Disseminated Intravascular Coagulation in

Acute Leukemia
Tiziano Barbui, M.D.,1 and Anna Falanga, M.D.1

ABSTRACT

Malignancy is associated with a hypercoagulable state and a high risk for

thrombohemorrhagic complications. Clinical complications may range from localized
thrombosis to bleeding of varying degrees of severity because of disseminated intravascu-

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lar coagulation (DIC). Life-threatening bleeding is frequent in acute leukemias, particu-
larly in acute promyelocytic leukemia (APL). Laboratory assessments show profound he-
mostatic imbalance in this condition, with activation of coagulation, fibrinolysis, and
nonspecific proteolysis systems. An important pathogenetic role is attributed to the leu-
kemic cell properties interfering with the hemostatic mechanisms. However, chemother-
apy and intercurrent infections also contribute to the bleeding risk in the patient with leu-
kemia. In this article, we will attempt to describe what is currently known about the
coagulopathy of acute leukemia, summarize the various aspects of the hemostatic abnor-
malities underlying this disorder, and revise the principal pathogenetic mechanisms. We
will also try to provide information on the current therapeutic tools and recommenda-
tions for the management of life-threatening bleeding in this disease. Finally, a special
focus will be devoted to the management of this complication in the era of all-trans
retinoic acid (ATRA), a drug now indispensable in curing APL that has completely
changed the natural history of APL and its coagulation/bleeding syndrome.

KEYWORDS: Malignancy, leukemia, hypercoagulability, DIC, ATRA

Objectives: Upon completion of this article, the reader should be able to (1) conceptualize the mechanisms underlying the develop-
ment of DIC in patients with acute leukemia and (2) plan appropriate management options for the bleeding associated with the DIC.
Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians. TUSM takes full responsibility for the content, quality, and scientific integrity of
this continuing education activity.
Credit: Tufts University School of Medicine designates this education activity for a maximum of 1.0 hours credit toward the AMA
Physicians Recognition Award in category one. Each physician should claim only those hours that he/she actually spent in the edu-
cational activity.

Thrombohemorrhagic complications are fre-
quent in patients with malignant disease.1,2 Clinical
manifestations can vary from localized deep venous
thrombosis, more frequent in solid tumors, to life-
threatening bleeding because of DIC with consumption
of coagulation factors and platelets, which is generally
associated with leukemias or widespread metastatic
cancer.35 The bleeding or thrombotic manifestations,
or both, represent the tip of the iceberg of a condition
of subclinical or chronic DIC, typically associated with

