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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1595-1599
Prospective Evaluation of the Thrombotic Risk in Children With Acute
Lymphoblastic Leukemia Carrying the MTHFR TT 677 Genotype, the
Prothrombin G20210A Variant, and Further Prothrombotic Risk Factors
By
Ulrike Nowak-Göttl,
Cornelia Wermes,
Ralf Junker,
Hans-Georg Koch,
Rosmarie Schobess,
Gudrun Fleischhack,
Dirk Schwabe, and
Silke Ehrenforth
From the Pediatric Hematology/ Oncology and Institute of Clinical and
Laboratory Medicine/Institute of Atherosclerosis Research, University
Hospitals Bonn, Frankfurt, Halle, Hanover, and
Münster, Germany.
 |
ABSTRACT |
The reported incidence of thromboembolism in children with acute
lymphoblastic leukemia (ALL) treated with L-asparaginase, vincristine,
and prednisone varies from 2.4% to 11.5%. The present study was
designed to prospectively evaluate the role of the TT677 methylenetetrahydrofolate reductase (MTHFR) genotype, the prothrombin G20210A mutation, the factor V G1691A mutation,
deficiencies of protein C, protein S, antithrombin, and increased
lipoprotein (a) concentrations in leukemic children treated according
to the ALL-Berlin-Frankfurt-Muenster (BFM) 90/95 study
protocols with respect to the onset of vascular events. Three hundred
and one consecutive leukemic children were enrolled in this study.
Fifty-five of these 301 subjects investigated had one established
single prothrombotic risk factor: 20 children showed the TT677 MTHFR genotype; 5 showed the heterozygous prothrombin G20210A variant; 11 were carriers of the factor V G1691A mutation (heterozygous, n = 10;
homozygous, n = 1); 4 showed familial protein C, 4 protein S, and 2 antithrombin type I deficiency; 9 patients were suffering from
familially increased lipoprotein (a) [Lp(a)] concentrations (>30
mg/dL). In addition, combined prothrombotic defects were found in a
further 10 patients: the FV mutation was combined with the prothrombin
G20210A variant (n = 1), increased Lp(a) (n = 3), protein
C deficiency (n = 1), and homozygosity for the C677T MTHFR
gene mutation (n = 1). Lp(a) was combined with protein C deficiency
(n = 2) and the MTHFR TT 677 genotype (n = 2). Two hundred
eighty-nine of the 301 patients were available for thrombosis-free survival analysis. In 32 (11%) of these 289 patients venous
thromboembolism occurred. The overall thrombosis-free survival in
patients with at least one prothrombotic defect was significantly
reduced compared with patients without a prothrombotic defect within
the hemostatic system (P < .0001). In addition, a clear-cut
positive correlation (P < .0001) was found between thrombosis
and the use of central lines. However, because the prothrombotic
defects diagnosed in the total childhood population studied were all
found within the prevalences reported for healthy Caucasian
individuals, the interaction between prothrombotic risk factors, ALL
treatment, and further environmental factors is likely to cause
thrombotic manifestations.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ALTERATIONS IN HEMOSTASIS have been
frequently observed in patients with acute lymphoblastic leukemia
(ALL), and thrombotic events are well documented in children receiving
L-asparaginase (ASP) as a single agent or in combination with
vincristine or prednisone, sometimes complemented by an
anthracycline.1-7 Escherichia coli ASP preparations
of different sources8-10 and dosages,5 including Erwinia ASP,11 are involved in venous occlusion.
In addition, thrombotic complications are described in leukemic
patients who received the drug intravenously3-5,12
and by intramuscular injection.9,10,13,14 The
reported incidence of vascular accidents in these patients varies from
2.4% to 11.5%.3,4,8,10,13,14
Besides numerous clinical conditions associated with enhanced thrombin
generation, thrombophilia in otherwise healthy individuals is caused by
inherited defects as well as protein deficiencies or dysfunction
involved in the hemostatic process. These disorders include mainly
defects of the protein C pathway: the factor V (FV) G1691A mutation,
protein C deficiency, or protein S deficiency. Deficiencies or
dysfunction of antithrombin, plasminogen, or fibrinogen have also been
reported to be associated with an increased thrombotic risk.15-18 Furthermore, the recently described G20210A
variant of the prothrombin gene and the TT677 genotype of the
methylenetetrahydrofolate reductase (MTHFR) seem to be common but
probably mild risk factors for venous thromboembolism.19-22
In addition, increased concentrations of lipoprotein (a) [Lp(a)]
greater than 30 mg/dL are found in patients with venous
thrombosis.23
Vascular insults reported in children with ALL are discussed mainly in
association with acquired quantitative deficiencies of protein C,
protein S, or antithrombin associated with enhanced thrombin
generation.1-3,5-7 However, we have recently found a possible association between thromboembolism in leukemic children treated according to the BFM protocols and the heterozygous FV G1691A
mutation.5,24 Because no prospective data are available so
far with respect to the thrombotic risk in children with ALL carrying
one or more prothrombotic risk factors, the present multicenter study
was conducted. Focused on hypercoagulability prevalences of the MTHFR
TT677 genotype, the prothrombin G20210A allele and further genetic
prothrombotic defects possibly affecting venous thrombosis in leukemic
children were investigated.
