Hematology

ISSN: (Print) 1607-8454 (Online) Journal homepage: https://www.tandfonline.com/loi/yhem20

Thrombosis and acute leukemia

Erick Crespo-Solís

To cite this article: Erick Crespo-Solís (2012) Thrombosis and acute leukemia, Hematology,
17:sup1, s169-s173, DOI: 10.1179/102453312X13336169156852

To link to this article: https://doi.org/10.1179/102453312X13336169156852

Published online: 12 Nov 2013.

Submit your article to this journal

Article views: 1041

View related articles

Citing articles: 2 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=yhem20
Thrombosis and acute leukemia
Erick Crespo-Solı́s
Clı́nica de Leucemia Aguda, Departamento de Hematologı́a y Oncologı́a, Instituto Nacional de Ciencias Médicas
y Nutrición Salvador Zubirán, Mexico City, Mexico

Thrombosis is a common complication in patients with acute leukemia. While the presence of central
venous lines, concomitant steroids, the use of Escherichia coli asparaginase and hereditary thrombophilic
abnormalities are known risk factors for thrombosis in children, information on the pathogenesis, risk
factors, and clinical outcome of thrombosis in adult patients with acute lymphoid leukemia (ALL) or acute
myeloid leukemia (AML) is still scarce. Expert consensus and guidelines regarding leukemia-specific risk
factors, thrombosis prevention, and treatment strategies, as well as optimal type of central venous catheter
in acute leukemia patients are required. It is likely that each subtype of acute leukemia represents a
different setting for the development of thrombosis and the risk of bleeding. This is perhaps due to a
combination of different disease-specific pathogenic mechanisms of thrombosis, including the type of
chemotherapy protocol chosen, the underlying patients health, associated risk factors, as well as the
biology of the disease itself. The risk of thrombosis may also vary according to ethnicity and prevalence of
hereditary risk factors for thrombosis; thus, it is advisable for Latin American, Asian, and African countries
to report on their specific patient population.
Keywords: Acute leukemia, Thrombosis, Risk factors

Thrombosis and Cancer Prophylaxis with low-molecular-weight heparin

Thrombosis is a common complication in cancer
patients and the association between these two
entities has been known for centuries. Deep venous
thrombosis and pulmonary embolism (PE) are the
most common cancer-associated thrombotic events.
Cancer patients account for 20% of all patients with
venous thromboembolism (VTE), and in recent years,
the reported incidence has been as high as 28% of
hospitalized cancer patients.1
The mortality rate in patients with cancer and
thrombosis is higher (16.3%) than in those without
thrombosis (6.3%), particularly in patients who
develop PE (24.8%).2 Some tumor types are more
likely to be associated with the development of
thromboses: pancreas, brain, ovary, and lung. About
10% of patients with idiopathic VTE will be diagnosed
with cancer within the following 10 years (more than
75% will be diagnosed within the first year).3
A validated scoring system predicting the develop-
ment of VTE in cancer patients has been proposed,
and is appropriate for solid tumors;4 yet, its para-
meters such as high leucocyte or platelet counts, are
not useful for patients with acute leukemia.
Correspondence to: E. Crespo-Solı́s, Clı́nica de Leucemia Aguda,
Departamento de Hematologı́a y Oncologı́a, Instituto Nacional de Ciencias
Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Sección XVI,
Tlalpan, CP 14000 Mexico City. Mexico. Email: erickerickmx@
yahoo.com.mx
(LMWH) or unfractionated heparin is indicated in
patients with cancer undergoing major surgery. This
same prophylactic measures may benefit medical
oncology patients admitted to the hospital with an
acute illness.3 However, prophylaxis may represent a
risk per se in patients with acute leukemia with very
low platelet counts or with coagulation disorders.
Initial treatment of VTE consists of anticoagulant
therapy; LMWH or unfractionated heparin are the
preferred frontline drugs. Secondary prophylaxis with
vitamin K antagonists can also be initiated on the
same day as heparin therapy. Treatment must be
adjusted to maintain an international normalized ratio
within 2.0–3.0. The annual incidence of recurrent VTE
in patients without cancer is 8%, but in patients with
cancer, this rate increases two- to threefold. This could
be a consequence of the difficulty in maintaining
an optimal international normalized ratio in these
patients, due to drug interactions, anorexia, malnutri-
tion, liver dysfunction, and poor gastrointestinal
tolerance,3 as well as the presence of tumor-related
prothrombotic factors such as mechanical vascular
compression or an increase in molecular activators of
coagulation due to the overexpression of tissue factor
by malignant cells.
The Italian Society for Haemostasis and Thrombosis
recommends LMWH for the first 6 months in patients
with VTE and hematological malignancies. In patients