Seminars in Thrombosis and Hemostasis, volume 27, number 6, 2001. Address for correspondence and reprint requests: A. Falanga, M.D.,
Hematology Department, Ospedali Riuniti, Largo Barozzi 1, 24128 Bergamo, Italy. E-mail: annafalanga@yahoo.com. 1Hematology
Department, Ospedali Riuniti, Bergamo, Italy. Copyright 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662. 0094-6176,p;2001,27,06,593,604,ftx,en;sth00763x.
593
594 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001
all types of malignancy. Indeed, very commonly patients
with solid tumors and leukemias present with abnor-
malities in laboratory tests of blood coagulation, even
without clinical manifestations of thromboembolism or
hemorrhage. These abnormalities demonstrate different
degrees of blood clotting activation and characterize the
so-called hypercoagulable state in these subjects.68
These observations have been confirmed by studies in
experimental animal models with different types of tu-
mors9 and show that tumor growth is associated with
the development of a hypercoagulable condition (or
low-grade intravascular coagulation) in the host.10,11
A very wide variety of laboratory hemostatic altera-
tions has been described in individuals with a malig-
nancy,12,13 demonstrating an activation of coagulation,
fibrinolysis, and compensatory homeostatic mecha-
nisms in this disease.
The relationship between malignancy and ve-
nous thromboembolism in solid tumors has been exten-
sively investigated and is the subject of several reviews.
However, in recent years, there has been new interest in
the severe DIC frequently complicating the onset of
acute leukemias. This interest is due to many factors,
specifically to a better understanding of the biology of
leukemia cells, an improvement in the laboratory tests
for detecting DIC, and, most importantly, the changes
in the management of this complication subsequent to
new therapies for curing leukemia. In this article, we
will focus on the pathogenesis and proposed treatments
of the DIC syndrome occurring in acute leukemia. Spe-
cial attention will also be devoted to the novel an-
tileukemia treatment employing ATRA, a drug that has
modified the natural history of APL in terms of both
the correction of DIC and the cure of leukemia.
PATHOGENESIS
The Coagulopathy of Acute Leukemia
Bleeding manifestations are frequent in acute leu-
kemias, particularly in acute myeloblastic leukemia
(AML), and are prominent in the early phase of the dis-
ease. Hemostatic disorders with consumption of coagu-
lation factors and platelets and thrombocytopenia due
to bone marrow invasion by blast cells are important
causes of these symptoms. Thrombosis of the large ves-
sels is rarely observed in AML, although it is an emerg-
ing problem in acute lymphoblastic leukemia (ALL) in
both children and adults.14
The probability of developing severe hemor-
rhages varies according to the type of acute leukemia
and the type of therapy. APL, the promyelocytic
M3 subtype of AML (according to the FAB classifica-
tion), typically presents with a life-threatening hemor-
rhagic syndrome.3,15 Before the introduction of ATRA
in the management of APL patients, fatal hemorrhages
because of APL-associated coagulopathy were a major
cause of induction remission failure.16 In a multicenter
study of 268 consecutive APL patients treated be-
tween 1984 and 1987, the overall remission rate was
62%, and the prevalence of hemorrhagic deaths in
induction was 14%. The rate of early hemorrhagic
deaths was similar among patients given heparin, an-
tifibrinolytics, or supportive therapy alone for man-
agement of the coagulopathy.17
The abnormalities of the blood clotting system
underlying the clinical pictures of the coagulopathy
well-described in APL include hypofibrinogenemia, in-
creased levels of fibrin degradation products (FDPs),
and prolonged prothrombin and thrombin times.18
These laboratory parameters often become more abnor-
mal with the initiation of cytotoxic chemotherapy, re-
sulting in severe hemorrhagic complications. These
findings reflect a complex interaction of several patho-
physiological processes. Indeed activation of coagula-
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tion, fibrinolysis, and nonspecific proteolysis can occur,
as confirmed by more recent and sophisticated labora-
tory tests. The results of new tests to detect enzyme-
inhibitor complexes and activation peptides demon-
strate that the levels of well-known plasma markers of
clotting activation, in other words, the prothrombin
fragment F1+2 (F1+2), thrombin-antithrombin (TAT)
complex, and fibrinopeptide A (FPA) are abnormally
elevated in this condition.3,19 In addition, plasma mark-
ers indicating ongoing hyperfibrinolysis, including high
levels of FDPs and urokinase plasminogen activator
(u-PA) together with low levels of plasminogen and 2-
antiplasmin, are present.2022 Finally, elevated plasma
levels of leukocyte elastase and fibrinogen split products
of elastase are also detected and demonstrate the activ-
ity of nonspecific proteases.22 New laboratory tests for
subclinical DIC clearly show that thrombin generation
is a constant finding in acute leukemia. Particularly im-
portant in this context is the detection of the D-dimer,
the lysis product of cross-linked fibrin, which shows hy-
perfibrinolysis occurring in response to clotting activa-
tion and fibrin formation in leukemia.2325
One laboratory finding that distinguishes the co-
agulopathy syndrome of acute leukemia from the DIC
associated with other clinical conditions is that the lev-
els of the coagulation inhibitors antithrombin (AT) and
protein C (PC) are often not decreased. This has raised
an argument against the interpretation of this syndrome
as being due to DIC and has led some authors to hy-
pothesize that primary hyperfibrinolysis rather than
DIC is responsible for severe bleeding in leukemia.
However, it must be considered that normal AT levels
are also found in experimental models of DIC26 and
that thrombin can partly be protected by AT inactiva-
tion. Furthermore, both AT and PC are synthesized in
the liver. Their plasma levels in part reflect hepatic
function: it has been demonstrated that in DIC with

