Comp Haematol Int (1995) 5:213-226
9 1995 Springer-Verlag London Limited
COMPARATIVE
HAEMATOLOGY
INTERNATIONAL
Review Article
Disseminated Intravascular Coagulation: Present and Future
Perspective
R. R. de G o p e g u i 1, H. B. Suliman 2 and B. F. Feldman 2
~Faculty of Veterinary Medicine, Department of Pathology and Animal Production, Autonomous University of Barcelona, Barcelona, Spain;
and 2Comparative Hemostasis Laboratory, Department of Biomedical Sciences and Pathobiology, Virginia Maryland Regional College of
Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
Introduction
Terminology
The haemostatic response could be considered a defensive function: it prevents or avoids blood loss from
damaged vasculature (haemorrhage) and ensures
adequate blood flow, maintaining the vascular tree free
of obstruction (thrombosis). Procoagulant activity
(inactive haemostatic proteins) is modulated or
inhibited by several mechanisms. Endothelial cells play
a key role in the control of these functions. The
adequate equilibrium between activation and inhibition
of haemostasis depends on interactions between
endothelial cells, platelets, circulating blood cells,
coagulation activators and inhibitors.
Disseminated intravascular coagulation (DIC) may
represent loss of haemostatic equilibrium - induced by
numerous clinical entities - resulting in life-threatening
consequences.
This review summarises the data recently obtained
concerning the aetiology, pathophysiology, clinical
findings and laboratory diagnostics as regards DIC.
Current and future DIC diagnostic and treatment
modalities are discussed. It should be realised at the
outset that disease presents differently among a continuum of events. Patients may undergo DIC anywhere
in this continuum and, depending on the position in the
continuum, exhibit radically different clinical and
laboratory effects.
Disseminated intravascular coagulation (DIC), is also
known as consumptive coagulopathy, an inappropriate
descriptor because, although some coagulation proteins
(factors and inhibitors) are consumed, many factors and
other plasma constituents are biodegraded by plasmin
(Jandl 1991). Another descriptor, defibrination syndrome, would be more appropriately retitled 'defibrinogenation syndrome', because fibrinogen is both
consumed and biodegraded. Therefore, the term disseminated intravascular coagulation is given preference
- it describes the dynamic process of disseminated
coagulation taking place intravascularly - expressed as
both haemorrhage and thrombosis (Feldman 1981;
Slappendel 1988b). DIC is obviously expressed by
haemorrhagic diatheses. But, DIC is also associated
with diffuse thrombosis (and is sometimes called diffuse
intravascular thrombosis; DIT) leading to impairment
of blood rheology, ischaemia and multiorgan failure,
perhaps causing irreversible damage and, ultimately,
patient mortality.
Correspondence and offprint requests to: Dr B. F. Feldman, Comparative Hemostasis Laboratory, Department of Biomedical Sciences
Virginia Maryland Regional College of Veterinary Medicine, Virginia
Polytechnic Institute, Blacksburg, VA 24061--0442, USA.
Aetiology
DIC is associated with numerous clinical conditions
(Table 1). Depending on the activation rate of the
haemostatic system, DIC may occur as an acute and lifethreatening event or as a chronic form without severe
thrombosis and haemorrhage. DIC may be initiated by
a single cause or by multiple causes occurring sequentially or simultaneously. The anticipated events inducing DIC - in most conditions - are related to:
214
R . R . de Gopeguiet al.
Table 1. Conditions associated with disseminated intravascular
coagulation
A. Intravascular haemolysis
Haemolytic transfusion reactions
Haemolytic anemia
B. Septicaemia (Table 2)
Gram negative (endotoxin)
Gram positive (bacterial coat
mucopolysaccharide)
C. Viraemia (Table 2)
D. Parasitic infections
P,totozoal infection
Metazoal infection
E. Obstetric complications
G. Malignancy (Table 3)
H. Massive tissue injury
Trauma
Burns
Surgical procedures
Heat stroke
I. Venoms and Toxins
Snake bite
Bee/insect sting
Aflatoxin (see J.)
J. Liver disease
K. Pancreatitis
F. Miscellaneous
Gastric dialtation/volvulus
Diabetes mellitus
1. Tissue factor (TF) or thromboplastin-like substances
liberated into the circulation;
2. Damaged endothelia/monocytes converting procoagulants into active forms (activated procoagulants);
3. Blood flow interruption preventing hemodilution of
activators;
4. Impaired removal of activated procoagulants by the
liver.
Table 2. Bacteria and viruses incriminated in disseminated intravascular coagulation
Bacteria a
Viruses b
Gram-negative bacteria
Escherichia coli
Pasteurella hemolytica
Pasteurella multocida
Salmonella species
Infectious canine hepatitis
Canine distemper
Canine herpes virus
Feline infectious peritonitis
Feline panleukopenia
Hog cholera
African swing fever
Blue tongue
Epizootic haemorrhage of deer
Fowl plague
Viral haemorrhagic disease of
rabbits
Gram-positive bacteria
Staphylococcus species
Streptococcus species
Clostridium species
Mycobacterium species
a Ellison et al. (1988), Kiper and Paulsen (1988), Isogai et al. (1989),
Bowersock et al. (1990), Braun et al. (1990), Kokosharov et al.
(1990), Stein and Libertin (1990), Morris (1991), Anderson et al.
(1992).
b Ward and Conway (1980), Howerth et al. (1988), Pan et al. (1988),
Greene (1990), Greene and Scott (1990), Huang (1991).
is accompanied by acidosis which may provide an
independent trigger for DIC (Bick 1985). However, the
clinical presentation is probably the summation of
several or all of these activation events.
Viruses
Intravascular Haemolysis
Intravascular haemolysis is a considerable trigger for
DIC. The acute haemolytic transfusion reaction represents a major DIC stimulus. The release of erythrocytic
adenosine diphosphate (ADP) and/or membrane phospholipoproteins may directly stimulate platelet aggregation and coagulation (Bick 1985; Borrego et al. 1991).
Even transfusion of autologous haemolysed blood was
found to cause decrease in factors X, VIII, fibrinogen
and to cause pulmonary arterial thrombosis in dogs
(Cotter 1992).
Infectious Agents
DIC has been reported in association with many
infectious agents (Table 2) including numerous Gramnegative and Gram-positive organisms (Stein and
Libertin 1990; Morris 1991). Bacterial coat lipopolysaccharide (LPS) released as a result of proliferation or
lysis of Gram-negative bacteria (endotoxin), has the
ability to initiate DIC (Warr et al. 1990) by direct
activation of endothelium, the contact system (the kinin
system and factors XII and XI), complement, leucocytes and platelets (Ewert et al. 1985; Moher 1988).
Gram-positive bacteria have mucopolysaccharide coats
which may induce DIC by the same mechanisms noted
with endotoxins. Septicaemia due to bacterial infection
Viruses responsible for triggering DIC may do so by
involvement in associated circulating antigen-antibody
complexes which activate the endothelium and possibly
the contact system. Viruses can also induce the platelet
release reaction (Bick 1985; Cosgriff 1989; Studdert
1994).
Parasitic Infections
Protozoal infections such as trypanosomiasis (Olubayo
and Mugera 1985; Suliman and Feldman 1989),
babesiosis (Krooshof et al. 1984; Blood and Radostits
1989), and sarcocystosis (Frelier and Lewis 1984;
Daugschies et al. 1989) may induce DIC.
Metazoal infection associated with DIC is exemplified by heartworms in dogs (Dillon and Braund 1982).
The vascular damage induced by these blood parasites
and the associated embolic phenomena causes release
of tissue thromboplastin, the key to triggering DIC in
heartworm patients (Kociba and Hathaway 1974;
Cooley et al. 1987).
Obstetric Complications
Obstetric complications commonly trigger DIC
(Seegers 1971). DIC may occur in association with
dystocia, eclampsia, Caesarean section, and retained
Disseminated Intravascular Coagulation (DIC)
fetal placenta (Dodds 1985; Braun et al. 1990). A
physiological potential hypercoagulable state has been
reported to be associated with parturition (Murano and
Bick 1980; Gentry et al. 1991). The proposed mechanisms that initiate DIC in obstetric complications
include: (1) the release of amniotic fluid (with activity
similar to thromboplastin, platelet factor 3 or phospholipoprotein into maternal circulation) (Lockwood et al.
1991; Parihar et al. 1991); (2) release of placental
enzymes or tissues with thromboplastin-like activity into
the maternal circulation (Bick 1985; Braun et al. 1990;
Wagner et al. 1990; Suchartwatnachai et al. 1991); and
(3) release of necrotic fetal tissue or enzymes (with
activation of the maternal haemostasis) into the maternal circulation (Angelov 1989; Bosner et al. 1989; Braun
et al. 1990).
Miscellaneous
DIC has been identified as an important complication
that affects both mortality and morbidity in gastric
dilatation-volvulus patients (Drazner 1982). The
damaged organs release large amounts of thromboplastins into the circulations; local acidosis may occur
leading to DIC (Hall 1972; Lippincott and Schulman
1989). Acidosis triggers DIC through sloughing of
endothelial cells and subsequent activation of the
contact system (Baker 1989).
In diabetic patients DIC may be initiated by injury of
the vascular endothelium (Bick 1979), peripheral capillary stasis (Bick 1982, 1985), microangiopathy, and
enhancement of platelet aggregation (Titova et al. 1989;
Barnett 1991).
Malignancy
Malignancy is reported as the underlying disease in 39%
of dogs diagnosed with DIC (Feldman et al. 1981).
Haemangiosarcoma, disseminated carcinomas, haematopoietic and lymphoreticular tumours are commonly
associated with DIC in small animals (Helfand 1988;
Hammer et al. 1991; Hargis and Feldman 1991). DIC
has been suggested as the major pathophysiological
mechanism underlying microangiopathic haemolytic
anaemia (MAHA) often associated with malignancy in
small animals (Helfand 1988; Slappendel 1988a). The
presence of large tumour burdens or tumours associated
with bone marrow, spleen or liver (specifically widespread infiltration - haemangiosarcoma, lymphosarcoma or leukaemia) are conditions associated with
MAHA in dogs (Madewell and Feldman 1980; Rebar et
al. 1980). There are five possible mechanisms that
trigger DIC in cancer patients and these are listed in
Table 3. Some cancer patients develop typical DIC with
secondary fibrinolysis and/or primary activation of
fibrinolysis that overwhelms the fibrinolytic inhibitor
response. In cancer patients, subclinical compensated
DIC is more common than either compensated DIC
215
Table 3. Mechanisms that incite disseminated intravascular coagulation in cancer patients
1. Stimulation of the coagulation cascade
(a) Cancer cells induce platelet activation and aggregation
(Hammer et al. 1991; Hargis and Feldman 1991; Suchartwatnachai et al. 1991).
