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Acute Leukemia
Tiziano Barbui, M.D.,1 and Anna Falanga, M.D.1
ABSTRACT
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- of coagulation factors and platelets, which is generally
quent in patients with malignant disease.1,2 Clinical associated with leukemias or widespread metastatic
manifestations can vary from localized deep venous cancer.35 The bleeding or thrombotic manifestations,
thrombosis, more frequent in solid tumors, to life- or both, represent the tip of the iceberg of a condition
threatening bleeding because of DIC with consumption 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 because of APL-associated coagulopathy were a major
with solid tumors and leukemias present with abnor- cause of induction remission failure.16 In a multicenter
malities in laboratory tests of blood coagulation, even study of 268 consecutive APL patients treated be-
without clinical manifestations of thromboembolism or tween 1984 and 1987, the overall remission rate was
hemorrhage. These abnormalities demonstrate different 62%, and the prevalence of hemorrhagic deaths in
degrees of blood clotting activation and characterize the induction was 14%. The rate of early hemorrhagic
so-called hypercoagulable state in these subjects.68 deaths was similar among patients given heparin, an-
These observations have been confirmed by studies in tifibrinolytics, or supportive therapy alone for man-
experimental animal models with different types of tu- agement of the coagulopathy.17
mors9 and show that tumor growth is associated with The abnormalities of the blood clotting system
the development of a hypercoagulable condition (or underlying the clinical pictures of the coagulopathy
low-grade intravascular coagulation) in the host.10,11 well-described in APL include hypofibrinogenemia, in-
A very wide variety of laboratory hemostatic altera- creased levels of fibrin degradation products (FDPs),
tions has been described in individuals with a malig- and prolonged prothrombin and thrombin times.18
nancy,12,13 demonstrating an activation of coagulation, These laboratory parameters often become more abnor-
fibrinolysis, and compensatory homeostatic mecha- mal with the initiation of cytotoxic chemotherapy, re-
nisms in this disease. sulting in severe hemorrhagic complications. These
The relationship between malignancy and ve- findings reflect a complex interaction of several patho-
nous thromboembolism in solid tumors has been exten- physiological processes. Indeed activation of coagula-
hepatic dysfunction they are often decreased, whereas in Table 1 Pathogenetic Mechanisms of the Hemostatic
DIC without hepatic dysfunction they can be normal.27 System Activation in Malignancy
Thus, normal AT levels do not exclude DIC in acute Tumor cellrelated factors
leukemia. Furthermore, although reactive fibrinolysis in Tumor cell activities
response to clotting activation is well-documented in Procoagulant activities
this condition, there is no clear definition or specific Fibrinolytic properties
tests to define primary hyperfibrino(geno)lysis. The Cytokine release
findings of profound reduction of 2-antiplasmin and Tumor cell interaction with other blood cells
plasminogen, which can be corrected with antifibri- Endothelial cells
nolytic agents,28,29 do not allow the distinction between Monocytes and macrophages
primary and reactive hyperfibrinolysis. In a recent arti- Platelets
cle, Menell et al30 described the increased annexin II Chemotherapy
dependent fibrinolytic activity of APL cells in vitro ver- Infections
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 to the phase of the disease, in fact this procoagulant has
words, the levels of fibrinogen, FDPs, and D-dimer. been detected in the patients bone marrow mononuclear
Particularly, the elevated D-dimer levels rather suggest cells at the onset of the disease but not in samples from
Fibrinolytic and Proteolytic Properties Fibrinolytic cept for an increase of u-PA. Similar results were ob-
and proteolytic properties of leukemic cells have long tained by others in the non-APL myeloid leukemia cell
been described.48 Leukemic promyelocytes contain line HL60.57 In the study by Menell et al,30 the annexin
both u-PA and tissue plasminogen activator (t-PA).49,50 IIassociated fibrinolytic activity of leukemic blasts was
The two-chain active form (tcu-PA) is prevalent in var- increased in APL cells compared with other AML sub-
ious leukemic cells, including those in APL.51 Also the type or ALL blast cells and was sensitive to ATRA
granulocytic proteases elastase and chymotrypsin have treatment in NB4 cells. Unfortunately, in that study no
been identified in the granules of myeloid blasts. When comparison was made with normal mature granulo-
released into the bloodstream, these proteases are neu- cytes; therefore, it is difficult to understand whether
tralized by their main inhibitor 1-antitrypsin. Indeed APL cells are abnormal in this property or may be
increased plasma levels of elastase-inhibitor complex closer to normal cells.