hepatic dysfunction they are often decreased, whereas in
DIC without hepatic dysfunction they can be normal.27
Thus, normal AT levels do not exclude DIC in acute
leukemia. Furthermore, although reactive fibrinolysis in
response to clotting activation is well-documented in
this condition, there is no clear definition or specific
tests to define primary hyperfibrino(geno)lysis. The
findings of profound reduction of 2-antiplasmin and
plasminogen, which can be corrected with antifibri-
nolytic agents,28,29 do not allow the distinction between
primary and reactive hyperfibrinolysis. In a recent arti-
cle, Menell et al30 described the increased annexin II
dependent fibrinolytic activity of APL cells in vitro ver-
sus non-APL blasts and hypothesize that this activity is
responsible for primary hyperfibrinolysis in vivo. How-
ever, the assessment of hyperfibrinolysis in the APL pa-
tient plasma still relies on nonspecific tests, in other
words, the levels of fibrinogen, FDPs, and D-dimer.
Particularly, the elevated D-dimer levels rather suggest
reactive hyperfibrinolysis.
Pathogenetic Factors
The intrinsic procoagulant properties of transformed
cells are important pathogenetic factors for the activa-
tion of blood coagulation in malignancy. However,
other factors, such as antitumor therapies and infec-
tions, also contribute to the activation of the hemostatic
system.
As summarized in Table 1, the major determi-
nants for the pathogenesis of the coagulopathy of acute
leukemia are (1) factors associated with leukemia cells,
including the expression of procoagulant, fibrinolytic,
and proteolytic properties, and the secretion of inflam-
matory cytokines, in other words, interleukin-1
(IL-1) and tumor necrosis factor (TNF-); (2) cytotoxic
therapy; and (3) concomitant infectious complications.
LEUKEMIC CELLRELATED FACTORS
Procoagulant Activities Many studies have focused
on the procoagulant activities (PCA) expressed by leu-
kemic cells. At least two cellular procoagulants have
been identified in these cells (Fig. 1): (1) tissue factor
(TF), which acts by forming a complex with factor VII
(FVII) to activate factors X (FX) and IX (FIX) and is
the procoagulant of normal and malignant tissues31,32;
and (2) cancer procoagulant (CP), a cysteine proteinase
that directly activates FX independently of the presence
of FVII33 and has been described in fetal and malignant
tissues.34,35
Studies have identified TF in leukemic cells.32,36,37
Our group has characterized CP in blasts of various
AML phenotypes, with the greatest expression in the
AML-M3 or APL subtype38 and also in 30% of ALL
blasts.39 In AML patients, CP levels appear to be related
DIC IN ACUTE LEUKEMIA/BARBUI, FALANGA 595
Table 1 Pathogenetic Mechanisms of the Hemostatic
System Activation in Malignancy
Tumor cellrelated factors
Tumor cell activities
Procoagulant activities
Fibrinolytic properties
Cytokine release
Tumor cell interaction with other blood cells
Endothelial cells
Monocytes and macrophages
Platelets
Chemotherapy
Infections
to the phase of the disease, in fact this procoagulant has
been detected in the patients bone marrow mononuclear
cells at the onset of the disease but not in samples from
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the same subjects during complete remission.40
More recently CP has been identified in the NB4
cell line, the first human APL line ever isolated, with
the typical t(15;17) chromosomal balanced transloca-
tion. Cellular differentiation induced by ATRA in these
cells was associated with the loss of the capacity to ex-
press CP.41 From studies of this cell line and of cultured
blasts taken from APL patients, it has been shown that
ATRA also depresses the expression of TF.42,43
Furthermore, ATRA exerts its inhibitory effect
on the leukemic cell PCA in vivo as much as in vitro,
and both TF and CP of APL marrow blasts are progres-
sively reduced in patients given ATRA for remission-
induction therapy of APL.25 The demonstration that
this effect parallels the improvement of the plasma hy-
percoagulation parameters provides the first evidence in
vivo for a role of tumor cell PCA in the clotting compli-
cations of malignancy. Reduction of leukemic cell PCA
by ATRA appears to be one mechanism involved in the
resolution of the coagulopathy.
Further studies have shown that CP activity
modulation by ATRA in APL cells is associated with
ATRA-induced cytodifferentiation, whereas TF activity
is reduced by ATRA, also in the absence of ATRA-
induced differentiation, in other words, in ATRA-
resistant cell lines (Fig. 2).44 This is in agreement with
known characteristics of the two procoagulants.
TF is a procoagulant of malignant cells but is also
found in normally differentiated cells.25,41 CP has been
found in extracts of neoplastic cells or in amnion-
chorion tissues but not in extracts of normally differenti-
ated cells.35,45 ATRA also downregulates TF expression
in normal human endothelial cells and monocytes.46,47
The different pathways of regulation of the cell procoag-
ulants CP and TF by ATRA may have important new
implications for these proteins during ATRA therapy in
human leukemia.
596 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001

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Figure 1 Mechanisms of intervention of leukemic cells in the activation of blood coagulation. Leukemic cells express intrinsic pro-
coagulant activities: TF forms a complex with FVII to activate coagulation FIX and FX; CP proteolitically activates FX in the absence
of FVII. Leukemic cells also release proinflammatory cytokines, including IL-1 and TNF-, which induce endothelium thrombogenic-
ity by upregulating the expression of TF, PAI-1 and cell adhesion molecules (CAM) and downregulating the expression of TM.