| |
PATIENTS AND METHODS |
Inclusion criteria.
Children greater than 6 months of age with acute onset of ALL treated
according to the BFM 90/95 induction/reinduction protocols between
December 1994 and June 1998 were included in this prospective multicenter study.
Exclusion criteria.
Leukemic children less than 6 months of age, leukemic children with
concomitant chronic diseases, subjects without complete remission of
the disease (day 30 of the induction protocol), hepatic failure, severe
septicemia, and adolescents with oral contraceptives or nicotine abuse
were excluded from the study (n = 5). In addition, all patients with a
known prothrombotic defect receiving heparin prophylactically
(individual decisions by the participating centers) were excluded from
the thrombosis-free survival analysis (n = 7).
Patients.
From December 1994 until June 1998, 301 newly diagnosed leukemic
children (median/range age, 5.5 years/6 months to 18 years; male, n = 158; female, n = 143) treated according to the ALL-BFM 90/95 study
protocols25 were prospectively enrolled in this study.
Leukemia therapy.
The induction treatment protocol for childhood ALL requires E
coli ASP medac (Kyowa, Hakko, Kyogo, Japan) in doses of 5,000 U/m2 at 3-day intervals, starting on day 12 through to day
33 (eight doses). Prednisone (60 mg/m2) on days 1 to 36 and
weekly vincristine (1.5 mg/m2) as well as daunorubicine (30 mg/m2) on days 8 and 15 (standard risk) and on days 22 and
29 (medium risk) are additional elements of therapy. In addition, ALL
children received prophylactically intrathecal methotrexate on days 1, 12, 30, 45, and 59 during induction therapy. In reinduction therapy the
children received ASP medac 10,000 U/m2 on days 8, 11, 15, and 18, along with dexamethasone (10 mg/m2) on days 1 to
21, weekly vincristine (1.5 mg/m2), and doxorubicin (30 mg/m2) on days 8, 15, 22, and 29, respectively.25 Depending on the individual decisions by
the participating centers, polychemotherapy was administered via
peripheral veins or via Broviac, Hickman, or Porth catheters implanted
within the first weeks of therapy. Prophylactically, Broviac and
Hickman catheters not in daily use were heparin-blocked at 7-day
intervals and Porth catheters were heparin-blocked every 4 weeks, in
each case with approximately 200 IU of unfractionated heparin.
Blood sampling.
With informed parental consent, at the onset of the disease
before induction therapy was started, blood samples were
collected by peripheral venipuncture into 3-mL plastic tubes containing 3.8% trisodium citrate (1/10 by volume; Sarstedt, Nümbrecht, Germany) and placed immediately on melting ice. Platelet-poor plasma
was prepared by centrifugation at 3,000g for 20 minutes at
4°C, aliquoted in polystyrene tubes, stored at  70°C, and
thawed immediately before the assay procedure. For genetic analysis, venous blood was collected in EDTA-treated sample tubes (Sarstedt) from
which cells were separated by centrifugation at 3,000g for 15 minutes. The buffy-coat layer was then removed and stored at 70°C until DNA extraction was performed by standard techniques.
Assays for gene analysis.
In all subjects, the presence of the C677T MTHFR gene mutation was
investigated by amplification by polymerase chain reaction (PCR) and
digestion of the fragment by endonuclease HinfI.20 The G20210A substitution in the prothrombin gene was detected by PCR
amplification and HindIII digestion,19 and the
G1691A mutation in the factor V gene was amplified and digested with Mnl I as previously reported.18
Assays for plasmatic factors.