have been described in acute leukemia.25,52 These en- Another study of NB4 cell fibrinolytic activity
zymes degrade several clotting factors in vitro53 and can has demonstrated that retinoids induce a prompt rise of
enhance the fibrinolytic system by proteolysing the two u-PA activity on the cell surface that is subsequently
plasmin inhibitors 2-antiplasmin and C1 esterase in- downregulated after 24 hours by the production of PA
hibitor.54 Finally, elastase can directly break down the inhibitors.58 Thus, various mechanisms can contribute
fibrinogen molecule, producing a pattern of peptides to a reduction of APL cell fibrinolytic potential. These
(FDP) different from those produced by plasmin.55,56 results agree with our finding that, in spite of changes in
These activities are believed to play a major role the plasma levels of some fibrinolysis proteins, the over-
in the pathogenesis of the bleeding syndrome of APL. all plasma fibrinolytic response (as measured by the eu-
However, in a recent study by De Stefano et al,43 leuke- globulin lysis area) is unaffected in APL patients re-
mic blasts freshly isolated from patients with APL ex- ceiving ATRA.25 In these patients, the initial signs of
pressed lower levels of fibrinolytic and proteolytic activ- reactive hyperfibrinolysis (i.e., elevated D-dimer)
ities than mature neutrophils did. Furthermore, the rapidly decreased, yet may reflect the activation of the
granulocytic differentiation induced by ATRA was not fibrinolytic system at a cellular site, where specific re-
associated with changes in these activities in vitro, ex- 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.
nents. Thereafter, ATRA-induced synthesis of PA in- levels in vivo, when administered to patients or healthy
hibitors or annexin II reduction may decrease the cellu- volunteers, they rapidly increase t-PA, followed by a
lar profibrinolytic potential as described in vitro. much larger increase of PAI-1.66,67 This demonstrates
Levels of circulating elastase are elevated at the that an initial increase of fibrinolytic activity is followed
onset of APL, possibly resulting from cell degranulation by a prolonged reduction of fibrinolysis.
and lysis. We found that these levels were not modified ATRA upregulates the ability of leukemic cells to
by ATRA therapy in patients with APL.25 Also, there produce cytokines.68,69 In theory, this effect should favor
was no relation between the plasma elastase concentra- the prothrombotic potential of the endothelium, but
tion and the levels of the D-dimer or other hemostatic this does not happen because of the protective role of
variables during treatment with ATRA. This raises the ATRA on EC. ATRA counteracts both the TM down-
question of whether this enzyme makes an important regulation and the TF upregulation of the endothelium
contribution to the bleeding disorders of APL. induced by TNF-.70 We recently demonstrated that
the TF expression induced in EC by the cytokines con-
Cytokine Release Leukemic cells produce inflamma- tained in the culture medium of APL NB4 cells treated
tory cytokines, including TNF- and IL-1.59 The evi- with ATRA was significantly prevented by the simulta-
dence that leukemic promyelocytes secrete more IL-1 neous presence of ATRA on the endothelium.46 There-
than APL blasts from patients with DIC than they do fore, although ATRA increases cytokine synthesis by
from patients without DIC suggests a role for the blast APL cells, it also protects the endothelium against the
cytokines in the pathogenesis of the acute leukemia co- prothrombotic assault of these mediators.
agulopathy.60 The suggested mechanism involves the It is worth mentioning here that the endothelium
interaction of cytokines with the hemostatic properties activation by IL-1 or TNF- also leads to an increase
of the vascular endothelium (Fig. 2). TNF-, IL-1, in the expression of EC surface adhesion molecules.71
and endotoxin can induce the expression of the proco- These molecules act as counterreceptors for the malig-
agulant TF by endothelial cells (EC).61,62 The same cy- nant cell membrane adhesion molecules and are respon-
tokines also downregulate the expression of EC throm- sible for tumor cell adhesion to EC and the EC ma-
bomodulin (TM), the surface high-affinity receptor for trix.7274 The attachment of the leukemic cell to the
thrombin.63 The TM-thrombin complex activates the vessel wall is one potential mechanism of vascular com-
PC system, which in turn functions as a potent antico- plications, because it can promote localized clotting ac-
agulant. Therefore, TF upregulation and TM downreg- tivation (through the release of leukemic cell cytokines
ulation lead to a prothrombotic condition of the vascu- and the attachment of other cells, i.e., leukocytes and
lar wall.64 In addition, TNF- and IL-1 can stimulate platelets). ATRA treatment of APL cells increases the
the EC to produce the t-PA inhibitor plasminogen acti- adhesion capacity of these cells to the endothelium.74
vator inhibitor type 1 (PAI-1).65 Inhibition of fibrinoly- However, we could observe that pretreatment of EC
sis contributes to the prothrombotic potential of EC. monolayers with ATRA actually impairs the adhesion
Although endotoxin and TNF- can also raise t-PA 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 agents to directly stimulate the expression of TF proco-
counterreceptors on the endothelium surface.75 agulant activity by macrophages and monocytes.83 This
activity demonstrates that chemotherapy can induce a
CHEMOTHERAPY procoagulant response from host cells.
