancreatol. 1988;3:105Y112.
7. Bhatia M, Saluja AK, Hofbauer B, et al. Neutral endopeptidase
(NEP) plays an anti-inflammatory role in acute pancreatitis and
pancreatitis-associated lung injury. Pancreas. 1997;15:428.
8. Algul H, Tando Y, Schneider G, et al. Acute experimental pancreatitis
and NF-kappaB/Rel activation. Pancreatology. 2002;2:503Y509.
9. Granger J, Remick D. Acute pancreatitis: models, markers, and
mediators. Shock. 2005;24(suppl 1):45Y51.
10. Ranson JH, Lackner H, Berman IR, et al. The relationship of coagulation
factors to clinical complications of acute pancreatitis. Surgery.
1977;81:502Y511.
11. Agarwal N, Pitchumoni CS. Acute pancreatitis: a multisystem disease.
Gastroenterologist. 1993;1:115Y128.
12. Bockman DE, Buchler M, Beger HG. Ultrastructure of human acute
pancreatitis. Int J Pancreatol. 1986;1:141Y153.
13. Jacobs RM, Murtaugh RJ, Fertel RH. Platelet function in experimentally
induced pancreatitis in the dog. Thromb Haemost. 1986;55:197Y200.
14. Lukaszyk A, Bodzenta-Lukaszyk A, Gabryelewicz A, et al. Does acute
experimental pancreatitis affect blood platelet function? Thromb Res.
1989;1:319Y325.
15. Feldman BF, Attix EA, Strombeck DR, et al. Biochemical and
coagulation changes in a canine model of acute necrotizing pancreatitis.
Am J Vet Res. 1981;42:805Y809.
16. Kerekes L, Arkossy P, Altorjay I, et al. Evaluation of hemostatic changes
and blood antioxidant capacity in acute and chronic pancreatitis.
Hepatogastroenterology. 2001;48:1746Y1749.
17. Redha F, Uhlschmid G, Ammann RW, et al. Injection of microspheres
into pancreatic arteries causes acute hemorrhagic pancreatitis in the rat: a
new animal model. Pancreas. 1990;5:188Y193.
18. Lasson A, Ohlsson K. Consumptive coagulopathy, fibrinolysis and
protease-antiprotease interactions during acute human pancreatitis.
Thromb Res. 1986;41:167Y183.
19. Aasen AO, Kierulf P, Ruud TE, et al. Studies on pathological plasma
proteolysis in patients with acute pancreatitis. A preliminary report. Acta
Chir Scand Suppl. 1982;509:83Y87.