ß W. S. Maney & Son Ltd 2012

DOI 10.1179/102453312X13336169156852 Hematology 2012 VOL . 17 SUPPL . 1 S 169
Crespo-Solı́s Thrombosis in patients with acute leukemia
with severe and prolonged thrombocytopenia, the use
of LMWH is preferable to oral anticoagulant therapy.5
Recommendations for treatment of thrombosis in
patients with cancer are mostly based on studies of
patients with solid tumors.3,5,6 Guidelines for prophy-
laxis and management of VTE based on prospective
studies conducted in acute leukemia patients are
lacking.
Thrombosis and Acute Leukemia
Patients with acute leukemia present both an
increased risk of hemorrhage, as well as of thrombo-
sis. The incidence of thrombosis varies between 2 and
36%.7–14
Relevant aspects regarding patients with acute
leukemia and thrombosis are as follows:
1. association between central catheters and throm-
bosis and its clinical variability on presentation
(symptomatic or asymptomatic);
2. association between L-asparaginase during induc-
tion chemotherapy and thrombosis in patients with
acute lymphoid leukemia (ALL);
3. recognition of thrombosis as a frequent and
perhaps underestimated complication in patients
with acute promyelocytic leukemia (APL);
4. inconsistencies among reports in the literature
regarding risk factors for thrombosis (gender, age,
leukemia subtype, catheter characteristics, comor-
bidity, and genetic mutations) and their impact on
overall survival.
ALL
As with any other disease, patients with ALL develop
thromboses as a result of an interaction of factors.
According to current evidence, the main contributors
include the disease itself, the type of administer-
ed chemotherapy, central venous catheters (CVC),
genetic abnormalities, as well as an acquired predis-
position. Most published studies are in pediatric
patients. As reported by Athale and Chan,15 the
average incidence of thrombosis in children with ALL
is 3%. According to a prospective study in adults with
ALL, the incidence of thrombosis increases to 9.6%.10
Variation in the incidence of thrombosis depends on
several factors, such as the study design, prospective
versus retrospective,16,17 whereby the former tend to
report higher incidences of thrombotic phenomena.
Furthermore, studies designed to detect asymptomatic
thrombosis have also reported increased thrombosis
incidence rates.15 The incidence of thrombosis is also
related to the treatment regimen.
The German group has reported different inci-
dence rates of thrombosis when comparing patients
receiving the Berlin–Frankfurt–Münster (BFM) or
the Cooperative Study Group for Childhood Acute
Lymphoblastic Leukemia (COALL) chemotherapy
protocols. Patients receiving the COALL protocol
had a 0.8% incidence of thrombosis during induction
chemotherapy, whereas patients receiving the BFM
S170 Hematology 2012 VOL . 17 SUPPL . 1