In recent years, there has been increasing evidence that The fourth mechanism involves the reduction in
medical therapies to cure cancer can worsen the pa- the levels of plasma anticoagulant proteins (AT, PC, and
tients thrombophilic state and increase the thrombotic protein S) induced by chemotherapy treatments.84 This
risk associated with this disease.18,76 defect in naturally occurring anticoagulants is likely to
Among the postulated mechanisms for anti- be a consequence of direct hepatotoxity of radiotherapy
cancer drugrelated activation of blood coagulation are and chemotherapy.
the (1) release of procoagulants and cytokines from In this setting, it is of particular interest to report
damaged malignant cells, (2) direct drug toxicity on the case of L-asparaginase (L-Ase), a drug considered
vascular endothelium, (3) direct induction of mono- mainly responsible for vascular complications during
cyte or tumor cell TF, and (4) decrease in physiological chemotherapy for ALL. L-Ase is known to be toxic to
anticoagulants. the liver, pancreas, and central nervous system and is re-
The release of procoagulants and cytokines by ported to impair the hemostatic system.85 In particular,
leukemic cells that have been damaged by chemother- significant reductions in fibrinogen, plasminogen,
apy is considered responsible for the exacerbation of 2-antiplasmin, AT, and PC have been consistently de-
DIC observed in laboratory and clinical data upon scribed.34,86 These hemostatic abnormalities have been
larly high in gram-negative sepsis. A unique character- 109/L in patients not actively bleeding and above 50
istic of gram-negative bacteria is the presence of endo- 109/L in patients actively bleeding.3,5
toxin on the cell walls. Endotoxin is a lipopolysaccha-
ride (LPS) possessing a wide variety of biological
effects, in other words, pyrogenic, lethal, hypotensive, Heparin and Antifibrinolytic Agents
and procoagulant effects. The latter is due to the capac- The role of heparin therapy in the treatment of the co-
ity of LPS to induce TF expression by different cells, agulopathy complicating acute leukemia, particularly
mainly monocytes and endothelial cells. This mecha- APL, is uncertain. The aim of heparinization is to in-
nism of blood clotting activation can trigger or worsen hibit intravascular fibrin formation preventing mi-
DIC and thrombocytopenia.93,94 crothrombus deposition and to reduce the consumption
of clotting factors and platelets, hence limiting the
bleeding tendency. A compilation of reported series of
MANAGEMENT OF BLEEDING patients with APL reveals a statistically significant ben-
AND DIC IN ACUTE LEUKEMIA efit from the use of the anticoagulant, with a 13% inci-
As for all the other clinical conditions associated with dence of hemorrhagic deaths being associated with the
severe DIC syndrome, the most important therapeutic use of heparin compared with a 24% death rate without
intervention is the cure of the underlying disease. How- heparin.3 However, the interpretation of these data re-
ever, in acute leukemia the early initiation of supportive quires caution because most studies involve small num-
measures is of particular importance, also considering bers of patients, are retrospective, and are not con-
the use of ATRA for APL treatment raises new ques- within 4 to 8 days (Fig. 3), PC was increased, the overall
tions in this field. fibrinolytic balance was unchanged, and elastase re-
mained elevated. In addition, ATRA therapy was ac-
companied by reduced proteolysis of von Willebrand
All-trans Retinoic Acid factor.106 The beneficial effect on hypercoagulation and
The advent of ATRA for remission induction therapy hyperfibrinolysis parameters paralleled the improve-
of APL has provided new perspectives in the manage- ment of clinical signs of the coagulopathy in these pa-
ment of this complication. Since the first clinical expe- tients. The benefit persisted when ATRA was given in
riences, ATRA has produced a high rate of CR and a combination with chemotherapy.14,106
rapid resolution of the coagulopathy without causing Some of the mechanisms by which ATRA can
bone marrow hypoplasia.5,101 ATRA promotes the ter- interact with the hemostatic system have been eluci-
minal differentiation of leukemic promyelocytes. In dated or are currently under investigation.