Laboratory evaluation included evaluation of protein C activity with
chromogenic substrate S-2366 (Coamatic Protein C; Chromogenix, Mölndal, Sweden; intraassay/interassay reproducibilities are 1.6%/2.8% at 50% protein C activity and 0.8%/1.7% at 100% protein C activity) and Lp(a) concentration (TintElize Lp(a); Biopool, Umea,
Sweden; CVs within/between days are 6.6%/7.7% at 10 mg/dL and
2.3%/2.7% at 40 mg/dL), both measured as described
earlier.23 Free protein S antigen was measured with
enzyme-linked immunosorbent assay (ELISA) technique (Asserachrom free
protein S, Stago, Ansieres-sur-Seine, France: intraassay/interassay
reproducibilities are 2.25%/2.74% at 100% of free protein S antigen
and 3.37%/3.62% at 50% protein S antigen) and antithrombin by
enzymatic procedure using chromogenic substrate S-2765 (Chromogenix;
CVs within/between days are 3.1%/2.5% at 50% antithrombin activity
and 4.8%/4.3% at 100% antithrombin activity). In addition, in all
individuals carrying the homozygous TT677 MTHFR genotype, fasting
plasma homocysteine concentrations were measured by high-performance
liquid chromatography using reagents and standards from Immuno (Vienna,
Austria: Cvs within/between days are 2.2%/3.5%).26
For classification of protein C and antithrombin
deficiency, a heterozygous type I deficiency state was
diagnosed when functional plasma activity and immunological antigen
concentration of the protein were below the lower age-related
limit.27,28 A type II deficiency was diagnosed with
repeatedly low functional activity levels along with normal antigen
concentrations. The diagnosis of protein S deficiency was based on
reduced free protein S antigen levels combined with decreased or normal
total protein S antigen concentrations, respectively. In addition, to
exclude artifically diluted protein C, protein S, or antithrombin
plasma activities due to dilution effects, a hematocrit correction was
performed in children with hematocrit readings less than 30% at the
onset of the disease.29 Criteria for the hereditary nature
of a hemostatic defect were its presence in at least one further first-
or second-degree family member and/or the identification of a
causative gene mutation.
Study end points.
The diagnosis of venous thrombosis used as the end point of this study
was made if, in a symptomatic patient, echogenic material was found
within the lumen of a vein on gray scale and if partial or complete
absence of flow was shown by pulse-wave and color Doppler sonography.
In addition, venography was used in children with suspected vascular
occlusion in the upper extremity, and cerebral venous thromboses were
diagnosed with magnetic resonance imaging or computed tomography.
Ethics.
The present multicenter study was performed in accordance with the
ethical standards laid down in a relevant version of the 1964 Declaration of Helsinki and approved by the medical ethics committee at
the Westfälische Wilhelms-University, Münster, Germany.
Statistics.
Statistical analysis was performed with the Stat View program (Abacus
Concepts, Berkeley, CA). The log-rank test adjusted for age was used to
compare the thrombosis-free survival in ALL patients carrying a
prothrombotic risk factor with ALL children without a prothrombotic
risk in the hemostatic system. The chi-square analysis was used to
describe the correlation between vascular accidents and the use of
central lines. In addition, Fischer's exact test was used to compare
thrombotic manifestations in children with two or more prothrombotic
risk factors versus one defect, respectively.
| |
RESULTS |
Thrombotic manifestations.
After exclusion of 12 leukemic children as defined in the Patients and
Methods section, 32 (male, n = 21; female, n = 11; 11%) of the
remaining 289 consecutive patients with ALL suffered venous
thromboembolism during induction (n = 29; protocol days 21 to 36) and
reinduction (n = 3; protocol days 18 to 21) therapy. Median age at
thrombotic onset was 5.5 years, ranging from 6 months to 15 years. With
a median age of 5 years, ranging from 6 months to 17 years, the age
distribution of the remaining ALL children was no different from the
thrombosis group.
In the majority of cases cerebral venous thrombosis was diagnosed (n = 15), five times associated with a central line placed in the internal
jugular vein; superior caval vein thrombosis was documented in 13, occlusion of femoral and pelvic veins in 2, and superficial vein
occlusion in a further 2 patients.