protocol had an incidence of 10%. Several risk factors
were evaluated in the multivariate analysis. Only
the concomitant administration of Escherichia coli
asparaginase/prednisone to leukemic children with a
prothrombotic risk factor was found to increase the
risk of thrombosis (odds ratio: 34.5; 95% confidence
interval: 4.39–271.42; P50.0008). Interestingly, the
differences in thrombosis rates were observed only
during induction chemotherapy.18
The incidence of thrombosis also varies according
to the study period (before or after 1990). The overall
incidence of VTE in studies conducted or reported
before or after 1990 is 1.8 and 4.7%, respectively. This
may be possibly explained by improved diagnostic
methods, different chemotherapy regimens or an
increase in suspicion and confirmation of the
diagnosis of thrombosis.15 Regarding the site of
thrombosis, a reported 52% of patients with central
nervous system thromboembolism have venous sinus
involvement. Thrombosis may affect overall survival,
quality of life, and cognitive function. There are no
data regarding the recurrence of thrombosis in this
population. Patients are reported to have residual
neurological deficits or seizure disorders. Associated
morbidity is approximately 15–20% in cases of cen-
tral nervous system (CNS) thrombosis.15
L-asparaginase decreases plasminogen, fibrinogen,
and antithrombin, resulting in impaired thrombin
inhibition which may contribute to the asparaginase-
related dose-limiting toxicity.19-21 Changes in anti-
thrombin (AT) and fibrinogen during induction che-
motherapy with L-asparaginase were reported in a
retrospective study of 214 adult patients with ALL.22
The median AT levels decreased from 120 to 59%
after the fourth L-asparaginase infusion. AT levels
below 60% were found in 50% of cases. Fibrinogen
levels decreased from 2.9 g/l at diagnosis, to 1.9 g/l
before the first infusion, they continued to decrease
after the first 10 days of induction therapy and
reached a median value of 1.1 g/l at the time of the
fourth L-asparaginase infusion. Infusion of AT
concentrate was followed by a significant increase in
AT levels, from 61 to 88%. Fibrinogen levels
significantly increased after fibrinogen concentrate
administration, from 1 to 1.4 g/l. Fresh frozen plasma
was not effective in significantly ameliorating AT or
fibrinogen levels. The incidence of thrombosis was
9.8% during induction therapy and all thrombotic
events occurred within 2–35 days after the first
injection of L-asparaginase during induction che-
motherapy. No mention of catheter-related throm-
boses was made, but 25% of thrombotic events
developed in the upper limbs. The use of oral
contraceptives was more frequent in women with
thrombosis than in those without. Other factors such
as familial thrombophilia, previous thrombosis, age,