these cells, the fusion of the nuclear retinoic acid recep- As discussed before, ATRA can interfere with
tor (RAR) gene on chromosome 17 with part of the each of the principal hemostatic properties of the leuke-
PML gene on chromosome 15 results in the expression mic cell, including the expression of procoagulant, fibri-
of a chimeric PML/RAR protein that is involved in nolytic, and proteolytic activities and the secretion of
both the leukemogenesis and the sensitivity to myeloid inflammatory cytokines, that is IL-1 and TNF-,
differentiation induced by ATRA.28 In nonrandomized which affect the hemostatic system at the vascular en-
studies, APL patients given ATRA showed a 9 to 20% dothelium and leukocytes. In particular, the profound
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)
DIC IN ACUTE LEUKEMIA/BARBUI, FALANGA 601
enhance the EC fibrinolytic functions by stimulating procoagulant factors or they can stimulate the pro-
t-PA production,108 thus inducing the EC to protect thrombotic properties of other blood cell components,
against fibrin deposition. including endothelial cells.
Furthemore, retinoids modulate several functions Bleeding can be a life-threatening complication
of mononuclear phagocytes, including interleukin-1 and in acute leukemia, particularly APL. Because of the
-3 production. Relevant to this article is the inhibitory high mortality risk, prevention of severe bleeding with
effect of ATRA on the expression of TF by human appropriate prophylactic platelet transfusion is recom-
monocytes. Like EC, these cells do not constitutively ex- mended. Furthermore, the start of chemotherapy and
press TF but respond to different stimuli by generating the occurrence of infections can substantially increase
and exposing this procoagulant on their surface. Mono- the rate of these complications. Thus, an effective con-
cyte and macrophage PCA generated in vivo may be im- trol of infective disease is very important. For the time
plicated in the activation of blood coagulation seen in being, the role of heparin and antifibrinolytic agents in
certain pathological conditions, including malignancy.109 the control of severe DIC remains uncertain. However,
ATRA dose dependently inhibits the procoagulant re- the advent of ATRA for the cure of APL has radically
sponse induced by endotoxin in human peripheral changed the perspectives in the management of patients
mononuclear cells.47 The inhibition of monocyte PCA with these complications.
generation might help explain the retinoid anticoagulant
effect.
ACKNOWLEDGMENTS
Research insights into this field might result in
REFERENCES
CONCLUSIONS
In conclusion, a continuous spectrum of coagulation 1. Rickles FR, Edwards RL. Activation of blood coagulation in
laboratory abnormalities, indicating an activation of the cancer: Trousseaus syndrome revisited. Blood 1983;62:1431
hemostatic system, can be detected in patients with ma- 2. Falanga A, Rickles FR. Pathophysiology of the throm-
lignancy who remain at increased risk for clotting com- bophilic state in the cancer patient. Semin Thromb Hemost
plications. In acute leukemia, bleeding manifestations 1999;25:173182
3. Tallman MS, Kwaan HC. Reassessing the hemostatic disor-
prevail over localized thrombosis of large vessels. The
der associated with acute promyelocytic leukemia. Blood
risk of bleeding, because of thrombocytopenia and mas- 1992;79:543553
sive blood clotting activation with coagulation factor 4. Barbui T, Finazzi G, Falanga A. The management of bleed-
consumption, varies according to the type of leukemia ing and thrombosis in acute leukemia and chronic myelopro-
and is maximum in patients with AML, particularly liferative disorders. In: Henderson ES, Lister TA, Greaves
with the APL subtype. The coagulopathy of APL is MF, eds. Leukemia, 7th ed. Philadelphia: W.B. Saunders;
characterized by low fibrinogen levels; prolonged pro- 2001: Chapter 16
5. Barbui T, Finazzi G, Falanga A. The impact of all-trans-
thrombin and thrombin times; and abnormal plasma
retinoic acid on the coagulopathy of acute promyelocytic
levels of markers of hypercoagulation, hyperfibrinolysis, leukemia. Blood 1998;91:30933102
and nonspecific proteolysis. The levels of coagulation 6. Rickles FR, Levine MN, Edwards RL. Hemostatic alter-
inhibitors AT and PC are often normal. This has raised ations in cancer patients. Cancer Met Rev 1992;11:237248
some arguments against DIC, favoring the hypothesis 7. Falanga A, Barbui T, Rickles FR, Levine MN. Guidelines
of primary hyperfibrinolysis as the major determinant for clotting studies in cancer patients. Thromb Haemost
of severe bleeding in leukemia. However, although sec- 1993;70:343350
8. Falanga A, Ofosu FA, Delaini F, et al. The hypercoagulable
ondary or reactive hyperfibrinolysis occurring in parallel
state in cancer: Evidence for impaired thrombin inhibition.