(b) Cancer cells release thromboplastin and/or other procoagulant
factors (PCA) that enhance coagulation (Madewell and Feldman 1980 Helfand 1988; Slappendel 1988a).
(c) Cancer cells stimulate macrophages and monocytes to release
PCA factors (Rebar et al. 1980; Radomski et al. 1991).
(d) Cancer cells release a specific factor X activator, a cysteine
protease known as cancer PCA factor which is released by a
variety of malignant cells including breast, liver, renal and,
lung carcinomas, undifferentiated sarcomas, liposarcomas,
melanomas (Edwards et al. 1990; Spearman et al. 1991).
(e) Non-enzymatic activation of factor X by the sialic moiety of
mucin in mucinous adenocarcinomas (Mohanty et al. 1991).
2. Vascular damage by neoplastic growth or vascular damage of
vessels within neoplastic tissues might lead to exposure of subendothelial collagen (Rebar et al. 1980).
3. Enhancement of the haemostatic system by complications of
malignancy such as surgery, chemotherapy and sepsis (Rebar et al.
1980).
4. Decrease hepatic synthesis of antithrombin III (AT III), and
protein C in metastatic cancer (Gordon 1984; Clouse and Comp
1986; O'Keefe and Couto 1988; Lefrere et al. 1989; Roncaglioni et
al. 1989; Clauss et al. 1990; Irimura et al. 1990; Kubota et al. 1991).
5. Activation of the fibrinolytic cascade by a plasminogen activator
(urokinase-like) (Clauss et al. 1990) or a tissue-type plasminogen
activator released from some tumour cells (Jones et al. 1980; Giger
and Gorman 1984; Badenoch et al. 1986; Camiolo and Greco 1986;
Kapina et al. 1986; Duffy 1990; Reilly et al. 1991).
with thrombosis or uncompensated DIC leading to
haemorrhage (Madewell and Feldman 1980; Giger and
Gorman 1984). Haemorrhagic DIC has been seen with
various tumours including thyroid carcinoma, haemangiosarcoma, mammary carcinoma, intrathoracic
carcinoma, and adrenal tumour (Jones et al. 1980;
Green 1981; O'Keefe and Couto 1988). In contrast to
humans, DIC appears to be uncommon in dogs with
leukaemia. It has been suggested that DIC may
complicate leukaemia in cats (Kobilinsky et al. 1979;
Jacobse-Geels et al. 1980).
Traumatic Shock
Traumatic shock is a well-recognised cause of DIC
(Hardaway 1981; Ordog and Wasserberger 1986).
Thromboplastic substances are released from traumatised tissue into the circulation, precipitating the development of DIC. In addition, the decreased flow of
capillary blood induced by hypovolaemia is a contributing factor (Hardaway 1980a,b). Clinical and laboratory
evidence indicate that the passage of blood through
traumatised tissue causes erythrocyte lysis triggering
coagulation (Hardaway and Williams 1987, 1990). The
release of cellular enzymes in combination vasoactive
substances already in the circulation also contribute to
216
the induction and perpetuation of DIC (Hardaway
1980a; Ordog and Wasserberger 1986; Hardaway and
Williams 1990). As the fibrinolytic system is also
activated both microthrombi and haemorrhage may be
observed (Hardaway 1981).
DIC may occur subsequent to bone fracture and
fracture surgery. The direct release of large amounts of
lipids and tissue thromboplastin from fractured bones
into the circulation initiates hypercoagulability in some
patients (Buntain 1980; Raphael 1982). All surgical
procedures activate the haemostatic system. This is
especially true of prolonged abdominal surgical
procedures (Buntain 1980; Lipowitz 1985).
Thermal injuries are relatively uncommon in
domestic animals, especially large animals. Severely
affected patients commonly develop DIC, with several
mechanisms operative (Johnston 1985; Iashvili et al.
1986; Ono 1987). DIC in burned animals presumably
results from both haemolysis and tissue necrosis and
release of tissue components, cellular enzymes, and
phospholipoprotein-like materials into the circulation
(Bick 1982). The aetiology of DIC in the early stages
after thermal injury remains unclear. However, massive
thrombin generation and decrease of anticoagulant
activity, mainly antithrombin III (ATIII) concentrations, have been observed (Goodwin 1989; Ueyama et
al. 1991).
Heat stroke can directly provoke DIC by widespread
vascular and tissue damage (Drazner 1982; Holman and
Schneider 1989).
Liver Disease
Development of DIC is a common event in severe
hepatopathy in dogs and cats (Green 1989). Impairment
of hepatic synthesis of coagulation proteins or impaired
hepatic clearance functions may manifest as thrombotic,
fibrinolytic or haemorrhagic complications (Hersch et
al. 1987; Green 1989). The enhanced plasmin generation noted in liver disease promotes activation of the
kinin system causing hypotension, shock and end-organ
damage, as well as biodegradation of coagulation
factors by plasmin (Kaplan and Silverberg 1987).
Failure of clearance of fibrin(ogen) degradation
products (FDPs) by the diseased liver will allow FDPs
to further impair fibrin polymerisation and platelet
aggregation (Drazner 1982). Ingestion of aflatoxin
contaminated dog food has been reported to cause DIC
(Hagiwara et al. 1990). The resultant severe hepatocellular degeneration and necrosis is sufficient to initiate
DIC through extensive release of tissue thromboplastin
(Baker and Green 1987).
Venoms and Toxins
Snake venoms contain enzymes that may trigger
haemostasis in unique ways. Venoms contain thrombinlike enzymes or substances that specifically activate
R. R. de Gopeguiet al.
factor X (Bothrops atrox) or factor II (Wintrobe et al.
1981). Echis carinatus venom was found to rapidly
induce DIC in mongrel dogs by direct activation of
prothrombin (Schaeffer et al. 1986). The venom of
Pseudonaja textilis textilis - an Australian snake contains prothrombinase. This converts prothrombin
into cr-thrombin directly, resulting in fibrinogen degradation (Masci et al. 1990). Crude venoms also contain
substances that act as thromboplastins and produce
intravascular red cell lysis and massive vascular endothelial damage (Wintrobe et al. 1981). Hymenoptera
(bees, wasps and hornets) stings in dogs result in acute
DIC which can be fatal, or more chronic forms of DIC
(Cowell et al. 1991). DIC is initiated by Hymenoptera
venom which includes components such as phospholipase A, histamine, acetylcholine, serotonin and kinins.
Pancreatitis
Pancreatitis may trigger DIC by activation of trypsin,
kallikrein (KK) and phospholipase A2 in the pancreatic
(and surrounding) tissue (Uehara et al. 1989; Williams
1989). These enzymes have thrombin-like activity or
factor Xa-like activity which results in activation of the
haemostatic system and DIC. The release of leucocyte
elastase during pancreatitis has the capacity to degrade
plasma proteins such as o:2-antiplasmin, ATIII and
factor XIII. This protein degradation may cause more
tissue damage and can further potentiate DIC (Axelsson et al. 1990).
Pathophysiology (Fig.
1)
Disseminated intravascular coagulation may be considered an uncontrolled burst of thrombin generation
and activity. This massive activation overwhelms
haemostatic inhibitors, depletes procoagulants and
platelets, induces thrombosis, and as a final result
tissues are severely damaged. Thrombus formation and
subsequent ischaemia and necrosis may activate an
enhanced fibrinolytic response which would impair
platelet function and deplete coagulation factors
(Schrier 1993).
The inflammatory response has important interactions with haemostasis, may activate haemostasis or
impair its inhibition. Recent studies, have described
some of these interactions.
1. Neutrophil activation and degranulation liberates
lactoferrin, a prominent component of neutrophil
secondary granules. Lactoferrin is an iron-binding
protein and thus has a physiological role in the regulation of inflammation and other host defence mechanisms. Lactoferrin has potent heparin-neutralising
activity during thrombin inhibition by serine proteinase
inhibitors ATIII and heparin cofactor II. It has been
observed that specific inflammatory mediators as
tumour necrosis factor-or (TNF-o0 increased the concentration of both platelet factor 4 (PF-4), which inhibits
217
Disseminated IntravascularCoagulation (DIC)
Kininogen
]
a f -
Prekallikrein
Endothelial
Dama*~
,d
"~i.
A~,-~*
I~
Cor
,lexv
~--
Collag en
l
(Factor Xala)**
Thromboplastin J
X
-'~-'-'~"
hosp~holi
pld///~~
I
Hageman Factor ~
t
t'
~
Plasmmogen
Thrombm
I
Factor XIII
f
"~
~ | rlasmm } ~ / ~ o m p i e m e n t
"
]
~l~
T/ ' . I .
t~ radykinin.)
I
~ Xa
~
/
Kall~krein/
~
.,,WFactorY.
I
Tieing,h.m~*~, ~
Damage Damage
~
v
Activated
Fibrinogen
] "
Fib .
Mono~
J
|
N
i
FDP,..~
l
~_ Activation.J
_ Pol me. A
~
Fibrin ~
D-dimer
~ Factor X I I I a ~
Fig. 1. Pathophysiologyof disseminated intravascularcoagulation (DIC). * Antigen-antibody complex; **Activated factor; ***Fibrin(ogen)
Degradation Products.
heparin, as well as plasma lactoferrin (Wu et ai. 1995).
Activated neutrophils adhere to endothelium and
release elastase which cleaves and may inactivate
thrombomodulin (TM) (Esmond 1994). Platelet
aggregation may be induced by activated neutrophils,
mediated by platelet activating factor-acether (PAFacether). PAF is a phospholipid produced by vascular
endothelium, platelets and monocytes (Nguyen et al.