* 2007 Lippincott Williams & Wilkins

Copyr ight Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Pancreas

& Volume 34, Number 1, January 2007

20. Radenkovic D, Bajec D, Karamarkovic A, et al. Disorders of hemostasis


during the surgical management of severe necrotizing pancreatitis.
Pancreas. 2004;29:152Y156.
21. Salomone T, Tosi P, Palareti G, et al. Coagulative disorders in human
acute pancreatitis: role for the D-dimer. Pancreas. 2003;26:111Y116.
22. Mimidis K, Papadopoulos V, Kotsianidis J, et al. Alterations of platelet
function, number and indexes during acute pancreatitis. Pancreatology.
2004;4:22Y27.
23. Lechin F, van der Dijs B. Platelet aggregation, platelet serotonin and
pancreatitis. JOP. 2004;5:237Y238.
24. Barradas MA, Mikhailidis DP. Serotonin, histamine and platelets in
vascular disease with special reference to peripheral vascular disease.
Braz J Med Biol Res. 1992;25:1063Y1076.
25. Prinz RA, Fareed J, Rock A, et al. Platelet activation by human
pancreatic fluid. J Surg Res. 1984;37:314Y319.
26. De Clerck F, David JL, Janssen PA. Inhibition of
5-hydroxytryptamineYinduced and Yamplified human platelet
aggregation by ketanserin (R 41468), a selective 5-HT2-receptor
antagonist. Agents Actions. 1982;12:388Y397.
27. Hara H, Osakabe M, Kitajima A, et al. MCI-9042, a new antiplatelet
agent is a selective S2-serotonergic receptor antagonist. Thromb
Haemost. 1991;65:415Y420.
28. Marcus AJ. Platelet aggregation. In: Coleman RW, Hirsch J, Marder VJ,
et al, eds. Hemostasis and Thrombosis Basic Principles and Clinical
Practice. Philadelphia, PA: Lippincott; 1982;380Y389.
29. Oguchi H, Terashima M, Koiwai T, et al. Effects of the S2-serotonergic
receptor antagonist, ketanserin, on cerulein-induced pancreatitis in the
rat. Life Sci. 1992;50:733Y737.
30. Yoshino T, Yamaguchi I. Possible involvement of 5-HT2 receptor
activation in aggravation of diet-induced acute pancreatitis in mice.
J Pharmacol Exp Ther. 1996;283:1495Y1502.
31. Ogawa T, Sugidachi A, Tanaka N, et al. Effects of R-102444 and its
active metabolite R-96544, selective 5-HT2A receptor antagonists, on
experimental acute and chronic pancreatitis: additional evidence for
possible involvement of 5-HT2A receptors in the development of
experimental pancreatitis. Eur J Pharmacol. 2005;521:156Y163.
32. Huval WV, Lelcuk S, Shepro D, et al. Role of serotonin in patients with
acute respiratory failure. Ann Surg. 1984;200:166Y172.
33. Lindstrom O, Kylanpaa L, Mentula P, et al. Upregulated but insufficient
generation of activated protein C is associated with development of
multiorgan failure in severe acute pancreatitis. Crit Care. 2006;10:R16.
34. Mimidis K, Papadopoulos V, Kartasis Z, et al. Assessment of platelet
adhesiveness and aggregation in mild acute pancreatitis using the
PFA-100 system. JOP. 2004;5:132Y137.
35. Johnson CD. Platelet-activating factor and platelet-activating factor
antagonists in acute pancreatitis. Dig Surg. 1999;16:93Y101.
36. Formela LJ, Galloway SW, Kingsnorth AN. Inflammatory mediators in
acute pancreatitis. Br J Surg. 1995;82:6Y13.
37. Kald B, Kald A, Ihse I, et al. Release of platelet-activating factor in acute
experimental pancreatitis. Pancreas. 1993;8:440Y442.
38. Anderson BO, Bensard DD, Harken AH. The role of platelet activating
factor and its antagonists in shock, sepsis and multiple organ failure.
Surg Gynecol Obstet. 1991;172:415Y424.
39. Bedirli A, Gokahmetoglu S, Sakrak O, et al. Beneficial effects of
recombinant platelet-activating factor acetylhydrolase and BN 52021 on
bacterial translocation in cerulein-induced pancreatitis. Eur Surg Res.
2004;36:136Y141.
40. Hofbauer B, Saluja AK, Bhatia M, et al. Effect of recombinant
platelet-activating factor acetylhydrolase on two models of experimental
acute pancreatitis. Gastroenterology. 1998;115:1238Y1247.
41. Whittaker M, Askew M, Beauchamp CL. Structure-activity relationships
for BB-823 and related PAF-antagonists. J Lipid Mediators Cell Signal.
1994;10:151Y152.
42. McKay CJ, Curran F, Sharples C, et al. Prospective placebo-controlled
randomized trial of lexipafant in predicted severe acute pancreatitis.
Br J Surg. 1997;84:1239Y1243.
43. Toh SKC, the British Acute Pancreatitis Study Group. Lexipafant, a
platelet activating factor (PAF) antagonist reduces mortality in a
randomized placebo controlled study in patients with severe acute
pancreatitis. Gut. 1997;40(suppl):A12.
44. Johnson CD, Kingsnorth AN, Imrie CW, et al. Double blind, randomised,
placebo controlled study of a platelet activating factor antagonist,

Coagulation, Platelets, and Acute Pancreatitis

45.
46.
47.
48.
49.

50.

51.
52.

53.
54.
55.
56.

57.
58.
59.
60.
61.
62.
63.
64.
65.

66.

67.