with the activation of blood coagulation is well- Blood Coagul Fibrinolysis 1994;5:S19S23
documented in acute leukemia, primary hyperfibrinoly- 9. Poggi A, Donati MB, Garattini S. Fibrin and cancer cell
sis cannot be defined or proved by specific tests in this growth: Problems in the evaluation of experimental models.
clinical condition. In: Donati MB, Davison JF, Garattini S, eds. Malignancy
Pathogenetic factors for the hemostatic system and the Hemostatic System. New York: Raven Press; 1981:
activation in leukemia include intrinsic properties of the 89101
10. Lyman GH, Bettigole RE, Robson E, Ambrus JL, Urban H.
leukemic cell and the concurrent role of chemotherapy
Fibrinogen kinetics in patients with neoplastic disease. Can-
and infections. Leukemic cells, like other malignant cer 1978;41:11131122
cells, possess the capacity to interact with the hemo- 11. Bani MR, Falanga A, Alessio MG, et al. Blood coagulation
static system in multiple ways. They can directly acti- changes in nude mice bearing human colon carcinomas. Int J
vate the coagulation cascade by producing their own Cancer 1992;50:7579
602 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001
12. Edwards RL, Rickles FR, Moritz TE, et al. Abnormalities 33. Falanga A, Gordon SG. Isolation and characterization of
of blood coagulation tests in patients with cancer. Am J Clin cancer procoagulant: A cysteine proteinase from malignant
Pathol 1987;88:596602 tissue. Biochemistry 1985;24:55585567
13. Goad KE, Gralnick HR. Coagulation disorders in cancer. 34. Donati MB, Gambacorti Passerini C, Casali B, et al. Cancer
Hematol Oncol Clin North Am 1996;10:457484 procoagulant in human tumor cells: Evidence from mela-
14. Barbui T, Finazzi G, Falanga A, Battista R, Bassan R. noma patients. Cancer Res 1986;46:64716474
Bleeding and thrombosis in acute lymphoblastic leukemia. 35. Gordon SG, Hashiba U, Poole MA, Cross BA, Falanga A. A
Leuk Lymphoma 1993;11(Suppl 2):4347 cysteine proteinase procoagulant from amnion-chorion.
15. Warrell RP, de The H, Wang ZY, Degos L. Acute promy- Blood 1985;66:12611265
elocytic leukemia. N Engl J Med 1993;329:177189 36. Gouault-Heilman M, Chardon E, Sultan E, Josso F. The
16. Fenaux P. Management of acute promyelocytic leukemia. procoagulant factor of leukemic promyelocytes: Demonstra-
Eur J Haematol 1993;50:6573 tion of immunologic cross-reactivity with human brain tis-
17. Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli sue factor. Br J Haematol 1975;30:151158
F. Early deaths and anti-hemorrhagic treatments in acute 37. Bauer KA, Conway EM, Bach R, et al. Tissue factor gene
promyelocytic leukemia. A GIMEMA retrospective study in expression in acute myeloblastic leukemia. Thromb Res
268 consecutive patients. Blood 1990;75:21122117 1989;56:425430
18. Falanga A. Mechanisms for hypercoagulation in malignancy 38. Falanga A, Alessio MG, Donati MB, Barbui T. A new pro-
and during chemotherapy. Haemostasis 1998;28(Suppl 3): coagulant in acute leukemia. Blood 1988;71:870875
5060 39. Alessio MG, Falanga A, Consonni R, et al. Cancer procoag-
19. Bauer KA, Rosenberg RD. Thrombin generation in acute ulant in acute lymphoblastic leukemia. Eur J Haematol
promyelocytic leukaemia. Blood 1984;64:791796 1990;45:7881
52. Egbring R, Schmidt W, Fuchs G, Havemann K. Demon- 68. Dubois C, Schlageter MH, de Gentile A, et al. Modulation
stration of granulocytic proteases in plasma of patients with of IL-8, IL-1, and G-CSF by all-trans retinoic acid in
acute leukemia and septicemia with coagulation defects. acute promyelocytic leukemia. Leukemia 1994;8:17501757
Blood 1977;49:219231 69. Giann M, Norio P, Terao M, et al. The effect of dexametha-
53. Schmidt W, Egbring R, Havemann K. Effect of elastase- sone on proinflammatory cytokine expression, cell growth