1995).
2. The cytokines TNF-o: and interleukin 1 (IL-1), may
initiate the endothelial expression of adhesion molecules (one of which is E-selectin; others have yet to be
identified) that bind monocytes and neutrophils. Pselectin requires thrombin activation to be mobilised
from endothelial Weibel-Palade bodies. This fact may
involve platelet adhesion to endothelial cells and monocytes, and could serve as a focal point to amplification
reactions involved in thrombin generation (Edmond
1994).
3. Complement terminal components C5b-9, induce a
procoagulant activity in platelets. Coagulation factors
can adhere to negatively charged phospholipids such as
phosphatidylserine, which normally, is not exposed on
the surface of inactivated platelets. It is suggested that
platelet activation may induce membrane vesiculation
and formation of microparticles. This may be considered a critical component of prothrombin activation
(Esmond 1994; Sandberg et al. 1985).
The contact system includes factors XII (FXII) and
XI (FXI) and the kinins. Activation of the contact
system occurs through contact with negatively charged
surfaces, cerebroside sulphates, glycosaminoglycans,
plasmin, hypersensitivity/anaphylactic reactions, and
lipid A component of endotoxins (Wachtfogel et al.
1993). The consequences are:
1. Coagulation factors VII and XI are activated (by
FXIIa);
2. Complement fraction C1 is activated (by FXIIa);
3. Prourokinase and plasminogen are activated by
FXIIa and kallikrein;
4. Neutrophils are activated by FXIIa and kallikrein;
5. Kininogens increased the activation of FXI, but
inhibit cellular adhesion to endothelium (monocytes,
neutrophils and platelets). In addition, bradykinin
increases vascular permeability and hypotension.
Endothelial cells and monocytes may express tissue
factor when these cells are exposed to endotoxins, IL-1
and TNF (Esmond 1994). The formation of factor VIITF complexes induces factor X and factor IX activation.
The inhibitory activity of tissue factor pathway inhibitor
(TFPI) may possibly be overwhelmed if TF exposure is
extensive. Furthermore, the experiment administration
of human recombinant TFPI in animal models of endotoxin-induced shock reduced mortality. The inhibitory
activity of TFPI on inflammatory response is also
suggested because lower concentrations of IL-6, were
found in these animals (Taylor 1994; Petersen et al.
1995).
Endothelial damage caused by circulating antigenantibody complexes, endotoxaemia, or other forms of
tissue damage can change the endothelial cell anticoagulant phenotype. This results in a massive procoagulant fibrinolytic counterattack on the luminal side
of the endothelial cell through the expression of TF and
release of tissue plasminogen activator (tPA) (Taylor
1994). Trauma and haemolysis may also liberate TF into
218
the circulation (Mant and King 1979; Slappendel 1988b;
Muller 1989; Nakamura et al. 1990). When one of these
insults occurs, there are many potential elements for
uncontrolled generation of circulating thrombin and
plasmin. Circulation of these two enzymes systematically may be considered DIC. Despite the differing
activation pathways by which thrombin and plasmin are
generated, the resultant pathophysiology of DIC
basically remains the same (Mant and King 1979;
Slappendel 1988b).
Thrombin activates the protein Cpathway. The early
activation of protein C (and subsequent consumption)
in-sepsis has been observed in human patients. Thrombin bound to TM - an endothelial cell surface receptoractivates protein C, and results in feedback inhibition of
thrombin (thrombin loses its coagulant effect). Activated protein C (APC) bound to the cofactor protein S,
cleaves FVa and FVIIIa. Protein S circulates free or
bound to C4b binding protein (C4bBP), an inhibitor of
complement (and at the same time an inhibitor of the
protein C pathway). Activated PC is inhibited by
protein C inhibitor (PCI) - a heparin-dependent
reaction - and a:l-antitrypsin. Protein C inhibitor also
binds KK. KK may also play a regulatory role in protein
C activity (Alcaraz et al. 1995). The effect of cytokines
on the protein C pathway has been studied, especially
related to septic shock. It has been observed that infants
with protein C deficiency may develop purpura fulminans. Patients with severe septic shock present with
similar cutaneous lesions which resemble this process
(Walsh et al. 1991). Thereafter, C4bBP behaves as an
acute phase reactant which can reduce free protein S
concentrations (Esmond 1994). Endotoxins and cytokines (IL-1 and TNF) also downregulate TM expression
(Edmond 1994). In conclusion, coagulation inhibition is
severely impaired potentiating thrombus formation.
Thrombin activates FV, FVIII:C and FXIII and
cleaves fibrinopeptides A and B from fibrinogen to yield
fibrin monomers. The monomers polymerise into fibrin
clots. This leads to microvascular and macrovascular
thrombosis and ensuing ischaemia and organ failure
(Muller 1989; Jandl 1991). Thrombin also binds
irreversibly to platelets promoting platelet adhesion to
endothelial cells, platelet aggregation, and induces
secretory release of platelet tr and dense granule contents (Nomura et al. 1991; Venturini and Kaplan 1992).
ADP and thromboxane A2 (TxA2) release will further
accelerate platelet aggregation causing amplification of
coagulation processes and thrombin generation. Platelets are trapped in micro- or macrothrombi. This results
in the clinical manifestations of thrombocytopenia
(Feldman 1981; Feldman et al. 1988; Jandl 1991).
Plasmin is generated by the enzymatic conversion of
circulating plasminogen (a proenzyme, synthesised by
kidneys, liver and eosinophils). Tissue PA is secreted by
injured endothelium and macrophages near the injured
area, and contact system activation also contributes to
plasmin generation. Plasmin is capable of hydrolysing
not only fibrin and fibrinogen but also other proteins
such as factors V, VIII, IX, XI, insulin, ACTH, casein
R. R. de Gopegui et al.
and gelatin (Muller 1989; Jandl 1991). Digestion of
fibrinogen by plasmin results in fibrin(ogen) degradation products (FgDP) composed of fragments X, Y,
D and E (Muller 1989). FDPs in the circulation interfere
with fibrin monomer polymerisation (basically by
inhibiting fibrin polymerisation and blocking the
receptor sites of fibrinogen on thrombin) causing
further amplification of fibrinolysis, impairment of
haemostasis and, resultant haemorrhage (Feldman
1981; Muller 1989; Jandl 1991). Other FDPs (fragments
D and E) have high affinity for platelet membranes,
inducing platelet dysfunction through granule release
and platelet aggregation inhibition (Wintrobe et al.
1981). This contributes to clinical haemorrhage. Thus,
systemic release of FDPs in large quantities also contributes to some of the bleeding problems encountered
in patients with DIC. Plasmin is capable of activating
the complement system (C1 and C3), and contributes to
the activation of the contact system. Subsequent
neutrophil activation, red cells iysis, platelet activation
and/or lysis results (Muller 1989; Carroll et al. 1990;
Nomura et al. 1991). Damage to both red cells and
platelets provides more substrate in the form of procoagulant materials accentuating thrombocytopenia.
Activation of the complement system and BK affects
the endothelium, enhancing vascular permeability
ultimately leading to hypotension and shock.
In summary, inflammation activates haemostasis
through neutrophil activation (inducing platelet
aggregation, inactivation of heparin-dependent serine
proteases and the protein C pathway), monocyte
expression of TF, complement activation (inducing
platelet procoagulant activity) and cytokine release
(which induces endothelial TF expression and endothelial changes more receptive to coagulation).
Activation of the contact system has several consequences: coagulation activation, activation of
fibrinolysis, complement activation, neutrophil activation, and kinin activation. Kinin activation may
inhibit adhesion of neutrophils, monocytes and platelets
to endothelium, increasing vascular permeability.
If these activation mechanisms overwhelm haemostatic inhibitors and thrombin formation is uncontrolled,
thrombus formation is potentiated and subsequent
organ failure may develop.
Thrombus formation, contact system activation and
endothelial leasin (liberating tPA) all activate fibrinolysis. If plasmin activation is extensive, some coagulation
factors are severely depleted.
Clinical Findings
Although the classic presentation of DIC may include
fever, acidosis, hypoxaemia, proteinuria, bleeding,
shock and evidence of multiple organ failure (Bick 1985;
Slappendel 1988b), it is essential to note that there is
considerable variability in clinical findings. DIC can be
219
Disseminated Intravascular Coagulation (DIC)
acute or chronic depending on whether the underlying
illness is acute (decompensated DIC) or chronic (compensated DIC). The clinical manifestations may also
differ among diseases, from patient to patient, and even
chronologically in the same patient. Physical findings
that accompany microthrombosis-associated DIC are
associated with decreased organ perfusion. Renal
thrombosis leads to severe renal dysfunction, common
sequelae in horses with DIC (Carlson 1990). Gastrointestinal thrombosis results in acute colic secondary to
submucosal necrosis and ulceration, a severe complicating event in equine patients with primary
gastrointestinal disease. This results in spontaneous
gastrointestinal haemorrhage clinically expressed as
gross or occult faecal blood (Carlson 1990). In acute
DIC, bleeding may occur at puncture sites, intravenous
catheter sites, and surgical wounds (Bick 1982; Morris
1988; Carlson 1990). Large vessel bleeding sites are
particularly prone to haematoma formation. The resulting pressure on other vital tissues may compound the
clinical problem (Ampel et al. 1985). Prominent clinical
manifestations in horses are the tendencies to major
vessel thrombosis, especially after catheterisation, and
thrombosis of smaller cutaneous blood vessels
manifested by arborising subcutaneous 'cords' (Morris
1988). Melena or haematochezia are seen mostly in
ruminants and dogs with DIC (Slappendel 1988b;
Carlson 1990). Digital ischaemia, subsequent to microthrombosis, frequently accompanies DIC in horses and
plays a key role in the development of laminitis
(McClure and McClure 1982; Holland et al. 1986).
Pulmonary function may also be compromised by microvascular thrombosis in DIC, causing tachypnoea and
hypoxaemia. Cerebral microvascular thrombosis might
lead to altered consciousness, convulsion and/or coma
(Carlson 1990). Compensated DIC develops in patients
with illness that produces a low-grade or intermittent
procoagulant release stimulus. This allows longer time
periods during which consumed or degraded coagulants, anticoagulant proteins, and platelets may be
replenished. This compensated state may become
unbalanced by stress, concurrent diseases, or worsening
of the primary disease. Veterinary clinicians rarely see
patients in the early phases of DIC. Fulminant DIC is
more likely with resultant poor prognoses.