Fibrinolytic and Proteolytic Properties Fibrinolytic
and proteolytic properties of leukemic cells have long
been described.48 Leukemic promyelocytes contain
both u-PA and tissue plasminogen activator (t-PA).49,50
The two-chain active form (tcu-PA) is prevalent in var-
ious leukemic cells, including those in APL.51 Also the
granulocytic proteases elastase and chymotrypsin have
been identified in the granules of myeloid blasts. When
released into the bloodstream, these proteases are neu-
tralized by their main inhibitor 1-antitrypsin. Indeed
increased plasma levels of elastase-inhibitor complex
have been described in acute leukemia.25,52 These en-
zymes degrade several clotting factors in vitro53 and can
enhance the fibrinolytic system by proteolysing the two
plasmin inhibitors 2-antiplasmin and C1 esterase in-
hibitor.54 Finally, elastase can directly break down the
fibrinogen molecule, producing a pattern of peptides
(FDP) different from those produced by plasmin.55,56
These activities are believed to play a major role
in the pathogenesis of the bleeding syndrome of APL.
However, in a recent study by De Stefano et al,43 leuke-
mic blasts freshly isolated from patients with APL ex-
pressed lower levels of fibrinolytic and proteolytic activ-
ities than mature neutrophils did. Furthermore, the
granulocytic differentiation induced by ATRA was not
associated with changes in these activities in vitro, ex-
cept for an increase of u-PA. Similar results were ob-
tained by others in the non-APL myeloid leukemia cell
line HL60.57 In the study by Menell et al,30 the annexin
IIassociated fibrinolytic activity of leukemic blasts was
increased in APL cells compared with other AML sub-
type or ALL blast cells and was sensitive to ATRA
treatment in NB4 cells. Unfortunately, in that study no
comparison was made with normal mature granulo-
cytes; therefore, it is difficult to understand whether
APL cells are abnormal in this property or may be
closer to normal cells.
Another study of NB4 cell fibrinolytic activity
has demonstrated that retinoids induce a prompt rise of
u-PA activity on the cell surface that is subsequently
downregulated after 24 hours by the production of PA
inhibitors.58 Thus, various mechanisms can contribute
to a reduction of APL cell fibrinolytic potential. These
results agree with our finding that, in spite of changes in
the plasma levels of some fibrinolysis proteins, the over-
all plasma fibrinolytic response (as measured by the eu-
globulin lysis area) is unaffected in APL patients re-
ceiving ATRA.25 In these patients, the initial signs of
reactive hyperfibrinolysis (i.e., elevated D-dimer)
rapidly decreased, yet may reflect the activation of the
fibrinolytic system at a cellular site, where specific re-
ceptors favor the assembly of all the fibrinolytic compo-
 DIC IN ACUTE LEUKEMIA/BARBUI, FALANGA 597

Figure 2 CP and TF are differently modulated by ATRA, a cytodifferentiating agent, in acute promyelocytic leukemia NB4 cells. Two
cell lines, one differentiation sensitive (NB4) and one differentiation resistant (NB4.306), were incubated with 1 M ATRA for 96
hours. The marker of differentiation was the increase in expression of CD11b membrane antigen by the different cells, detected by
cytofluorimetric analysis (left panel). After ATRA treatment, CP was lost only in ATRA-differentiated NB4 cells (middle panel),
whereas TF was reduced in both cell lines (NB4, NB4.306) independently from differentiating mechanisms (right panel). * = p <0.05.

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(Modified from Falanga et al.44)