68.
69.

lexipafant, in the treatment and prevention of organ failure in predicted


severe acute pancreatitis. Gut. 2001;48:62Y69.
Abu-Zidan FM, Windsor JA. Lexipafant and acute pancreatitis: a critical
appraisal of the clinical trials. Eur J Surg. 2002;168:215Y219.
Kaska M, Pospisilova B, Slizova D. Pathomorphological changes in
microcirculation of pancreas during experimental acute pancreatitis.
Hepatogastroenterology. 2000;47:1570Y1574.
Hackert T, Pfeil D, Hartwig W, et al. Platelet function in acute
experimental pancreatitis induced by ischaemia-reperfusion. Br J Surg.
2005;92:724Y728.
Sakorafas GH, Tsiotou AG. Etiology and pathogenesis of acute
pancreatitis: current concepts. J Clin Gastroenterol. 2000;30:343Y356.
Gao HK, Zhou ZG, Chen YQ, et al. Expression of platelet endothelial
cell adhesion moleculeY1 between pancreatic microcirculation and
peripheral circulation in rats with acute edematous pancreatitis.
Hepatobiliary Pancreat Dis Int. 2003;2:463Y466.
Gao HK, Zhou ZG, Han FH, et al. Differences in platelet endothelial cell
adhesion moleculeY1 expression between peripheral circulation and
pancreatic microcirculation in cerulein-induced acute edematous
pancreatitis. World J Gastroenterol. 2005;11:661Y664.
Inoue K, Hirota M, Kimura Y, et al. Further evidence for endothelin as an
important mediator of pancreatic and intestinal ischemia in severe acute
pancreatitis. Pancreas. 2003;26:218Y223.
Andrzejewska A, Dlugosz JW. The endothelin-1 receptor antagonists
ameliorate histology and ultrastructural alterations in the pancreas and
decrease trypsinogen activation in severe taurocholate pancreatitis in
rats. Int J Exp Pathol. 2003;84:221Y229.
Jagroop IA, Daskalopoulou SS, Mikhailidis DP. Endothelin-1 and human
platelets. Curr Vasc Pharmacol. 2005;3:393Y399.
Ma ZH, Ma QY. Resveratrol: a medical drug for acute pancreatitis.
World J Gastroenterol. 2005;11:3171Y3174.
Olas B, Wachowicz B, Saluk-Juszczak J, et al. Effect of resveratrol, a
natural polyphenolic compound, on platelet activation induced by
endotoxin or thrombin. Thromb Res. 2002;15:141Y145.
Shigematsu S, Ishida S, Hara M, et al. Resveratrol, a red wine constituent
polyphenol, prevents superoxide-dependent inflammatory responses
induced by ischemia/reperfusion, platelet-activating factor, or oxidants.
Free Radic Biol Med. 2003;34:810Y817.
Wallerath T, Deckert G, Ternes T, et al. Resveratrol, a polyphenolic
phytoalexin present in red wine, enhances expression and activity of
endothelial nitric oxide synthase. Circulation. 2002;106:1652Y1658.
Foulis AK. Morphological study of the relation between accidental
hypothermia and acute pancreatitis. J Clin Pathol. 1982;35:1244Y1248.
Mikhailidis DP, Hutton RA, Dandona P. Effect of cooling on
prostaglandin mediated inhibition of platelet aggregation. Clin Sci.
1981;61:28.
Mikhailidis DP, Hutton RA, Jeremy JY, et al. Hypothermia and
pancreatitis. J Clin Pathol. 1983;36:483Y484.
Jeremy JY, Mikhailidis DP, Dandona P. Simulating the diabetic
environment modifies in vitro prostacyclin synthesis. Diabetes.
1983;32:217Y221.
Mikhailidis DP, Ganotakis ES. Plasma albumin and platelet function:
relevance to atherogenesis and thrombosis. Platelets. 1996;7:125Y137.
Penner JA. Disseminated intravascular coagulation in patients with
multiple organ failure of non-septic origin. Semin Thromb Hemost.
1998;24:45Y52.
Carey MJ, Rodgers GM. Disseminated intravascular coagulation:
clinical and laboratory aspects. Am J Hematol. 1998;59:65Y73.
Satake K, Ha S, Hiura A, et al. Effect of a synthetic protease inhibitor
(Fut-175) on coagulation abnormalities during experimental acute
pancreatitis in dogs. Gastroenterol Jpn. 1990;25:720Y726.
Moberg L, Johansson H, Lukinius A, et al. Production of tissue factor by
pancreatic islet cells as a trigger of detrimental thrombotic reactions in
clinical islet transplantation. Lancet. 2002;360:2039Y2045.
Beuneu C, Vosters O, Movahedi B, et al. Human pancreatic duct cells
exert tissue factor-dependent procoagulant activity. Diabetes.
2004;53:1407Y1411.
Hirota M, Sugita H, Maeda K, et al. The concept of SIRS and severe
acute pancreatitis. Nippon Rinsho. 2004;62:2128Y2136.
Bogdanov VY, Balasubramanian V, Hathcock J, et al. Alternatively
spliced human tissue factor: a circulating, soluble, thrombogenic protein.
Nature Med. 2003;9:458Y462.