Laboratory Findings
Laboratory results vary according to the underlying
cause of DIC and the evolution of the process. Many
newer analytes have become available for evaluating
patients with DIC; however, many of these are not, as
yet, validated for veterinary use. The diagnosis of DIC
cannot be achieved with a single test result and it is not
possible to define which alterations are pathognomonic
for DIC. But, the tests described below are helpful to
diagnose DIC and to monitor therapy.
Red Cell Fragmentation
Schistocyte or fragmentocyte formation is usually
abundant in patients with low-grade DIC, but as only
occasionally seen in fulminant DIC. The presence of
fragmentocytes may also be seen in a variety of conditions such as M A H A , Heinz body anaemia, iron
deficiency, and may even be seen as spurious finding of
blood smear preparation (Slappendel 1988b).
Thrombocytopenia and~or Thrombopathia
The platelet count is typically decreased in DIC; though
the percentage decrease may be quite variable. Platelet
counts are often elevated as a non-specific inflammatory
response. Decreased platelet numbers may, therefore,
be relative. Platelet function tests including the
template bleeding time and platelet aggregation are
abnormal, as a late stage finding in patients with DIC.
Therefore, platelet function in DIC patients may be
variable (Bick 1988; Muller 1989). Increased platelet
turnover and decreased survival is common with DIC
patients; platelet factor 4, fl thromboglobulin, and TxA2
concentrations are markers of overall platelet reactivity
and release. These concentrations are usually elevated
in DIC patients (Bick 1988).
Tests of Secondary Haemostasis
The prothrombin time (PT) is anticipated to be prolonged in DIC for multiple reasons. The PT depends
upon the ultimate conversion of fibrinogen into fibrin.
In DIC there is usually consumption-induced hypofibrinogenaemia and increased FDPs, which interfere with
fibrin monomer polymerisation. Also lysis of factors V
(and numerous other factors) by plasmin could prolong
the PT. However, a PT within the reference interval in
DIC patients may be observed as the underlying process
progresses from peracute to acute; PT changes from a
shortened t e s t - activation of factors X and prothrombin
(II) - through the reference interval and, finally, becoming prolonged.
The activated partial thromboplastin time ( A P T f ) is
also anticipated to be prolonged in fulminant DIC
because of plasmin-induced biodegradation of coagulation factors. However, APTT may not be prolonged in
DIC patients for the same reasons mentioned above in
reference to PT.
Thrombin time (q'T) or Reptilase time, tests of the
final common coagulation pathway, are anticipated to
be prolonged in DIC. Both tests may be prolonged by
circulating FDPs and subsequent interference with
fibrin monomer polymerisation (Jandl 1991). Appropriate results for these tests can be observed in DIC
patients when FDP accumulations are a relatively late
happening.
Coagulation factor assays provide insufficient clinically useful information in patients with DIC (Feldman
R. R. de Gopeguiet al.
220
1981). Fibrinogen concentration is dramatically
decreased in patients with fulminant DIC (Feldman
1981). However, normal or elevated concentrations
may be seen in patients with early and compensated
DIC - where fibrinogen production exceeds degradation (McKay 1983). In addition, most of the underlying disease processes are actively inflammatory
(Feldman 1981; Slappendel 1988b). This results in
elevated concentrations of fibrinogen early in the
process. Fibrinogen concentration is not reliable for
diagnosis of DIC in horses, since horses rarely develop
hypofibrinogenaemia (Johnstone and Crane 1986).
However, return of fibrinogen concentration in other
species towards the reference interval may be the best
prognosticator of therapeutic success.
Thrombin Activation
Coagulation activation markers as thrombin-antithrombin III complexes (TAT) are widely used in
human medicine to observe thrombin activation in
hypercoagulable state (Asakura et al. 1991). ThrombinATIII complex determination has been performed in
veterinary medicine (Monreal et al. 1993).
Production of fibrinopeptide A is related to thrombin
activation. It is usually elevated in patients with DIC as
well as in a wide variety of other micro- or macrovascular thrombotic events. The test provides an overall
assessment of haemostasis activation indicating the
presence of thrombin-induced fibrinogen proteolysis.
Disappearance of fibrinopeptide A may aid in assessing
the efficicacy of therapy in DIC (Jensen and Ens 1991).
Determination of an effective test of prothrombin
activation markers - F1 + 2 fragments - was not shown
to be useful in rabbits (Monreal et al. 1993).
Soluble fibrin monomer (FM) - the complex of FDPs
and fibrin monomer - can be detected by protamine
gelation and agglutination tests. Positive results may
appear in patients with a variety of diseases which might
be associated with DIC but definite proof of DIC
diagnosis is still lacking. Therefore, the tests for FM are
valuable mainly as broad screening tests (Slappendel
1988b). Recently, an immunological assay was developed in human medicine which can directly quantify the
amount of soluble fibrin monomers (SF) formed in
blood. This study examined this assay system in the
diagnosis of DIC and found that it was a good indicator
for both fibrin formation and for DIC. It also correlated
well with serum levels of FDPs (Nakagawa et al. 1994).
ing human) or secondary as in DIC. FDP concentration
results are variable and inconsistent in cats (O'Rourke
et al. 1982). Canine patients with FDP concentrations of
10 #g/ml or more are considered to have increased
fibrinolysis; the concentration may be as high as 320 ~g/
ml in overt DIC patients (Slappendel 1988b). FDPs
greater than 40 #g/ml in equine patients are only
suggestive of DIC (Morris 1988). In the horse, interpreting FDP concentrations is difficult and their
presence is certainly not pathognomonic for DIC.
Newer analytes for diagnosis of DIC such as quantification of B-fl 15-42 fragments and distinct fibrinogen or
fibrin degradation products are widely used in human
medicine, and begin to be utilised in veterinary medicine (Monreal et al. 1993). Fibrinogen degradation
products (FgDP) and fibrin degradation products
(FbDP) by ELISA have been suggested to be reliable
and sensitive assays for diagnosis of DIC (Jensen and
Ens 1991; Bick and Backer 1992). As yet, however,
these analytes have not been validated for routine use in
veterinary medicine. The radioimmunoassay for B-fl
15-42 and related peptides, when performed in conjunction with fibrinopeptide A, can aid in the differential diagnosis of DIC versus primary fibrinolysis (Bick
1988; Muller 1989). B-fl 15-42 and related peptides
result from cleavage of B-fl peptides from the B-fl chain
of fibrinogen by plasmin (Fig. 2). Elevation of B-fl 15-42
and related peptides without concurrent fibrinopeptide
A elevation is strong evidence for primary fibrinolysis,
whereas the elevation of both is evidence of DIC (Bick
1988).
Plasminogen and tr-antiplasmin concentrations may
be reduced in DIC. But enhanced fibrinolysis may be
assessed by plasmin-~2-antiplasmin complex (PIC)
quantification in human medicine. It has been observed
Thrombin
Fibrinogen
~
~
"~
--'.
~ibrinopeptide
B-Betachain
Plasmin
Fibrinolysis
Elevated FDP concentrations are late-stage findings in
most patients with DIC (Feldman 1981; Slappendel
1988b). FDPs are the result of plasmin biodegradation
of fibrinogen or fibrin, and thus are indicative of plasmin
presence in the circulation. This may be a result of
primary fibrinolysis (rare in most animal species includ-
Fragments X,Y,D,E
(Fragment B-Beta 15-42
~.
other peptides ,,)
Fig.2. Formation of fragment B-beta 15-42 from fibrin(ogen).
Disseminated Intravascular Coagulation (DIC)
that the highest concentrations of PIC corresponded to
DIC induced by acute promyelocytic leukaemia (APL),
the concentrations being relatively lower than in DIC
induced by sepsis.
Plasminogen activator inhibitors (PAl) are determined in human medicine. A significant elevation in
active PAI was observed in DIC due to acute leukaemia, chronic myeloid leukaemia and sepsis, but not in
APL, non-Hodgkin lymphoma, and cancer. Active PAI
was higher in patients with multiple organ failure
(MOF) than in those without MOF whereas PIC was
lower in patients with this complication. Thus, the
balance of coagulation and fibrinolysis varied according
to the underlying cause of DIC; APL having more
activation of fibrinolysis, whereas sepsis had greater
activation of coagulation. It is suggested that the
inhibition of secondary fibrinolytic activation plays an
important role in the progression of MOF (Asakura et
al. 1994).
Coagulation Inhibitors
Functional ATIII concentration in patients with DIC is
commonly decreased (Tanaka et al. 1986). ATIII is a
regulator of several procoagulation proteases including
thrombin, factors IXa, Xa, XIa, XIIa and plasma KK
(Green 1988; High 1988). Although a diagnosis of DIC
can not be made from ATIII concentrations, monitoring ATIII activity is important in the management of
DIC especially prior to heparin therapy and is helpful in
prognosing clinical recovery (Gerhards 1987; Green
1988). Antithrombin III activity was not a useful coindicator of DIC in cats infected with feline infectious
peritonitis (Boudreaux et al. 1989). This might be due to
increased hepatic synthesis of ATIII and decreased
catabolism secondary to diffuse vasculitis (ATIII may
be rendered non-functional and thus unable to inhibit
activated serine proteases) (Boudreaux et al. 1989).
Determinations of protein C pathway activation and
contact system activation such as APC:PCI complex,
KK:PCI complex, and APC-cd-antitrypsin complex,
have been accomplished in human medicine in relation
to septic shock and early coagulation activation
(Alcaraz et al. 1995). In acute malaria, reduction in
plasma AT III concentrations, protein C, factor XII and
prekallikrein (PK) activities were observed (Clemens et
al. 1994).
221
Thromboelastography
Thromboelastography (TEG), is a less commonly available technique used to assess haemostatic function.