nents. Thereafter, ATRA-induced synthesis of PA in-
hibitors or annexin II reduction may decrease the cellu-
lar profibrinolytic potential as described in vitro.
Levels of circulating elastase are elevated at the
onset of APL, possibly resulting from cell degranulation
and lysis. We found that these levels were not modified
by ATRA therapy in patients with APL.25 Also, there
was no relation between the plasma elastase concentra-
tion and the levels of the D-dimer or other hemostatic
variables during treatment with ATRA. This raises the
question of whether this enzyme makes an important
contribution to the bleeding disorders of APL.
Cytokine Release Leukemic cells produce inflamma-
tory cytokines, including TNF- and IL-1.59 The evi-
dence that leukemic promyelocytes secrete more IL-1
than APL blasts from patients with DIC than they do
from patients without DIC suggests a role for the blast
cytokines in the pathogenesis of the acute leukemia co-
agulopathy.60 The suggested mechanism involves the
interaction of cytokines with the hemostatic properties
of the vascular endothelium (Fig. 2). TNF-, IL-1,
and endotoxin can induce the expression of the proco-
agulant TF by endothelial cells (EC).61,62 The same cy-
tokines also downregulate the expression of EC throm-
bomodulin (TM), the surface high-affinity receptor for
thrombin.63 The TM-thrombin complex activates the
PC system, which in turn functions as a potent antico-
agulant. Therefore, TF upregulation and TM downreg-
ulation lead to a prothrombotic condition of the vascu-
lar wall.64 In addition, TNF- and IL-1 can stimulate
the EC to produce the t-PA inhibitor plasminogen acti-
vator inhibitor type 1 (PAI-1).65 Inhibition of fibrinoly-
sis contributes to the prothrombotic potential of EC.
Although endotoxin and TNF- can also raise t-PA
levels in vivo, when administered to patients or healthy
volunteers, they rapidly increase t-PA, followed by a
much larger increase of PAI-1.66,67 This demonstrates
that an initial increase of fibrinolytic activity is followed
by a prolonged reduction of fibrinolysis.
ATRA upregulates the ability of leukemic cells to
produce cytokines.68,69 In theory, this effect should favor
the prothrombotic potential of the endothelium, but
this does not happen because of the protective role of
ATRA on EC. ATRA counteracts both the TM down-
regulation and the TF upregulation of the endothelium
induced by TNF-.70 We recently demonstrated that
the TF expression induced in EC by the cytokines con-
tained in the culture medium of APL NB4 cells treated
with ATRA was significantly prevented by the simulta-
neous presence of ATRA on the endothelium.46 There-
fore, although ATRA increases cytokine synthesis by
APL cells, it also protects the endothelium against the
prothrombotic assault of these mediators.
It is worth mentioning here that the endothelium
activation by IL-1 or TNF- also leads to an increase
in the expression of EC surface adhesion molecules.71
These molecules act as counterreceptors for the malig-
nant cell membrane adhesion molecules and are respon-
sible for tumor cell adhesion to EC and the EC ma-
trix.7274 The attachment of the leukemic cell to the
vessel wall is one potential mechanism of vascular com-
plications, because it can promote localized clotting ac-
tivation (through the release of leukemic cell cytokines
and the attachment of other cells, i.e., leukocytes and
platelets). ATRA treatment of APL cells increases the
adhesion capacity of these cells to the endothelium.74
However, we could observe that pretreatment of EC
monolayers with ATRA actually impairs the adhesion
of APL cells to EC. ATRA can exert an antiadhesive
598 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001
effect by downregulating the expression of specific
counterreceptors on the endothelium surface.75
CHEMOTHERAPY
In recent years, there has been increasing evidence that
medical therapies to cure cancer can worsen the pa-
tients thrombophilic state and increase the thrombotic
risk associated with this disease.18,76
Among the postulated mechanisms for anti-
cancer drugrelated activation of blood coagulation are
the (1) release of procoagulants and cytokines from
damaged malignant cells, (2) direct drug toxicity on
vascular endothelium, (3) direct induction of mono-
cyte or tumor cell TF, and (4) decrease in physiological
anticoagulants.
The release of procoagulants and cytokines by
leukemic cells that have been damaged by chemother-
apy is considered responsible for the exacerbation of
DIC observed in laboratory and clinical data upon
starting chemotherapy.5 The downregulation of TF and
CP in APL blast cells in vivo is associated with a reduc-
tion in laboratory and clinical signs of hypercoagulation
in the same subjects, which provides strong evidence for
a role of these activities in the pathogenesis of DIC.25
The release of cytokines in response to chemotherapy
may also have important implications for increasing
clotting activation in vivo. This was suggested by
Bertomeu et al,77 who demonstrated that patient plasma
samples collected post chemotherapy contained higher
levels of IL-1 and were able to increase the adhesion
capacity of the endothelium toward platelets in vitro.
The second mechanism involves the direct dam-
age exerted by chemoradiotherapy on vascular endothe-
lium. An assay published some years ago identified dif-
ferent categories of chemotherapeutic agents on the
basis of the lethal effects they induced on endothelial in-
tegrity in tissue culture.78 These differences may depend
on the different mechanisms of the drug cytotoxicity. In
addition, radiation therapy can cause endothelial injury,
as demonstrated by the release of von Willebrand pro-
tein from cultured EC irradiated with doses up to 40
Gy.79 In animal studies, bleomycin has been implicated
in determining morphological damage to vascular endo-
thelium of the lung, which may result in pulmonary
thrombosis and subsequent fibrosis. Furthermore, adri-
amycin, in some experimental models, directly affected
glomerular cells, impairing their permeability and lead-
ing to a nephrotic syndrome accompanied by hypercoag-
ulation and increased thrombotic tendency.80 The clini-
cal counterpart of this experimental condition has not
yet been completely clarified. However, profound
changes in plasma markers of endothelial damage were
reported in patients receiving chemotherapy.81,82
Another procoagulant mechanism associated to
therapy is due to the capacity of some chemotherapeutic
agents to directly stimulate the expression of TF proco-
agulant activity by macrophages and monocytes.83 This
activity demonstrates that chemotherapy can induce a
procoagulant response from host cells.
The fourth mechanism involves the reduction in
the levels of plasma anticoagulant proteins (AT, PC, and
protein S) induced by chemotherapy treatments.84 This
defect in naturally occurring anticoagulants is likely to
be a consequence of direct hepatotoxity of radiotherapy
and chemotherapy.
In this setting, it is of particular interest to report
the case of L-asparaginase (L-Ase), a drug considered
mainly responsible for vascular complications during
chemotherapy for ALL. L-Ase is known to be toxic to
the liver, pancreas, and central nervous system and is re-
ported to impair the hemostatic system.85 In particular,
significant reductions in fibrinogen, plasminogen,
2-antiplasmin, AT, and PC have been consistently de-
scribed.34,86 These hemostatic abnormalities have been
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considered suggestive of a prothrombotic state, as indi-
cated also by the significant increase of plasma markers,
such as FPA, TAT complex, and F1+2.87 However, the
report from Sarris et al88 of a 12% incidence of throm-
boembolic complications in patients not receiving
L-Ase for the remission induction of ALL casts some
doubt on the role of this drug in the pathogenesis of
vascular events. Rather, in that study, the correlation be-
tween the laboratory signs of hemostatic system impair-
ment and the occurrence of vascular complications sug-
gested that in ALL, as in APL, a systemic clotting
activation with a laboratory picture of DIC is a risk fac-
tor for severe bleeding and thrombosis.
CONCURRENT INFECTIONS
Life-threatening bleeding occurs much more frequently
when patients with acute leukemia have concomitant
infections.89,90 The mechanisms by which infection can
cause bleeding include DIC, thrombocytopenia, and
vascular damage.
Some infections are particularly important in
the setting of acute leukemia, such as viral (cyto-
megalovirus, herpes, varicella), bacterial (sepsis due to
gram-negative or gram-positive microorganisms), and
mycotic (Aspergillus spp.) infections.
In some instances, thrombocytopenia is pro-
duced by suppression of hemostatic function; in other
cases, the drop in platelets or the lack of recovery after
platelet transfusion can be due to increased platelet de-
struction. This latter case may result from a worsening
of the clinical picture of DIC or from the direct interac-
tion between bacteria or viruses and platelets.91,92 This
interaction can produce platelet aggregation, release of
platelet constituents, phagocytosis of the infectious
agent and ultimately a shortened life span. The contri-
bution of infection to bleeding complications is particu-