* 2007 Lippincott Williams & Wilkins

Copyr ight Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

19

Pancreas

Kakafika et al

70. Versteeg HH. Tissue factor as an evolutionary conserved cytokine


receptor: implications for inflammation and signal transduction. Semin
Hematol. 2004;1(suppl 1):168Y172.
71. Papadopoulos V, Tsangaris I, Giaglis S, et al. The pattern of F3 gene
expression in human sepsis [abstract]. In: 9th State-of-the-Art
Interdisciplinary Review Course on Pulmonary Diseases, Critical Care,
Emergency Medicine and Nursing Care; April 22Y24, 2005; Athens.
72. Price GC, Thompson SA, Kam PCA. Tissue factor and tissue factor
pathway inhibitor. Anaesthesia. 2004;59:483Y492.
73. Gando S, Kameue T, Matsuda N, et al. Imbalances between the levels of
tissue factor and tissue factor pathway inhibitor in ARDS patients.
Thromb Res. 2003;109:119Y124.
74. Dobosz M, Mionskowska L, Hac S, et al. Heparin improves organ
microcirculatory disturbances in caerulein-induced acute pancreatitis in
rats. World J Gastroenterol. 2004;10:2553Y2556.
75. Dobosz M, Wajda Z, Hac S, et al. Heparin and nitric oxide treatment in
experimental acute pancreatitis in rats. Forum (Genova). 1998;8:303Y310.
76. Goulbourne IA, Watson H, Davies GC. 111In-platelet and
125I-fibrinogen deposition in the lungs in experimental acute
pancreatitis. J Surg Res. 1987;43:521Y526.
77. Rabenstein T, Fischer B, Wiessner V, et al. Low-molecular-weight
heparin does not prevent acute post-ERCP pancreatitis. Gastrointest
Endosc. 2004;59:606Y613.
78. Hackert T, Werner J, Gebhard MM, et al. Effects of heparin in

20

79.
80.

81.
82.
83.
84.

85.

& Volume 34, Number 1, January 2007

experimental models of acute pancreatitis and post-ERCP pancreatitis.


Surgery. 2004;135:131Y138.
Murray B, Carter R, Imrie C, et al. Diclofenac reduces the incidence of
acute pancreatitis after endoscopic retrograde
cholangiopancreatography. Gastroenterology. 2003;124:1786Y1791.
Jaworek J, Bonior J, Tomaszewska R, et al. Involvement of
cyclooxygenase-derived prostaglandin E2 and nitric oxide in the
protection of rat pancreas afforded by low dose of lipopolysaccharide.
J Physiol Pharmacol. 2001;52:107Y126.
Harvey MH, Wedgwood KR, Reber HA. Vasoactive drugs,
microvascular permeability, and hemorrhagic pancreatitis in cats.
Gastroenterology. 1987;93:1296Y1300.
Mentes A, Batur Y, Bayol U. Salycylate-induced pancreatic injury in
the cat: a preliminary study. Rom J Gastroenterol. 2002;11:309Y312.
Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign
guidelines for management of severe sepsis and septic shock. Intensive
Care Med. 2004;30:536Y555.
Abraham E, Reinhart K, Opal S, et al, OPTIMIST Trial Study Group.
Efficacy and safety of tifacogin (recombinant tissue factor pathway
inhibitor) in severe sepsis: a randomized controlled trial. JAMA.
2003;290:256Y258.
Pendurthi UR, Meng F, Mackman N, et al. Mechanism of
resveratrol-mediated suppression of tissue factor gene expression.
Thromb Haemost. 2002;87:155Y162.

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