Analysis of TEG yields qualitative information about
platelet function, thromboplastin, and their interaction
with the intrinsic coagulation cascade to form a stable
clot. Additional information is obtained about fibrinogen and factor XIII concentrations as well as the
fibrinolytic system. TEG is more sensitive and accurate
than the traditional universal coagulation tests (PT,
APTT) in revealing haemostatic disorders (Bigeleisen
and Kang 1991). The test has also been used in diagnosis
of DIC in dogs (Johnson et al. 1983).
It is not possible, as yet, to establish minimal criteria
for an early diagnosis of DIC, although such criteria
may clearly improve therapy and the outcome of some
patients. But DIC diagnosis is frequently based on a
constellation of laboratory findings, such as thrombocytopenia, hypofibrinogenaemia and high concentrations of FDPs (Mora et al. 1995), red blood cell
fragmentation, thrombocytopenia, prolonged coagulation tests and increased FDPs concentrations
(Chuamsumrit et al. 1993. It is also suggested that the
compensated form of activation of intravascular coagulation may be diagnosed by a decrease in ATIII, an
increase in TAT, the appearance of FM and D-dimers
(FbDP). Prolonged bleeding time, PT, PTT and hypofibrinogenaemia are found in severe DIC (Schneider
1994).
Rational Therapy
The treatment of DIC remains controversial. There is a
global perception that therapy is often futile and that
most patients die. Difficulties with therapeutics in DIC
are extant because of the diverse aetiologies and clinical
manifestations. Simply stated, therapy should be highly
individualised.
The therapy of acute DIC should be sequential and
have a logical strategy (Table 4). The most important
therapeutic modality is removal of the inciting cause. If
the removal of the inciting cause is not possible
(exemplified by widespread metastatic disease) a specific approach may be indicated (Ruehl et al. 1982).
Supportive therapy must be aggressively instituted concomitant with therapy for treatment or mitigation of the
underlying event.
Fluid Therapy
Fibronectin
Fibronectin is one of the endothelial adhesion glycoprotiens which has been recently used as a molecular
marker for endothelial injury (Toschi et al. 1991; Saleh
et al. 1992). The concentration of fibronectin was found
to be decreased in canine patients with DIC (Feldman et
al. 1985).
Fluid therapy is indicated to correct hypovolaemia, for
prevention or alleviation of vascular stasis, and for
dilution of thrombin, FDPs and activators of fibrinolysis
(Ruehl et al. 1982). The use of electrolytes and/or
volume expanders such as plasma protein fractions,
albumin, dextran 70, hdyroxyethyl starch and hypertonic saline solution combined with colloids (Ruehl et
222
Table 4. Sequential therapy in fulminantdisseminatedintravascular
coagulation
1. Removeincitingcause
Use of antimicrobialor antineoplastictherapy
Control shock
Volume replacement
Glucocorticoids,antimicrobials(endotoxaemia)
2. Inhibithaemostasis
Application of heparin or
Other anticoagulantdrugs (hirudin, gabexate)
Antiplatelet agents
3. "Specificblood componenttherapy
Platelet concentrates - not currently applicable in veterinary
medicine
Packed red cells (washed)
Antithrombinconcentrates
or frozenplasma
Cryoprecipitate
4. Inhibitfibrinolysis(?a)
Epsilon-aminocaproicacid
Transexamicacid
air is questionable if inhibition of fibrinolysis in a patient with
disseminatedintravascularcoagulationis indicated.It may,in fact, be
problematic and contraindicated.
al. 1982; Concannon et al. 1992; Zoran et al. 1992)
depend upon the primary disease, blood pH and
electrolyte and hydration status of the patient.
R. R. de Gopeguiet al.
ATIII-dependent activity. Preliminary studies indicated
that LMWH are effective in treatment of DIC and have
less risk of haemorrhage (Oguma et al. 1990). Recently,
it has been observed that administration of LMWH to
horses may avoid some undesirable effects related to
standard heparin administration, such as erythrocyte
agglutination (Monreal et al. 1995).
Newer agents with potential therapeutic benefits for
fulminant and compensated DIC are recombinant hirudin and gabexate mesilate (Hauptmann and Bruggener
1988; Umeki et al. 1988). These drugs are capable of
inhibiting thrombin or factor Xa in the absence of
ATIII. Experimental studies proved that hirudin
(Nowak and Markwardt 1991) and gabexate mesilate
(Suzuki et al. 1988) inhibit different triggering mechanisms for DIC induced by endotoxins. Further studies in
the use of these products in veterinary medicine might
affect morbidity and mortality from endotoxin-induced
DIC. An orally active new specific inhibitor of factor
Xa, DX-9065a, has been studied against two kinds of
experimental DIC in rats (Yamazaki et al. 1994).
Antiplatelet Aggregant Therapy
This has been used in patients with compensated DIC
(Ruehl et al. 1982; Morris 1988; Slappendel 1988b).
Acetylsalicylic acid inhibits platelet aggregation and
blocks TxA2 release (Yao et al. 1991). However, platelet inhibitors should not be used in patients with severe
thrombocytopenia (Ruehl et al. 1982).
Coagulation Inhibitors
Blood Product Therapy
Heparin is the most common anticoagulant used in
correction of DIC. However, it has a limited effect
depending on the availability of functional patient
ATIII. The anticoagulant effect of heparin is due to its
ability to form complexes with plasma ATIII, potentiating the action of the complex to neutralise thrombin,
factors Xa, XIIa, XIa, as well as plasmin, KK, complement and trypsin (Rosenberg 1975; Green 1988).
Administration of high-dose heparin may increase the
risk of haemorrhage in patients with acute DIC.
Heparin therapy can be successful in compensated DIC
when functional ATIII concentrations are available
(Ruehl et al. 1982). Transfusion of fresh plasma would
provide ATIII and other serine protease inhibitors and
subsequent administration of low doses of heparin may
sustain appropriate haemostasis (Wisecarver and Haire
1989; Welch et al. 1992). Heparin may be added to the
container of fresh frozen plasma and incubated, to
ensure a continuous ATIII infusion and avoiding ATIII
depletion (Feldman 1990). Low-molecular-weight
heparins (LMWH) are obtained from standard heparin.
They have greater inhibitory effects on factor Xa than
on thrombin, less interaction with platelets, and may
have potentially new therapeutic applications (Samama
and Babinet 1991). Their mode of action on the haemostatic system is based in their anti-factor Xa and IIa
This is indicated if haemorrhage occurs. This form of
therapy necessitates the ability to continually assess the
patient's haemostatic system. The severity of blood loss,
thrombocytopenia, hypofibrinogenaemia, and coagulopathy, indicates the selection of blood products. Packed
red cells, platelet concentrates, platelet rich plasma,
fresh frozen plasma, cryoprecipitate, or fresh whole
blood may be considered (Mora et al. 1955). In patients
that appear to be clinically stable, administration of
fresh or stored frozen plasma or cryoprecipitate may be
indicated. It has been proposed that administration of
blood products to a patient with ongoing DIC and
microvascular thrombosis carries the risk of plasmin
biodegradation of the administered coagulation factors
(Bick et al. 1976; Bick 1988). Experimental administration of recombinant human activated protein C has also
been studied in tissue thromboplastin-induced disseminated intravascular coagulation (DIC) in rabbits
(Katsura et al. 1994). The use of ATIII concentrates in
human medicine is not thoroughly discussed in relation
to the clinical improvement observed (Lechner and
Kyrle 1995) ' . . . the doses [of ATIII] applied in adult
intensive care patients with septicaemia does not appear
to improve outcome in terms of mortality' (van Beek et
al. 1994).
Disseminated Intravascular Coagulation (DIC)
Fibrinolytic Inhibitors
Fibrinolytic inhibitors are rarely indicated, unless
secondary fibrinolysis continues to biodegrade plasma
proteins. If this occurs, antifibrinolytic (e-aminocaproic
acid) therapy may be considered. It is, however, important to note that this therapy is contraindicated for
patients with ongoing DIC, as these patients are dependent on fibrinolysis to clear microthrombi. Also antifibrinolytic therapy should never be applied unless
increased fibrinolytic activity and subsequent haemorrhage have been documented. Tranexamic acid has
recently been used as a potent antifibrinolytic agent
(Takada et al. 1990).
For effective therapy of DIC and to avoid complicating the existing condition, therapy should be monitored.
Return of fibrinogen concentration, ATIII concentration, platelet numbers, and PT and APTT towards
reference intervals are among the most consistent
signals of therapeutic success. It should be noted that
this statement is in direct opposition to the myth of
prolonging the universal tests of coagulation (PT and
AP'I-T) towards some predetermined time.
Finally, preventive measures to reduce morbidity and
mortality from endotoxaemia-induced DIC in horses
have been studied. Studies involved feeding horses a
diet enriched with ~-3 fatty acids. These fatty acids alter
the cell-membrane phospholipid composition. Results
indicated that mononulcear phagocytes from horses on
this diet have reduced ability to produce inflammatory
mediators including eicosanoids and TNF, in response
to endotoxins in vitro (Henry et al. 1991; Morris et al.
1991).
References
Alcaraz A, Espafia F, Sfinchez-Cuenca J et al. (1995) Activation of the
protein C pathway in acute sepsis. Thromb Res 79:83-93
Ampel LL, Marshall S, Caprini JA (1985) Etiology, diagnosis, and
treatment of recovery room bleeding/hemorrhage. Heart Lung
14:556-561
Anderson KL, Smith LA, DeGraves FJ et al. (1992) Polymorphonuclear neutrophil leukocyte function in clinical bovine patients and
in cows with or without Staphylococcus aureus mastitis. Vet Res
Commun 16:.107-115
Angelov A (1989) Intravascular coagulation in relation to pregnancy
and delivery. Zentralbl Gyn~ikol 111:1169-1175
Asakura H, Jokaji H, Saito Met al. (1991) The course of disseminated
intravascular coagulation is predicted by changes in thrombinantithrombin III complex levels - is there any difference between
treatment with standard heparin or low-molecular-weight heparin?