AT levels ,60%, fibrinogen levels ,0.5 g/l and low
doses of heparin were similar between groups of
patients with and without thrombosis. The complete
remission rate was similar in patients with and
without thrombosis, but thrombus development was
associated with a decreased median overall survival
(19 months versus 53 months), as well as a decreased
disease-free survival (14 months versus 58 months).
Some studies have reported a genetic prothrombo-
tic predisposition as an important host factor in
the development of VTE in children with ALL,23
whereas others have failed to demonstrate such an
association.24 Whether to administer primary antic-
oagulant prophylaxis with LMWH to children with
ALL during induction chemotherapy, remains con-
troversial. A recent retrospective study of 80 children
with ALL,25 demonstrated an incidence of genetic
thrombophilia of 22.5% (factor II G20210A and
factor V Leiden). These patients received prophylac-
tic enoxaparin, but 7.5% developed thromboembolic
events. VTE was not detected in patients with factor
V Leiden, suggesting that ALL patients with the PT
gene mutation are at increased risk of developing
clotting complications in comparison with those
harboring the factor V Leiden mutation.
All patients with acute leukemia require placement
of a CVC for cytotoxic chemotherapy administration.
All types of CVCs are associated with infection and
thrombosis. Actually, thrombosis is a risk factor for
developing infection of the CVC and this association
has been documented for over 25 years.26,27 Autopsy
and venographic studies have demonstrated that soon
after the insertion of a catheter, practically all will
develop a fibrin sheath.28,29
Different diagnostic methods have been used to
demonstrate that the aforementioned fibrin sheaths
are always colonized by cocci.30–32 The type of
catheter-related thrombosis may be due to either
clotting of the lumen (13–93%) or the development of
mural thrombi in the vessel where the catheter is
placed (12–74%).33–35
Approximately, a third of CVC-related thromboses
are symptomatic. Factors favoring the development of
CVC-related thromboses include malignancy, throm-
bophilia, endothelial cell injury due to the CVC itself or
to chemotherapy, the position of the catheter in the
vascular system and the number of catheter lumens.34
The most important sequelae are pulmonary emboli,
post-phlebitic syndrome, and infection, with an esti-
mated frequency of 6, 15–35, and 18%, respectively.33
Acute Myeloid Leukemia (AML)
Additional risk factors for VTE in AML patients
include the increased expression of tissue factor in
leukemic cells, its activation on cellular surfaces, and
hyperleukocytosis.36 Treatment of VTE in AML
Crespo-Solı́s Thrombosis in patients with acute leukemia
patients is challenging, because of the considerable
risk of hemorrhage due to severe thrombocytopenia
and coagulation and/or fibrinolysis abnormalities. A
patient with bleeding and PE is not an uncommon
picture for clinicians treating AML, especially at
diagnosis and during the induction phase.
Thromboses are treated with LMWH. Monitoring
of anti-Xa and maintenance of peak levels between
0.5 and 1 IU/ml in patients with renal failure, obesity,
pregnancy, and children, as well as close observation
of the platelet count are mandatory. LMWH should
be decreased by 50%, if the platelet count drops to
50610(9)/l or below, or temporarily discontinued if
,20610(9)/l.37
Important data obtained by Ku et al.11 in a
population-based cohort, was used to determine the
incidence of thrombosis in an American population
(California) of 5394 patients with AML or ALL. The
2-year cumulative incidence of VTE was 5.2%,
comparable to that in patients with solid tumors.
Interestingly, 64% of thrombotic events developed
within the first 3 months of the leukemia diagnosis.
Risk factors for VTE in AML included female
gender, older age, the number of chronic comorbid-
ities, and the presence of an indwelling catheter. In
ALL patients, the 2-year cumulative incidence of
VTE was 4.5%. Risk factors for VTE included the
presence of a central venous catheter, older age, and
the number of chronic comorbidities. As opposed to
AML patients in whom survival was not affected by