larly high in gram-negative sepsis. A unique character-
istic of gram-negative bacteria is the presence of endo-
toxin on the cell walls. Endotoxin is a lipopolysaccha-
ride (LPS) possessing a wide variety of biological
effects, in other words, pyrogenic, lethal, hypotensive,
and procoagulant effects. The latter is due to the capac-
ity of LPS to induce TF expression by different cells,
mainly monocytes and endothelial cells. This mecha-
nism of blood clotting activation can trigger or worsen
DIC and thrombocytopenia.93,94
MANAGEMENT OF BLEEDING
AND DIC IN ACUTE LEUKEMIA
As for all the other clinical conditions associated with
severe DIC syndrome, the most important therapeutic
intervention is the cure of the underlying disease. How-
ever, in acute leukemia the early initiation of supportive
measures is of particular importance, also considering
the fact that the start of chemotherapy often worsens
the coagulation/bleeding syndrome. The most impor-
tant supportive tool in this condition is undoubtedly
platelet transfusions; the use of heparin and antifibri-
nolytic agents is still debated and remains uncertain. Fi-
nally, the advent of ATRA to cure APL has started a
new era in the management of this complication and
deserves particular attention.
Platelet Transfusions
Platelet transfusions represent an essential part of the
modern supportive care for all patients with acute leu-
kemia. Prophylactic transfusion of platelets has resulted
in a significant bleeding decrease and prolonged sur-
vival and has allowed for the intensification of chemo-
therapy.95,96 It is important in patients with APL that
the bleeding risk and platelet transfusional require-
ments also remain higher in the retinoic acid era.5 APL
is the variety of acute leukemia in which the correction
of thrombocytopenia with platelet transfusion is of spe-
cial value. In a study conducted by Kantarajian et al,97
the incidence of fatal bleeding in patients with APL was
related to the severity of thrombocytopenia, as well as to
high blast and promyelocyte count, anemia, and ad-
vanced age. Similarly, in a small group of patients with
APL, Goldberg et al98 have shown that the bleeding
tendency could be successfully managed by vigorous
platelet support combined with a prompt start of cyto-
toxic chemotherapy to disrupt the cause of the coagu-
lopathy. This was also our experience: in a series of
65 adults with APL, complete remission (CR) rate was
higher in patients transfused intensively with platelets
and not given heparin.99 Current recommendations for
patients with APL suggest that platelets should be
transfused to maintain the platelet count above 20 
DIC IN ACUTE LEUKEMIA/BARBUI, FALANGA 599
109/L in patients not actively bleeding and above 50 
109/L in patients actively bleeding.3,5
Heparin and Antifibrinolytic Agents
The role of heparin therapy in the treatment of the co-
agulopathy complicating acute leukemia, particularly
APL, is uncertain. The aim of heparinization is to in-
hibit intravascular fibrin formation preventing mi-
crothrombus deposition and to reduce the consumption
of clotting factors and platelets, hence limiting the
bleeding tendency. A compilation of reported series of
patients with APL reveals a statistically significant ben-
efit from the use of the anticoagulant, with a 13% inci-
dence of hemorrhagic deaths being associated with the
use of heparin compared with a 24% death rate without
heparin.3 However, the interpretation of these data re-
quires caution because most studies involve small num-
bers of patients, are retrospective, and are not con-
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trolled. The benefit of heparin therapy has never been
proved by prospective randomized trials. Furthermore,
in several studies the beneficial effects of heparin were
demonstrated by comparing the data with historical se-
ries, thus not taking into account the more intensive
chemotherapy regimens used in the most recent years or
the increased availability of blood products. In a large
retrospective analysis,17 268 consecutive patients were
analyzed: 94 received heparin, 67 received an antifibri-
nolytic agent, and 107 were given only supportive care.
The results indicated no significant benefit with hepa-
rin with respect to the incidence of early hemorrhagic
deaths, CR rate, or overall survival. Thus, the routine
use of heparin in the management of coagulopathy
in patients with acute leukemia cannot be presently
recommended.
Because increased fibrinolytic and other protease
activities5 have been implicated in the pathogenesis of
the coagulopathy, therapeutic regimens including an-
tifibrinolytic agents such as -aminocaproic acid and
tranexamic acid or protease inhibitors such as aprotinin
have been suggested. However, as commented on be-
fore, even most recently published observations fail to