Blood Coagul Fibrinolysis 2:623-627
Asakura H, Jokaji H, Saito M e t al. (1994) Study of the balance
between coagulation and fibrinolysis in disseminated intravascular
coagulation using molecular markers. Blood Coagul and Fibrinolysis 5:829-832
Axelsson L, Bergenfeldt M, Bjork P e t al. (1990) Release of
immunoreactive canine leukocyte elastase normally and in endotoxin and pancreatitis shock. Scand J Clin Lab Invest 50:35-42
Badenoch JP, Ramshaw IA, Grant A (1986) Cellular and secreted
tumor plasminogen activator: the effects of NaCI. Experientia
42:433--435
Baker WF (1989) Clinical aspects of disseminated intravascular
223
coagulation: a clinician's point of view. Semin Thromb Hemost
15:1-43
Baker DC, Green RA (1987) Coagulation defects of aflatoxin
intoxicated rabbits. Vet Pathol 24:62-70
Barnett AH (1991) Pathogenesis of diabetic microangiopathy: an
overview. Am J Med 90:675-735
Bick RL (1979) Vascular disorders associated with thrombohemorrhagic phenomena. Semin Thromb Hemost 5:167-183
Bick RL (1982) Disseminated intravascular coagulation: clinical/
laboratory correlation. Am J Clin Pathol 77:244-253
Bick RL (1985) Disorders of hemostasis and thrombosis. Thieme,
New York, pp 157-204
Bick RL (1988) Disseminated intravascular coagulation and related
syndromes: a clinical review. Semin Thromb Hemost 14:299-338
Bick RL, Baker WF (1992) Diagnostic efficacy of the D-dimer assay in
disseminated intravascular coagulation (DIC). Thromb Res
65:785--790
Bick RL, Schmalhorst WR, Fekete LF (1976) Disseminated intravascular coagulation and blood component therapy. Transfusion
16:361-376
Bigeleisen PE, Kang Y (1991) Thromboelastography as an aid to
regional anesthesia: preliminary communication. Reg Anaesth
16:59-61
Blood DC, Radostits OM (1989) Veterinary medicine. Bailliere
Tindall, London, pp 984-992
Borrego D, Maria TP, Cascales P e t al. (1991) Massive intravascular
hemolysis in septicemia caused by Clostridium perfringens. Sangre
36:315-317
Bosner H, Pavesic D, Masovcic J e t al. (1989) Acute renal failure
following necrosis of a myoma in the puerperium. Jugosl Ginekol
Perinatol 29:55-58
Boudreaux MK, Weiss RC, Cox N et al. (1989) Evaluation of
antithrombin-III activity as a coindicator of disseminated intravascular coagulation in cats with induced feline infectious
peritonitis virus infection. Am J Vet Res 50:1910-1913
Bowersock TL, Walker RD, Maddux JM et al. (1990) Hematological
changes in calves exposed to a mixture of lipopolysaccharide and
crude leukotoxin of Pasteurella haernolytica. Can J Vet Res 54:415421
Braun U, Bearth G, Dieth V e t al. (1990) A case of disseminated
intravascular coagulation (DIC) in a cow with endometritis and
fetal death. Schweiz Arch Tierheilkd 132:239-245
Buntain B (1980) Disseminated intravascular coagulopathy (DIC) in a
cow with left displaced abomasum, metritis, and mastitis. Agri
Pract 1023-1026
Camiolo SM, Greco WR (1986) Piasminogen activator content of
human tumor and adjacent normal tissue measured with fibrin and
non-fibrin assays. Cancer Res 46:1788-1794
Carlson GP (1990) Diseases of the hematopoietic and hemolymphatic
systems. In: Smith PB (ed) Large animal medicine. CV Mosby,
Philadelphia, pp 1068--1082
Carroll RC, Rubinstein E, Worthington RE et ai. (1990) Extensive
Ciq-complement initiated iysis of human platelets by IgG subclass
murine monoclonal antibodies to the CD9 antigen. Thromb Res
59:831-839
Chuamsumrit kA, Hotrakitya S, Hathirat Pet al. (1993) Disseminated
intravascular coagulation in children: diagnosis, management and
outcome. Southeast Asian J Trop Med Public Health 24 Suppl
1:229-233
Clauss M, Murray JC, Vianna M e t al. (1990) A polypeptide factor
produced by fibrosarcoma cells that induces endothelial tissue
factor and ehnhances the procoagulant rsponse to tumor necrosis
factor/cachectin. J Biol Chem 265:7078-7083
Clemens R, Pramoolsinsap C, Lorenz R et al. (1994) Activation of the
coagulation cascade in severe falciparum malaria through the
intrinsic pathway. Br J Haematol 87:100-105
Clouse LH, Comp PC (1986) The regulation of hemostasis: the
protein C system, N Engl J Med 314:1298-1304
Concannon KT, Haskins SC, Feldman BF (1992) Hemostatic defects
associated with two infusion rates of dextran 70 in dogs. Am J Vet
Res 53:1369-1375
Cooley AJ, Clemmons RM, Gross TL (1987) Heartworm disease
224
manifested by encophalomyelitis and myositis in a dog. J AM Vet
Med Assoc 190:431-432
Cosgriff TM (1989) Viruses and hemostasis. Rev Infect Dis 11 Suppl
4:$672-688
Cotter SM (1992) Hematological emergencies and transfusion
medicine. Proc Am Anim Hosp Assoc (59th annual meeting, New
Orleans, Louisiana) pp 78--80
Cowell AK, Cowell. RL, Tyler RD et al. (1991) Severe systematic
reactions to Hymenoptera stings in three dogs. J Am Vet Med
Assoc 198:1014-1416
Daugschies A, Altfeld E, Rommel M (1989) Hemostatic alterations in
pigs fed sublethal doses of Sarcocystis rniescheriana. Vet Parasitol
34:1-13
Dillon AR, Braund KG (1982) distal polyneuropathy after canine
heartworm disease therapy complicated by disseminated intravascular coagulation. J Am Vet Med Assoc 181:239-242
Dodds WJ (1985) Blood dyscrasias affecting the surgical patienthemostatic and thrombotic disorders. In: Slatter DH (ed) Textbook
of small animal surgery. WB Saunders, Philadelphia, pp 1184-1194
Drazner FH (1982) Clinical implication of disseminated intravascular
coagulation. Comp Cont Ed Vet Pract 4:974-891
Duffy MJ (1990) Plasminogen activators and cancer. Blood Coagul
Fibrinolysis 1:681-687
Edwards RL, Morgan DL, Rickles FR (1990) Animal tumor procoagulants: registry of the Subcommittee on Haemostasis and
Malignancy of the Scientific and Standardization Committee,
International Society of Thrombosis and Hameostasis. Thromb
Haemost 63:133-138
Ellison GW, King RR, Calderwood MM (1988) Medical and surgical
management of multiple organ infarctions secondary to bacterial
endocarditis in a dog. J Am Vet Med Assoc 193:1289-1291
Edmond CT (1994) Possible involvement of cytokines in diffuse
intravascular coagulation and thrombosis. Baillieres Clin Hameatol
7:453-468
Ewert KM, Fessler JF, Templeton CB et al. (1985) Endotoxininduced hematologic and blood chemical changes in ponies: effect
of flunixin meglumine, dexamethasone, and prednisolone. Am J
Vet Res 46:24-30
Feldman BF (1981) Disseminated intravascular coagulation. Comp
Cont Ed Vet Pract 3:45-52
Feldman BF (1990) Disseminated Intravascular Coagulation (DIC)
Disseminated Intravascular Thrombosis (DIT) Consumption
Coagulopathy (CC). In: Proceedings of Second International
Veterinary Emergency and Critical Care Symposium, San Antonio,
Texas
Feldman BF, Madewell BR, O'Neill S (1981) Disseminated intravascular coagulation: antithrombin, plasminogen, and coagulation
abnormalities in 41 dogs. J Am Vet Med Assoc 179:151-154
Feldman BF, Thomason KJ, Jain NC (1988) Quantitative platelet
disorders. Vet Clin North Am Small Anim Pract 18:35--49
Feldman BF, Thomson DB, O'Neill S (1985) Plasma fibronectin
concentrations in dogs with disseminated intravascular coagulation.
Am J Vet Res 46:1171-1174
Frelier PF, Lewis RM (1984) Hematologic and coagulation abnormalities in acute bovine sarcocystosis. Am J Vet Res 45:40--48
Gentry PA, Feldman BF, Liptrap RM (1991) Haemostasis and
parturition re-visited; comparative profiles in mammals. Comp
Haematol Int 1:150-154
Gerhards H (1987) Antithrombin III determination in horses. Reference values and acquired antithrombin III deficiency, Tierarztl Prax
15:47-55
Giger U, Gorman NT (1984) Oncologic emergencies in small animals.
Part 1. Chemotherapy related and hematologic emergencies. Comp
Cont Ed Pract Vet 6:689-698
Goodwin-MN (1989) Selected anatomic burn pathology review for
clihicians and pathologists. Aviat Space Environ Med 60:B39--43
Gordon SG (1984) Evidence of a tumor proteinase in blood coagulation. In: Honn KV, SIoane BF (eds) Hemostatic mechanisms and
metastasis. Martinus Nijhoff, Boston, pp 72-83
Green RA (1981) Hemostasis and disorders of coagulation. Vet Clin
North Am Small Anim Praet 11:289-317
Green RA (1988) Pathophysiology of antithrombin III deficiency. Vet
Clin North Am Small Anim Pract 18:95-104
R. R. de Gopegui et al.
Green RA (1989) Hemostatic disorders: coagulopathies and thrombotic disorders. In: Ettinger SJ (ed) Textbook of veterinary internal
medicine. WB Saunders, Philadelphia, pp 2246-2264
Greene CE (1990) Infectious canine hepatitis and canine acidophil cell
hepatitis. In: Green CE (ed) Infectious diseases of the dog and cat.
WB Saunders, Philadelphia pp 242-244
Greene CE, Scott FW (1990) Feline panleukopenia. In: Greene CE
(ed) Infectious diseases of the dog and cat. WB Saunders, Philadelphia, pp 291-299
Hagiwara MK, Kogika MM, Maluceli BE (1990) Disseminated
intravascular coagulation in dogs with aflatoxicosis. J Small Anim
Pract 31:239-243
Hall DE (1972) Blood coagulation and its disorders in the dog.