VTE, ALL individuals had a 40% increase in the risk
of death during the first year after diagnosis.
APL
APL patients present a particular scenario, whereby
fatal hemorrhages due to disseminated intravascular
coagulation were the major cause of early death be-
fore the use of all trans-retinoic acid as part of the
induction treatment. Currently, the rate of fatal he-
morrhages ranges between 2.4 and 6.5%.38 Increased
fibrinolysis has been documented and overexpression
of annexin A2 may be one of the underlying
mechanisms, conditioning the hemorrhagic complica-
tions in these patients. Abnormally high levels of
annexin A2 on APL cells increase plasmin generation
that in turn, activates fibrinolysis. Furthermore,
annexin II mRNA levels are reduced after treatment
with all trans-retinoic acid39 and arsenic trioxide.40
Thrombosis is probably an underestimated complica-
tion in APL patients.41 Concomitant hemorrhage and
thrombosis have also been reported during induction
chemotherapy. A retrospective study of 34 consecutive
APL patients in a single referral center in Israel,
reported an incidence of severe thrombosis of 12%.
Life-threatening bleeding occurred in 29% of patients.
The most consistent hemostatic abnormality was
Hematology 2012 VOL . 17 SUPPL . 1 S 171
Crespo-Solı́s Thrombosis in patients with acute leukemia
decreased fibrinogen (,150 mg/dl) in 61% of cases. On
multivariate analysis, only the leukocyte count
(,30610(9)/ml) reached statistical significance as a
predictor of bleeding. Interestingly, none of the hemo-
static parameters (platelet, fibrinogen, PT, and APTT)
were identified as risk factors for bleeding or
thrombosis. Of note, three out six patients with
thrombotic events were found to be thrombophilic.42
There is a case report of a patient with APL who
developed splenic, renal, and intestinal infarction
due to severe acquired protein C deficiency; no evi-
dence of disseminated intravascular coagulation was
documented.43 In an Italian study,44 patients with
thrombosis had a higher white blood cell count and an
increased prevalence of the short PML/RARA iso-
form (bcr3), FLT3/ITD, CD2, and CD5 expression.
The PETHEMA study45 did not confirm these
thrombosis risk factors. Instead, the identified risk
factors included: fibrinogen ,170 mg/dl, an M3
variant at diagnosis and tranexamic acid prophylaxis
during induction chemotherapy.
Conclusions
Thrombosis is a common complication in patients
with acute leukemia. Most of the information on ALL
patients has been obtained from studies in children
and the information in adult patients remains scant.
Expert consensus and guidelines on risk factors,
optimum catheter care, use and management, preven-
tion and treatment of thrombosis are required. The
role of newer anticoagulants needs to be explored in
multicenter clinical trials, and risk factors should be
standardized, in order to understand the disease’s
pathogenesis and provide adequate treatment to these
patients within a complicated setting of thrombosis
and hemorrhage.
Ideally, guidelines should be based on prospectively
designed studies conducted only in patients with acute
leukemia. Furthermore, they should be designed sepa-
rately, according to leukemia subtype (ALL, AML,
and APL). It is very probable that each acute leukemia
subtype represents a different physiopathogenic set-
ting favoring the development of thrombosis.
References
1 Khorana AA. Venous thromboembolism and prognosis in
cancer. Thromb Res. 2010;125:490–3.
2 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman
GH, James P. Frequency, risk factors, and trendsfor venous
thromboembolism among hospitalized cancer patients. Cancer.
2007;110:2339–46.
3 Lee AY. Epidemiology and management of venous throm-
boembolism in patients with cancer. Thromb Res.
2003;110:167–72.
4 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis
CW. Development and validation of a predictive model for
chemotherapy-associated thrombosis. Blood. 2008;111:4902–7.
5 Imberti D, di Nisio M, Donati MB, Falanga A, Ghirarduzzi A,
Guarneri D, et al. Treatment of venous thromboembolism in
patients with cancer: guidelines of the Italian Society for
S172 Hematology 2012 VOL . 17 SUPPL . 1