demonstrate the occurrence of primary hyperfibrinoly-
sis in vivo; thus, no clear data are available so far to sup-
port the use of antifibrinolytic drugs for the hemor-
rhagic complications of acute leukemia. The efficacy of
tranexamic acid in controlling the hemorrhagic syn-
drome in APL with a concurrent substantial reduction
of the transfusion requirements has been suggested on
the basis of results obtained with a small series of pa-
tients.37 In addition, it is of great importance to con-
sider the clinical finding of thromboembolism when an-
tifibrinolytic agents are given in the course of ATRA
induction therapy.100 Previous experience with these
agents28 concerns non-ATRAtreated APL patients, so
600 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001
the use of ATRA for APL treatment raises new ques-
tions in this field.
All-trans Retinoic Acid
The advent of ATRA for remission induction therapy
of APL has provided new perspectives in the manage-
ment of this complication. Since the first clinical expe-
riences, ATRA has produced a high rate of CR and a
rapid resolution of the coagulopathy without causing
bone marrow hypoplasia.5,101 ATRA promotes the ter-
minal differentiation of leukemic promyelocytes. In
these cells, the fusion of the nuclear retinoic acid recep-
tor (RAR) gene on chromosome 17 with part of the
PML gene on chromosome 15 results in the expression
of a chimeric PML/RAR protein that is involved in
both the leukemogenesis and the sensitivity to myeloid
differentiation induced by ATRA.28 In nonrandomized
studies, APL patients given ATRA showed a 9 to 20%
improvement in the CR rate and a 5 to 6% reduction of
early hemorrhagic deaths compared with historical con-
trols treated with conventional chemotherapy.5 These
preliminary findings were confirmed more recently by
randomized clinical trials.102105 APL patients treated
with different combinations of ATRA plus chemother-
apy showed a prevalence of early hemorrhagic deaths
ranging between 2.4 and 6.5%.
A number of laboratory studies has documented
the decrease or normalization of clotting and fibrino-
lytic variables during the first 1 or 2 weeks of therapy
with ATRA.2325 In our study,25 plasma hemostatic vari-
ables measured at the onset of APL showed elevated
hypercoagulability markers (TAT, F1+2, D-dimer), low
mean PC, normal AT, normal fibrinolysis proteins, and
increased elastase. After starting ATRA, all markers of
clotting activation and fibrin degradation dropped
Figure 3 Markers of hypercoagulation in patients (n = 9) with APL receiving ATRA for remission induction therapy with or without
chemotherapy. Values (median) of fibrinogen, D-dimer, and TAT complex measured at different time intervals during the first week of
ATRA treatment. After 2 to 4 days of therapy, fibrinogen significantly increased, whereas D-dimer and TAT complex were significantly
reduced. (Modified from Falanga et al.25)
within 4 to 8 days (Fig. 3), PC was increased, the overall
fibrinolytic balance was unchanged, and elastase re-
mained elevated. In addition, ATRA therapy was ac-
companied by reduced proteolysis of von Willebrand
factor.106 The beneficial effect on hypercoagulation and
hyperfibrinolysis parameters paralleled the improve-
ment of clinical signs of the coagulopathy in these pa-
tients. The benefit persisted when ATRA was given in
combination with chemotherapy.14,106
Some of the mechanisms by which ATRA can
interact with the hemostatic system have been eluci-
dated or are currently under investigation.
As discussed before, ATRA can interfere with
each of the principal hemostatic properties of the leuke-
mic cell, including the expression of procoagulant, fibri-
nolytic, and proteolytic activities and the secretion of
inflammatory cytokines, that is IL-1 and TNF-,
which affect the hemostatic system at the vascular en-
dothelium and leukocytes. In particular, the profound
Downloaded by: University of Queensland. Copyrighted material.
inhibitory effect on the expression of the two major
procoagulant activities that parallels the improvement
of hemostatic variables in APL patients, may propose a
mechanism for the beneficial effect observed in vivo in
the correction of the coagulopathy recorded within the
first week of treatment with ATRA.25
However, ATRA can also interfere with the he-
mostatic properties of normal cells, including EC and
monocytes. ATRA was shown to affect the EC coagu-
lant functions. As previously reported, ATRA is able to
counteract both the downregulation of TM and the up-
regulation of TF induced by TNF- and IL-1 in
human EC in vitro.70 In addition to this effect, ATRA
directly increases TM expression by cultured human
EC.107 These effects on endothelium hemostasis pro-
vide evidence for an antithrombotic action of this drug
in tumor and inflammatory diseases. ATRA can also