The thrombosis-free survival time during ALL treatment according to the
ALL-BFM 90/95 study protocols in patients carrying at least one
prothrombotic risk factor compared with children carrying no thrombotic
risk factor is shown in Fig 1. Twenty-seven out of 58 (46.5%) leukemic children with a prothrombotic defect were
suffering from venous thrombosis compared with 5 out of 231 (2.2%)
children with no identified prothrombotic defect (P < .0001; chi-square 137.0). In addition, a clear-cut positive correlation (P < .0001; chi-square 84.8) between thrombosis and the use
of central lines was found in ALL children with at least one
established prothrombotic risk factor within the hemostatic system.
View larger version (14K):
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| Fig 1.
Thrombosis-free cumulative survival in children with ALL.
Prothrombotic defects within the hemostatic system (27 out of 58)
versus children without a prothrombotic defect diagnosed so far (5 out
of 231).
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Thrombosis-associated deaths.
A 16-month-old girl with venous sinus thrombosis due to protein C
deficiency type I and secondary intracranial bleeding died on day 36 protocol I.
Table 1 shows single (n = 19) and combined
(n = 8) prothrombotic conditions predisposing for thrombosis found
among 32 symptomatic children out of 289 leukemic patients included in
the survival analysis. In addition, we can show clearly an increased
risk of thrombotic complications in patients with combined
prothrombotic risk factors compared with ALL children suffering from at
least one established prothrombotic defect (P = .009). No
thrombotic risk factors have been found in 5 patients so far.
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Table 1.
Single (n = 19) and Combined (n = 8)
Prothrombotic Risk Factors Found Among 32 Symptomatic Children With
ALL (Absolute and Relative Frequencies)
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Interestingly, the 7 ALL patients carrying a prothrombotic risk factor
and receiving prophylactic heparin administration and therefore
excluded from the statistical analysis did not suffer thromboembolism
during the study period.
Prevalence of single established prothrombotic risk factors.
Fifty-five (18.2%) out of the total of 301 subjects investigated had
one established single prothrombotic risk factor: the TT677 MTHFR
genotype was found in 20 children, while 5 showed the heterozygous
prothrombin G20210A variant, and 11 were carriers of the FV G1691A gene
mutation (heterozygous, n = 10; homozygous, n = 1). With respect to the
definitions given in the Patients and Methods section
(age-dependency,27,28 hematocrit correction29) 4 showed protein C deficiency type I, 4 protein S deficiency type I, 2 antithrombin deficiency type I, and 9 familially increased Lp(a)
concentrations greater than 30 mg/dL.
Prevalence of combined prothrombotic risk factors.
Combined prothrombotic defects were found in a further 10 (3.2%)
patients investigated; the heterozygous FV G1691A mutation was combined
with high Lp(a) concentrations (n = 3), protein C type I deficiency (n = 1), the prothrombin 20210A allele (n = 1), and homozygosity for the
MTHFR C677T gene mutation (n = 1). Lp(a) greater than 30 mg/dL was combined with protein C type I deficiency (n = 2) and
homozygosity for the MTHFR TT677 genotype (n = 2). No type II protein
deficiencies were found in the population studied.
Homocysteine concentrations in patients with the TT677 MTHFR
genotype.
In the 23 leukemic patients with the TT677 MTHFR genotype, total
fasting homocysteine concentrations were as follows: greater than 18 µmol/L, n = 7; 12 to 17 µmol/L, n = 2; 9 to 11 µmol/L, n = 5;
less than 9 µmol/L, n = 9, respectively. However, fasting total
homocysteine concentrations in the 7 homozygous carriers of the TT677
MTHFR gene mutation and thrombosis were clearly elevated greater than
20 µmol/L.
| |
DISCUSSION |
The present prospective multicenter study was focused on the role of
prothrombotic risk factors in consecutively admitted newly diagnosed
children with ALL carrying prothrombotic risk factors. Thirty-two out
of 289 consecutively admitted leukemic children (11%) treated
according to the ALL-BFM 90/95 study protocols25 and
receiving E coli ASP 5,000 U/m2 during induction
therapy (8 doses) suffered venous thromboembolism. The rate of
thrombotic events reported here (11%) was found to be within the range
recently published in leukemic children during combined steroid and ASP
administration.3,4,8,10,13,14 Within the total patient
group the TT677 MTHFR genotype (7.6%), the heterozygous
prothrombin G20210A allele (2%), and the heterozygous FV G1691A
mutation (5.6%), protein C-(2.3%), protein S-(1.3%), or antithrombin
deficiency (0.7%) and Lp(a) greater than 30 mg/dL (5%) were all found
within the prevalences reported for healthy white
individuals.30,31 However, we have shown here that venous thromboembolism occurred in 46.5% of leukemic children with a prothrombotic risk factor diagnosed.