Williams & Wilkins, Baltimore, pp 109-128
Hammer AS, Couto CG, Swardson C et al. (1991) Hemostatic
abnormalities in dogs with hemangiosarcoma. J Vet Intern Med
5:11-14
Hardaway RM (1980a) Mechanism of traumatic shock. Surg Gynecol
Obstet 151:65--69
Hardaway RM (1980b) Influence of flbrinogen levels in dogs on
mortality from hemorrhagic and traumatic shock. J Trauma 20:417419
Hardaway RM (1981) Prediction of survival or death of patients in a
state of severe shock. Surg Gynecol Obstet 152:200-206
Hardaway RM, Williams CH (1987) Influence of steroids on hemorrhagic and traumatic shock. J Trauma 27:667-670
Hardaway RM, Williams CH (1990) A new treatment for traumatic
shock and ARDS. Resuscitation 19:61-76
Hargis AM, Feldman BF (1991) Evaluation of hemostatic defects
secondary to vascular tumors in dogs: 11 cases (1983-1988). J Am
Vet Med Assoc 198:891-894
Hauptmann J, Bruggener E (1988) Influence of hiridun on the
consumption of antithrombin III in experimental DIC. Folia
Haematol Leipz 115:83-87
Helfand SC (1988) Platelets and neoplasia. Vet Clin North Am Small
Anim Pract 18:131-135
Henry MM, Moore JN, Fischer JK (1991) Influence of an omega-3
fatty acid-enriched ration on in vivo responses of horses to endotoxin. Am J Vet Res 52:523-527
Hersch SL, Kunelis T, Francis RB (1987) The pathogenesis of
accelerated fibrinolysis in liver cirrhosis: a critical role for tissue
plasminogen activator inhibitors. Blood 69:1315-1319
High KA (1988) Antithrombin III, protein C, and protein S. Naturally
occurring anticoagulant proteins. Arch Pathol Lab Med 112:28-36
Holland M, Kelly AB, Synder JR (1986) Antithrombin III activity in
horses with large colon torsion. Am J Vet Res 47:897-900
Holman ND, Schneider AJ (1989) Multi-organ damage in exertional
heat stroke. Neth J Med 35:38--43
Howerth EW, Greene CE, Prestwood AK (1988) Experimentally
induced bluetongue virus infection in white-tailed deer: coagulation, clinical pathologic, and gross pathologic changes. Am J Vet
Res 49:1906-1913
Huang HB (1991) Vaccination against and immune response to viral
haemorrhagic disease of rabbits: a review of research in the
People's Republic of China. Rev Sci Tech 10:481-498
Iashvili BP, Baluda VP, Lukhoyanova TI et al. (1986) The effects of
administration of drugs influencing during treatment of patients
with burns. Burns Incl Therm Inj 12:184-187
Irimura T, Mclsaac AM, Carlson DA et al. (1990) Soluble factor in
normal tissues that stimulates high-molecular-weight sialoglycoprotein production by human colon carcinoma cells. Cancer Res
50:3331-3338
Isogai E, Isogai H, Onuma M et al. (1989) Escherichia coli associated
endotoxemia in dogs with parvovirus infection. Jpn J Vet Sci
51:597-606
Jacobse-Geels HEL, Daha MR, Horzinek MC (1980) Isolation and
characterization of feline C3 and evidence for the immune complex
pathogenesis of feline infectious peritonitis. J Immunol 125:16061610
Jandl JH (1991) Blood: pathophysiology. Blackwell Scientific
Publications, Boston, pp 510-533
Jensen R, Ens GE (1991) Diagnostic application of thrombotic
markers. Clin Hemost Rev 5:1-7
Disseminated Intravascular Coagulation (DIC)
Johnson .IT, Zuckerman L, Dunkin PG et al. (1983) Thromboelastography used to monitor a dog with disseminated intravascular
coagulation. ,i Am Anim Hosp Assoc 19:182-186
Johnstone DE (1985) Burns, electrical, chemical and cold injuries. In:
Slatter DH (ed) Textbook of small animal surgery. WB Saunders,
Philadlephia, p 510-533
Johnstone IB, Crane S (1986) Hemostatic abnormalities in equine
colic. Am J Vet Res 47:356--358
Jones DRE, Gruffydd ,ITJ, McCullagh KG (1980) Disseminated
intravascular coagulation in a dog with thoracic neoplasia. ,i Small
Anim Pract 21:303-309
Kapina MA, Zelenin MG, Egorov BB (1986) Screening of human and
animal tissue cell cultures as potential producers of plasminogen
activator. Antibiot Med Biotekhnol 31:756--760
Kaplank AP, Silverberg M (1987) The coagulation-kinin pathway of
human plasma. Blood 70:1-15
Katsuura Y, Aoki K, Tanabe H et al. (1994) Characteristic effects of
activated human protein C on tissue thromboplastin-induced
disseminated intravascular coagulation in rabbits. Thromb Res
76:353-362
Kiper ML, Paulsen DP (1988) Acute mastitis and disseminated
intravascular coagulopathy caused by Pasteurella haemolytica in a
cow. J Am Vet Med Assoc 192:205-206
Kobilinsky L, Hardy WD, Day NK (1979) Hypocomplementemia
associated with naturally occurring lymphosarcoma in pet cats. J
Immunol 122:1239-1242
Kociba G J, Hathaway ,IE (1974) Disseminated intravascular coagulation associated with heartworm disease in the dog. J Am Anim
Hosp Assoc. 10:373-378
Kokosharov T, Khristov KH, Nikolov N (1990) Disseminated
intravascular coagulation in fowls after experimentally induced
acute salmonellosis. Vet Sbirka 88:28-31
Krooshof Y, Hellebrekers 1.2, Feldman BF (1984) Two cases of
combined babesiosis and ehrlichiosis in dogs. Canine Pract 11:1216
Kubota T, Andoh K, Sadakata H et al. (1991) Tissue factor released
from leukemic cells. Thromb Haemost 65:59--63
Lechner K, Kyrle PA (1995) Antithrobin III concentrates - are they
clinically useful? Thromb Haemost 73:340-348
Lefrere J,i Conard ,i, Lerable J et al. (1989) Antithrombin III and
hepatocelhilar carcinoma. Thromb Haemost 62:817
Lipowitz A,I (1985) Surgical complications. In: Slatter DH (ed)
Textbook of small animal surgery. WB Saunders, Philadelphia, pp
165-171
Lippincott CL, Schulman AJ (1989) Gastric dilatation volvulus-torsin
syndrome. In: Ettinger S,I (ed) Textbook of veterinary internal
medicine. WB Saunders, Philadelphia, pp 1278-1288
Lockwood CJ, Bach R, Ghuha A e t al. (1991) Amniotic fluid contains
tissue factor, a potent initiator of coagulation. Am J Obstet
Gynecol 165:1335-1341
Madewell BR, Feldman BF (1980) Characterization of anemias
associated with neoplasia in small animals. J Am Vet Med Assoc
176:419--425
Mant M,I, King EG (1979) Severe, acute disseminated intravascular
coagulation. A reappraisal of its pathophysiology, clinical significance and therapy, based on 47 patients. Am ,i Med 67:559
Masci PP, Rowe EA, Whitaker AN et al. (1990) Fibrinolysis as a
feature of disseminated intravas.cular coagulation (DIC) after
Pseudonaja textilis textilis envenomation. Thromb Res 59:859-870
McClure JR, McChire J,i (1982) Intravascular coagulopathies associated with alimentary-induced acute laminitis in the pony. In:
Proceedings of the frst equine endotoxemia-laminitis symposium,
(Colden, Colorado, American Association of Equine Practitioners)
pp 124--127
McKay DG (1983) Clinical significance of intravascular coagulation.
Bibl Haematol 49:63
Mohanty D, Ghosh K, Das KC (1991) Studies on the mechanism of
synthesis and release of the procoagulant activity from leukaemic
cells. Med Oncol Tumor Pharmacother 8:15-21
Moher DF (1988) Disorders of blood coagulation. In: Wyngaarden
JB, Smith LN (eds), Cecil textbook of medicine. WB Saunders,
Philadelphia, pp 1060-1081
Monreai L, Anglrs AM, Ruiz de Gopegui R et al. (1993) Valores
225
normales de los parttmetros hematoi6gicos y hemost,'iticos en el
conejo. Determinaci6n de nuevos par~imetros para modelos experimentales de trombosis y hemostasia. Sangre 38:365-369
Monreal L, Villatoro A J, Monreal M e t al. A comparison of the
effects of Low-Molecular Weight and Unfractionated Heparin in
horses. Am J Vet Res 56,10:1281-1289
Mora A, Cortrs C, Roige J e t ai. (1995) Trasplante hep,-itico
ortot6pico por hemangioma cavernoso gigante y sindrome de
Kasabach-Merritt. Rev Esp Anestesiol Reanim 42:71-74
Morris DD (1988) Recognition and management of disseminated
intravascular coagulation in horses. Vet Clin North Am Equine
Pract 4:115-143
Morris DD (1991) Endotoxemia in horses. A review of cellular and
humoral mediators involved in its pathogenesis. ,i Vet Intern Med
5:167-181
Morris DD, Henry MM, Moore JN et al. (1991) Effect of dietary
alpha-lineolenic acid on endotoxin-induced production of tumor
necrosis factor by peritoneal macrophages in horses. Am J Vet Res
52:528-532
Muller BG (1989) Pathophysiologic and biochemical events in disseminated intravascular coagulation: dysregulation of procoagulant
and anticoagulant pathways. Semin Thromb Hemost 15:58--87
Murano G, Bick RL (1980) Basic concepts of hemostasis and
thrombosis. CRC Press, Boca Raton, pp 43-78
Nakagawa K, Tsuji H, Masuda H et al. (1994) Plasma levels of sohible
fibrin in patients with malignancy-associated disseminated intravascular coagulation. Blood Coagul Fibrinolysis 5:725-730
Nakamura S, Shimokama T, Yoshikawa Y e t al. (1990) Immune
complex-induced disseminated intravascular coagulation (DIC).