enhance the EC fibrinolytic functions by stimulating
t-PA production,108 thus inducing the EC to protect
against fibrin deposition.
Furthemore, retinoids modulate several functions
of mononuclear phagocytes, including interleukin-1 and
-3 production. Relevant to this article is the inhibitory
effect of ATRA on the expression of TF by human
monocytes. Like EC, these cells do not constitutively ex-
press TF but respond to different stimuli by generating
and exposing this procoagulant on their surface. Mono-
cyte and macrophage PCA generated in vivo may be im-
plicated in the activation of blood coagulation seen in
certain pathological conditions, including malignancy.109
ATRA dose dependently inhibits the procoagulant re-
sponse induced by endotoxin in human peripheral
mononuclear cells.47 The inhibition of monocyte PCA
generation might help explain the retinoid anticoagulant
effect.
Research insights into this field might result in
an overall improved understanding of the coagulopathy
mechanism in APL and perhaps have therapeutic
relevance.
CONCLUSIONS
In conclusion, a continuous spectrum of coagulation
laboratory abnormalities, indicating an activation of the
hemostatic system, can be detected in patients with ma-
lignancy who remain at increased risk for clotting com-
plications. In acute leukemia, bleeding manifestations
prevail over localized thrombosis of large vessels. The
risk of bleeding, because of thrombocytopenia and mas-
sive blood clotting activation with coagulation factor
consumption, varies according to the type of leukemia
and is maximum in patients with AML, particularly
with the APL subtype. The coagulopathy of APL is
characterized by low fibrinogen levels; prolonged pro-
thrombin and thrombin times; and abnormal plasma
levels of markers of hypercoagulation, hyperfibrinolysis,
and nonspecific proteolysis. The levels of coagulation
inhibitors AT and PC are often normal. This has raised
some arguments against DIC, favoring the hypothesis
of primary hyperfibrinolysis as the major determinant
of severe bleeding in leukemia. However, although sec-
ondary or reactive hyperfibrinolysis occurring in parallel
with the activation of blood coagulation is well-
documented in acute leukemia, primary hyperfibrinoly-
sis cannot be defined or proved by specific tests in this
clinical condition.
Pathogenetic factors for the hemostatic system
activation in leukemia include intrinsic properties of the
leukemic cell and the concurrent role of chemotherapy
and infections. Leukemic cells, like other malignant
cells, possess the capacity to interact with the hemo-
static system in multiple ways. They can directly acti-
vate the coagulation cascade by producing their own
DIC IN ACUTE LEUKEMIA/BARBUI, FALANGA 601
procoagulant factors or they can stimulate the pro-
thrombotic properties of other blood cell components,
including endothelial cells.
Bleeding can be a life-threatening complication
in acute leukemia, particularly APL. Because of the
high mortality risk, prevention of severe bleeding with
appropriate prophylactic platelet transfusion is recom-
mended. Furthermore, the start of chemotherapy and
the occurrence of infections can substantially increase
the rate of these complications. Thus, an effective con-
trol of infective disease is very important. For the time
being, the role of heparin and antifibrinolytic agents in
the control of severe DIC remains uncertain. However,
the advent of ATRA for the cure of APL has radically
changed the perspectives in the management of patients
with these complications.
ACKNOWLEDGMENTS
Downloaded by: University of Queensland. Copyrighted material.
Part of the authors work mentioned in this article has
been supported by Associazione Italiana per la Ricerca
sul Cancro (AIRC).
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