The homozygous MTHFR C677T gene mutation along with increased fasting
homocysteine concentrations32 was diagnosed in 4 children with sagittal venous sinus thrombosis and in a further 3 children with
venous thrombosis combined with the common FV mutation or increased
Lp(a). Thus, the findings presented here confirm recently published
data that in ALL children the MTHFR TT677 genotype associated with
increased fasting homocysteine concentrations is involved also in
venous thromboembolism.21,22 In addition, as previously reported, the common heterozygous factor V G1691A mutation alone or in
combination with a further prothrombotic risk factor led to vascular
occlusion in 7 out of 12 leukemic children included in the statistical
analysis. In contrast, only 1 out of 6 children with the heterozygous
prothrombin G20210A variant developed catheter-related thrombosis
during the observation period.
In leukemic children undergoing combined steroid and asparaginase
administration, a high frequency of acquired protein C, protein S, or
antithrombin type I deficiencies was repeatedly described.1-3,7-11,14 In contrast, results of the study
presented here show protein C, protein S, and antithrombin type I
deficiency prevalence rates no different from those found in healthy
whites.15,30 Thus, when using commercially available
premarked citrated coagulation tubes evidence is given that, due to
disease- and therapy-related hematocrit reductions, a hematocrit
correction29 is mandatory to distinguish between acquired
and inherited protein deficiency states. However, patients of the
present study classified as protein C, protein S, or antithrombin type
I deficient developed thromboembolism in the majority of cases.
Besides the involvement of the above mentioned genetic risk factors of
thrombophilia, additional factors such as endothelial cell injury or
further acquired coagulation imbalance, commonly described during
combined steroid and asparaginase administration1-4 in
childhood leukemia, may function as trigger mechanisms for early
thrombotic manifestation during childhood ALL. However, because we
excluded ALL patients with concomitant chronic diseases without
remission of the disease or with hepatic failure, oral contraceptives,
or nicotine abuse, evidence is given that leukemia treatment applied in
the patient population studied along with a genetic prothrombotic risk
factor is causative for the early thromboembolism diagnosed. In
addition, the significant positive correlation between thrombosis in
leukemic children with thrombophilia and a central line confirms
literature data that endothelial damage induced by the use of central
venous lines is an important cause of venous thrombosis in infants and
children, especially when genetic risk factors are
involved.33
In conclusion, data of this multicenter study suggest that leukemic
children with at least one prothrombotic risk factor treated with the
combination of ASP and steroids are at high risk of developing venous
vascular occlusion. However, because the prothrombotic defects
diagnosed in this childhood population studied were all found within
the prevalences reported for healthy white
individuals,15,30,31 ALL treatment is one subject of
discussion on the increased thrombotic risk due to gene polymorphisms.
Thus, while the MTHFR TT677 genotype, the prothrombin G20210A allele,
Lp(a), and further established prothrombotic risk factors should be
included in a screening program in children with ALL treated according
to the BFM study protocols,25 further prospective studies
are recommended to establish adequate anticoagulant treatment during
polychemotherapy of ALL patients carrying hereditary prothrombotic risk
factors within the hemostatic system.
| |
APPENDIX |
Coinvestigators were as follows:
J. Boos, A. Heinecke, H. Pollmann (Münster), R. Dickerhoff (St
Augustin), W. Eberl (Brunswick), R. Geib (Winterberg), A.K. Gnekow
(Augsburg), J. Göbel (Siegen), N. Graf (Saarbrücken), F.B.
Kremens (Essen), A. Laupert (Frankfurt), H. Lenk (Leipzig), R. Mertens
(Aachen), M. Rister (Koblenz), H. Rütschle (Ludwigshafen), R. Schneppenheim (Kiel), U. Schwarzer (Nuremberg), B. Selle (Heidelberg), M. Solf (Würzburg), H. Wehinger (Kassel), and G.F. Wündisch (Bayreuth).
| |
ACKNOWLEDGMENT |
We thank Susan Griesbach for editing the manuscript.
| |
FOOTNOTES |
Submitted July 21, 1998; accepted October 19, 1998.
Supported by the "Deutsche Krebshilfe."
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to Ulrike Nowak-Göttl, MD, Pediatric
Hematology/Oncology, University Children's Hospital, Albert
Schweitzer Str 33, D-48149 Münster, Germany.
| |
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Abstract
Introduction