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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
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Kakafika et al
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.
16
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
* 2007 Lippincott Williams & Wilkins
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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
18
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.
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