Haemostasis and Thrombosis (SISET). Thromb Res.
2009;124:e32–40.
6 Louzada ML, Majeed H, Wells PS. Efficacy of low-molecular-
weight-heparin versus vitamin K antagonists for long term
treatment of cancer-associated venous thromboembolism in
adults: a systematic review of randomized controlled trials.
Thromb Res. 2009;123:837–44.
7 Ziegler S, Sperr WR, Knöbl P, Lehr S, Weltermann A, Jäger U,
et al. Symptomatic venous thromboembolism in acute leuke-
mia: incidence, risk factors and impact on prognosis. Thromb
Res. 2005;115:59–64.
8 Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M,
Lutze G, Franke A. Increased risk of venous thromboembolism
in patients with acute leukemia. Br J Cancer. 2006;94:200–2.
9 de Stefano V, Sorà F, Rossi E, Chiusolo P, Laurenti L, Fianchi
L, et al. The risk of thrombosis in patients with acute leukemia:
ocurrence of thrombosis at diagnosis and during treatment. J
Thromb Haemost. 2005;3:1985–92.
10 Melillo L, Grandone E, Colaizzo D, Cappucci F, Valvano MR,
Cascavilla N. Symptomatic venous thromboembolism and
thrombophilic status in adult acute leukemia: a single center
experience of 114 patients at diagnosis. Acta Haematol.
2007;117:215–20.
11 Ku GH, White RH, Chew HK, Harvey DJ, Zhou H, Wun T.
Venous thromboembolism in patients with acute leukemia.
Incidence, risk factors and effect on survival. Blood.
2009;113:3911–7.
12 Athale UH, Chan AK. Thrombosis in children with acute
lymphoblastic leukemia Part I. Epidemiology of thrombosis in
children with acute lymphoblastic leukemia. Thromb Res.
2003;11:125–31.
13 Athale U, Siciliano S, Thabane L, Pai N, Cox S, Lathia A, et al.
Epidemiology and clinical risk factors predisposing to throm-
boembolism in children with cancer. Pediatr Blood Cancer.
2008;51:792–7.
14 Caruso V, Lacoviello L, di Castelnuevo A, Storti S, Mariani G,
de Gaetano G, et al. Thrombotic complications in childhood
acute lymphoblastic leukemia: a meta-analysis of 17 prospective
studies comprising 1752 pediatric patients. Blood.
2006;108:2216–22.
15 Payne JH, Vora AJ. Thrombosis and acute lymphoblastic
leukemia. Br J Haematol. 2007;138:430–45.
16 Korte W, Fledges A, Baumgartner C, Ullmann S, Niederer V,
Schmid L. Increased thrombin generation during fibrinogen
and platelet recovery as an explanation for hypercoagulability
in children with L-asparaginase therapy for ALL or NHL: a
preliminary report. Klin Padiatr. 1994;206:331–3.
17 Sutor AH, Mall V, Thomas KB. Bleeding and thrombosis in
children with acute lymphoblastic leukemia, treated according
to the ALL-BFM-90 ptrotocol. Klin Padiatr. 1999;211:201–4.
18 Nowak-Göttl U, Heinecke A, von Kries R, Nürnberger W,
Münchow N, Junker R. Thrombotic events revisited in children
with acute lymphoblastic leukemia. Impact of concomitant
Escherichia coli asparaginase/prednisone administration.
Thromb Res. 2001;103:165–72.
19 Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD,
Clavell LA, et al. Improved outcome for children with acute
lymphoblastic leukemia: results of the Dana-Farber
Consortium Protocol 91-01. Blood. 2001;97:1211–8.
20 Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M.
Increased endogenous thrombin generation in children with
ALL: risk of thrombotic complications in L-asparaginase
induced antithrombin deficiency. Blood. 1994;83:386–91.
21 Bushman JE, Palmieri D, Whinna HC, Church FC. Insight into
the mechanism of asparaginase-induced depletion of antith-
rombin III in treatment of childhood ALL. Leuk Res.
2000;24:559–65.
22 Hunault-Berger M, Chevallier P, Delain M, Bulabois CE,
Bologna S, Bernard M, et al. Changes in antithrombin and
fibrinogen levels during induction chemotherapy with L-
asparaginase in adult patients with acute lymphoblastic
leukemia or lymphoblastoc lymphoma. Use of supportive
coagulation therapy and clinical outcome: the CAPELAL
study. Haematologica. 2008;93;1488–94.
23 Nowak-Gottl U, Wermes C, Junker R, Koch HG, Schobess R,
Fleischhack G, et al. Prospective evaluation of the thrombotic
risk in children with ALL carrying the MTHFR TT 677
genotype, the prothrombine G20210A variant and further
prothrombotic risk factors. Blood. 1999;93:1595–9.
24 Mitchell LG, Andrew M, Hanna K, Abshire T, Halton J,
Anderson R, et al. A prospective cohort study determining the