like and chymotrypsin-like neutral proteases from human and maturation during granulocytic differentiation of acute
granulocytes on isolated clotting factors. Thromb Res 1975; promyelocytic leukemia cells. Eur Cytokine Network 1995;
6: 315329 6:157165
54. Brower MS, Harpel PC. Proteolytic cleavage and inactiva- 70. Ishii H, Horie S, Kizaki K, Kazama M. Retinoic acid coun-
tion of -2-plasmin inhibitor and C1 inactivator by human teracts both the downregulation of thrombomodulin and the
polymorphonuclear leukocyte elastase. J Biol Chem 1982; induction of tissue factor in cultured human endothelial cells
257:98499854 exposed to tumor necrosis factor. Blood 1992;80:25562562
55. Sterrenberg L, van Liempt GJ, Nieuwenhuizen W, Her- 71. Mantovani A, Bussolino F, Dejana E. Cytokine regulation
mans J. Anticoagulant properties of purified X-like frag- of endothelial cell function. FASEB J 1992;6:25912599
ments of human fibrinogen produced by degradation with 72. Giavazzi R, Foppolo M, Dossi R, Remuzzi A. Rolling and
leukocyte elastase. Thromb Haemost 1984;51:398402 adhesion of human tumor cells on vascular endothelium
56. Sterrenberg L, Nieuwenhuizen W, Hermans J. Purification under physiological flow conditions. J Clin Invest 1993;92:
and characterization of a D-like fragment from human fi- 30383044
brinogen produced by human leukocyte elastase. Biochim 73. Rickles FR, Edwards RL. Leukocytes and tumor cells in
Biophys Acta 1983;775:300306 thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman
57. Wijermans PW, Rebel VI, Ossenkoppele GJ, Huijgens PC, EW, eds. Hemostasis and Thrombosis. Basic Principles and
function in children with leukemia. J Clin Oncol 1987; 100. Hashimoto S, Koike T, Tatewaki W, et al. Fatal thromboem-
5:811817 bolism in acute promyelocytic leukemia during all-trans-
87. Leone G, Gugliotta L, Mazzucconi MG, et al. Evidence of a retinoic acid therapy combined with antifibrinolytic therapy
hypercoagulable state in patients with acute lymphoblastic for prophylaxis of hemorrhage. Leukemia 1994;8:
leukemia treated with low dose of E. coli L-asparaginase: A 11131115
GIMEMA study. Thromb Haemost 1993;69:1215 101. Castaigne S, Chomienne, Daniel MT, et al. All-trans
88. Sarris AH, Kempin S, Berman E, et al. High incidence of retinoic acid as a differentation therapy for acute promyelo-
disseminated intravascular coagulation during remission in- cytic leukemia. Blood 1990;76:17041709
duction of adult patients with acute lymphoblastic leukemia. 102. Tallman MS, Andersen JW, Schiffer CA, et al. A prospec-
Blood 1992;79:13051310 tive randomized study of all-trans-retinoic acid induction
89. Anderlini P, Luna M, Kantarjian HM, et al. Causes of initial and maintenance therapy for patients with acute promyelo-
remission induction failure in patients with acute myeloid cytic leukemia. N Engl J Med 1997;337:10211028
leukemia and myelodysplastic syndromes. Leukemia 1996; 103. Burnett AK, Grimwade D, Solomon E, et al. Presenting
10:600608 white blood cell count and kinetics of molecular remission
90. Bishop JF, Lowenthal RM, Joshua D, et al. Etoposide in predict prognosis in acute promyelocytic leukemia treated
acute nonlymphocytic leukemia. Blood 1990;75:2732 with all-trans-retinoic acid: Results of the randomized
91. Clawson CC, Rao GHR, White JG. Platelet interaction MRC trial. Blood 1999;93:41314143
with bacteria. IV Stimulation of the release reaction. Am J 104. Fenaux P, Chastang C, Chevret S, et al. A randomized com-
Pathol 1975;81:411420 parison of all trans-retinoic acid (ATRA) followed by
92. MacIntyre DE, Allen AP, Thorne KJI. Endotoxin-induced chemotherapy and ATRA plus chemotherapy and the role
platelet aggregation and secretion I. Morphological changes of maintenance therapy in newly diagnosed acute promyelo-