An experimental study. Acta Pathol Jpn 40:476-485
Nguyen P, Petitfrere E, Potron G (1995) Mechanisms of the platelet
aggregation induced by activated neutrophils and inhibitory effect
of specific PAF receptor agonists. Thromb Res 78:33--42
Nomura S, Nagata H, Suzuki Met al. (1991) Microparticle generation
during in vitro platelet activation by anti-CD9 murine monoclonal
antibodies. Thromb Res 62:429-439
Nowak G, Markwardt F (1991) Hirudin in disseminated intravascular
coagulation. Haemostasis. 21 Suppl 1:142-148
Oguma Y, Sakuragawa N, Maki M e t al. (1990) Treatment of
disseminated intravascular coagulation with low molecular weight
heparin. Research Group of FR-860 on DIC in Japan. Semin
Thromb Hemost 16:34-40
O'Keefe DA, Couto CG (1988) Coagulation abnormalities associated
with neoplasia. Vet Clin north Am Small Anim Pract 18:157-168
Olubayo RO, Mugera GM (1985) Pathogenesis of haemorrhages in
Trypanosoma vivax infection in cattle. 1. Disseminated intravascular coagulation. Bull Anim Heal Prod Africa 33:211-217
Ono I (1987) Alteration in coagulation and fibrinolysis after burn
injury and significance of anticoagulation therapy using heparin and
antithrombin III concentrate. Hokkaido Igaku Zasshi 62:108--121
Ordog G,I, Wasserberger ,i (1986) Coagulation abnormalities in
traumatic shock. Crit Care Med 14:519--523
O'Rourke L, Feldman BF, Ito RK (1982) coagulation, fibrinolysis,
and kinin generation in adult cats. Am J Vet Res 43:1478-1489
Papinger I (1986) Clinical relevance of protein C. Blut 53:63-75
Pan IC, Whyard TC, Hess WR et al. (1988) Epitopic diversity of
African swine fever virus. Virus Res 9:93-106
Parihar MS, Kailashi SC, Pandey AK (1991) A comparison study of
phospholipids in human, goat and chick amniotic fluid. Biomed
Biochem Acta 50:955-958
Peterson LC, Valentin S, Hedner, U (1995) Regulation of extrinsic
pathway system in health and disease: the role of factor Vlla and
Tissue Factor Pathway Inhibitor. Thromb Res 79:1-35
Radomski MW, Jenkins DC, Holmes L e t al. (1991) Human colorectal adenocarcinoma cells: differential nitric oxide synthesis
determines their ability to aggregate platelets. Cancer Res 51:60736078
Raphael BG (1982) Disseminated intravascular coagulation during
surgery for scoliosis. Ciin Orthop 162:41-46
Rebar AH, Hahn FF, Halliwell WH (1980) Microangiopathic hemolytic anemia associated with radiation-induced hemangiosarcomas.
Vet Pathoi 17:443--454
Reilly D, Andreasen PA, Dully MJ (1991) Urokinase-plasminogen
R. R. de Gopegui et al.
226
activator in breast cancer: assay by both catalytic and immunoassay.
Blood Coagul Fibrinolysis 2:47-50
Roncaglioni MC, Falanga A, D'Alessandro AP et al. (1989) Evidence
of a warfarin-sensitive cancer procoagulant in V2 carcinoma.
Haematologica 74:143-147
Rosenberg RD (1975) Actions and interactions of antithrombin and
heparin. N Engl J Med 292:146-151
Ruehl W, Mills C, Feldman BF (1982) Rational therapy in disseminated intravascular coagulation. J Am Vet Med Assoc 181:76--78
Saleh AA, Bottoms SF, Farag AM et al. (1992) Markers for
endothelial injury, clotting and platelet activation in preeclampsia.
Arch Gynecol Obstet 51:105-110
Samama M, Babinet BA (1992) The new heparins. J Mal Vasc 17:91106
Sandberg H, Bode AP, Dombrose FA et al. (1985) Expression of
coagulant activity in human platelets: release of membranous
vesicles providing platelet factor 1 and platelet factor 3. Thromb
Res 39:63--79
Schaeffer RC, Briston C, Chilton SM et al. (1986) Disseminated
intravascular coagulation following Echis carinatus venom in dogs:
effects of a synthetic thrombin inhibitor. J Lab Clln Med 107:488497
Schneider H (1994) Leberpathologie im Rahmen des HELLPSyndroms. Arch Gynecol Obstet 255 Suppl 2:$245--254
Schrier SL (1993) Disorders of hemostasis and coagulation. In:
Rubinstein E, Federman DD (eds) Scientific American medicine.
New York, Scientific American, vol 5 pp 1-59
Seegers WH (1971) Use and regulation of blood clotting mechanisms.
In: Seegers WH (ed) Blood clotting enzymology, Academic Press,
New York, p 1
Slappendel RJ (1988a) disseminated intravascular coagulation
associated with neoplasia. Vet Clin North Am Small Anim Pratt
18:271-273
Slappendel ILl (1988b) Disseminated intravascular coagulation. Vet
Clin North Am Small Anim Pract 18:169-184
Spearman MA, Ballon BC, Gerrard JM et al. (1991) The inhibition of
platelet aggregation of metastatic H-ras-transformed 10T1/2 fibroblasts with castanospermine, an N-linked glycoprotein processing
inhibitor. Cancer Lett 60:185-191
Stein DS, Libertin CR (1990) Disseminated intravascular coagulation
in association with cavitary tuberculosis. South Med J 83:60-63
Studdert MJ (1994) Rabbit haemorrhagic disease virus: a calicivirus
with differences. Aust Vet J 71:266-264
Suchartwatnachai C, Linasmita V, Chaturachinda K (1991) Obstetric
hysterectomy: Ramathibodi's experience 1969-1987. Int J Gynaecol Obstet 36:183-186
Suliman HB, Feldman BF (1989) Pathogenesis and aetiology of
anaemia in trypanosomiasis with special reference to T. brucei and
T. evansi. Vet Bull 59:99-107
Suzuki M, Suematsu M, Miura S et al. (1988) Microcirculatory
disturbances in endotoxin-induced disseminated intravascular
coagulation. The effects of heparin and gabexate mesilate on
locomotive and metabolic changes of neutrophils. Adv Exp Med
Biol 242:135-141
Takada A, Takada Y, Mori T et al. (1990) Prevention of severe
bleeding by tranexamic acid in a patient with disseminated intravascular coagulation. Thromb Res 58:101-108
Tanaka H, Kobayashi N, Maekawa T (1986) Studies on production of
antithrombin II with special reference to endotoxin-induced DIC in
dogs. Thromb Haemost 56:137-143
Taylor FB Jr (1994) Studies on the inflammatory-coagulant axis in the
baboon response to E. coil: regulatory roles of proteins C, S,
C4bBP and of inhibitors of tissue factor. Prog Ciin Biol Res
388:175-194
Titova SI, Kozlov GI, Mamedgasanov RM (1989) Disorders of blood
coagulation and microcirculation in diabetics. Probl Endokrinol
Mosk 35:3-7
Toschi V, Fiorini GF, Motta A et al. (1991) Clinical significance of
endothelial damage markers in essential mixed cryoglobulinemia.
Acta Haematol 86:90-94
Uehara S, Honjyo K, Furukawa Set al. (1989) Role of the kallikreinkinin system in human pancreatitis. Adv Exp Med Biol 247B:643648
Ueyama M, Yamamoto I, Sawada Y (1991) Disseminated intravascular coagulation in the early stage after severe burn: the role of
excessive thrombin generation. Nippon Geka Gakkai Zasshi
92:907-912
Umeki S, Adachi M, Watanabe Met al. (1988) Gabexate as a therapy
for disseminated intravascular coagulation. Arch Intern Med
148:1409-1412
Van Beck EJ, von der Mohlen MA, ten Cate JW et al. (1994)
Antithrombin III concentrate in the treatment of DIC: a retrospective follow-up study. Neth J Med 45:206-210
Venturini CM, Kaplan JE (1992) Thrombin induces platelet adhesion
to endothelial cells. Semin Thromb Hemost 18:275-283
Wachtfogel YT, de la Cadena R, Colman R (1993) Structural biology,
cellular interactions and pathophisiology of the contact system.
Thromb Res 72:1-21
Wagner DS, Klein RL, Robinson HB et al. (1990) Placental emboli
from a fetus papyraceousm. J Pediatr Surg 25:538-542
Walsh LJ, Trincheri G, Waldorf HA et al. (1991) Human dermal mast
cells contain and release tumor necrosis factor o~, which induces
endothelial leukocyte adhesion molecule E. Proc Nat Acad Sci
USA 88:4220-4224
Ward MV, Conway DL (1980) A severe case of acute suppurative
dermatitis with disseminated intravascular coagulation in a dog. Vet
Med Small Anim Clin 75:1564-1568
Warr TA, Rao LV, Rapaport-SI (1990) Disseminated intravascular
coagulation in rabbits induced by administration of endotoxin or
tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood 75:14811489
Welch RD, Watkins JP, Taylor TS et al. (1992) Disseminated
intravascular coagulation associated with colic in 23 horses (19841989). J Vet Intern Med 6:29-35
Williams DA (1989) Exocrine pancreatic disease. In Ettinger SJ (ed)
Textbook of veterinary internal medicine. WB Saunders, Philadelphia, pp 1520-1554
Wintrobe MW, Lee GR, Boggs DR et al. (1981) Clinical hematology.
Lea & Febiger, Philadelphia, pp 104-162
Wisecarver JL, Haire WD (1989) Disseminated intravascular
coagulation with multiple arterial thromboses responding to
antithrombin-III concentrate infusion. Thromb Res 54:709-717
Wu HF, Lundblad RL, Church FC (1995) Neutralization of heparin
activity by neutrophil lactoferrin. Blood 85:421-428
Yamazaki M, Asakura H, Aoshima K et al. (1994) Effects of DX9065a, an orally active, newly synthesized and specific inhibitor of
factor Xa, against experimental disseminated intravascular
coagulation in rats. Thromb Haemost 72:392-396
Yao SK, Benedict CR, Rosolowsky M et al. (1991) Effect of aspirin on
local prostaglandin production and serotonin accumulation in a
canine model with coronary cyclic flow variatins or thrombosis. J
Mol Cell Cardiol 23:473--482
Zoran DL, Jergens AE, Riedesel DH et al. (1992) Evaluation of
hemostatic analytes after use of hypertonic saline solution
combined with colloids for resuscitation of dogs with hypovolemia.
Am J Vet Res 53:1791-1796