prevalence of thrombotic events in children with ALL and a
central venous line who are treated with L-aparaginase: results
of the Prophylactic Antithrombin Replacement in Kids with
ALL Treated with sparaginase (PARKAA) study. Cancer.
2003;97:508–16.
25 Harlev D, Zaidman I, Sarig G, Ben Arush MW, Brenner B,
Elhasid R. Prophylactic therapy with enoxaparin in children
with acute lymphoblastic leukemia and inherited thrombophilia
during L-asparaginase treatment. Thromb Res. 2010;126:93–7.
26 Press OW, Ramsey PG, Larson EB, Fefer A, Hickman RO.
Hickman catheter infections in patients with malignancies.
Medicine (Baltimore). 1984;63:189–200.
27 Raad II, Luna M, Khalil SA, Costerton JW, Lam C, Bodey
GP. The relationship between the thrombotic and infection
complications of central venous catheters. JAMA.
1994;271:1014–6.
28 Balestreri L, de Cicco M, Matorio M, Coran F, Morassut S.
Central venous catheter-related thrombosis in clinically asymp-
tomatic oncologic patients: a plebography study. Eur J Radiol.
1995;20:108–11.
29 de Cicco M, Matorio M, Balstreri L, Panarello G, Fantin D,
Morassut S, et al. Central venous thrombosis: an early and
frequent complication in cancer patients bearing long-term
silastic catéter. A prospective study. Thromb Res. 1997;86:101–
13.
30 Starkhammar H, Bengtsson M, Morales O. Fibrin sleeve
formation after long term brachial catheterization with
implantable port device. A prospective study. Eur J Surg.
1992;158:481–4.
31 Raad I, Custerton W, Sabharwal U, Sacilowski M, Anaissie E,
Bodey GP. Ultrastructural analysis of indwelling vascular
catheters: a quantitative relationship between luminal coloniza-
tion during of placement. J Infect Dis. 1993;168:400–7.
32 Tenney JH, Moody MR, Newman KA, Schimpff SC, Wade JC,
Costerton JW, et al. Adherent microorganisms on luminal
surfaces of a long-term intravenous catheters. Importance of
Staphylococcus epidermidis in patient with cancer. Arch Intern
Med. 1986;146:1949–54.
33 Kuter DJ. Thrombotic complications of central venous
catheters in cancer patients. The Oncologist. 2004;9:207–16.
Crespo-Solı́s Thrombosis in patients with acute leukemia
34 Hurtubise MR, Bottino JC, Lawson M, McCredie KB.
Restoring patency of occluded central venous catheters. Arch
Surg. 1980;115:212–3.
35 Beckers MM, Ruven HJ, Seldenrijk CA, Prins MH, Biesma
DH. Risk of thrombosis and infections of central venous
catheters and totally implanted access ports in patients treated
for cancer. Thromb Res. 2010;125:318–21.
36 Oehadian A, Iqhal M, Sumantri R. Deep vein thrombosis in
acute myelogenous leukemia. Acta Med Indones-Indones J
Intern Med. 2009;41:200–4.
37 Falanga A, Rickles FR. Management of thrombohemorrhagic
syndrome (THS) in hematologic malignancies. Hematology.
2007;165–71.
38 Falanga A, Marchetti M. Venous thromboembolism in the
hematological malignancies. J Clin Oncol. 2009;27:4848–57.
39 Menell JS, Cesarman GM, Andrew T, McLaughlin MA, Lev
EA, Hajjar KA. Annexin II and bleeding in acute promyelo-
cytic leukemia. N Eng J Med. 1999;340:994–1004.
40 Liu YH, Wang ZY, Shen WH. Influence of arsenic trioxide and
daunorubicin on the expression of annexin II and fibrinolytic
activity in NB4 cells. Zhongua Xue Ye Xue Za Zhi.
2010;12:813–6. Chinese.
41 Sanz MA, Montesinos P. Open issues on bleeding and
thrombosis in acute promyelocytic leukemia Thromb Res.
2010;125 Suppl 2:S51–4.
42 Dally N, Hoffman R, Haddad N, Sarig G, Rowe JM, Brenner
B. Predictive factors of bleeding and thrombosis during
induction therapy in acute promyelocytic leukemia — a single
center experience in 34 patients. Thromb Res. 2005;116:109–14.
43 Kwaan HC, Huyck T. Thromboembolic and bleeding compli-
cations in acute leukemia. Expert Rev Hematol. 2010;6:719–30.
44 Breccia M, Avvisati G, Latagliata R, Carmosino I, Guarini A,
de Propris MS, et al. Occurrence of thrombotic events in acute
promyelocytic leukemia correlates with consistent immunophe-
notyping and molecular features. Leukemia. 2007;21:79–83.
45 Montesinos P, de la Serna J, Vellenga E, Rayon C, Bergua J,
Parody R, et al. Incidence and risk factors for thrombosis in
patients with acute promyelocytic leukemia. Experience of the
PETHEMA LPA96 and LPA99 Protocols. Blood (ASH Ann
Meet Abstr). 2006;108:1503.
Hematology 2012 VOL . 17 SUPPL . 1 S 173