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CORRESPONDENCE Hemophilia A (HA) and B (HB) are X-linked genetic
hemorrhagic disorders resulting from deficiencies of blood coagulation
factor VIII or IX, respectively. Subjects suffering from plasma levels of factor VIII coagulant activity or factor IX below 1% of normal are
classified as severe hemophiliacs. Although bleeding symptoms correlate
with the levels of the remaining factor activity, it is reported that
some hemophilic subjects with factor VIII levels below 1% do not all
bleed with the same severity, and in rare cases of severe HA,
thrombotic episodes have also been reported in
childhood.1-8 Since the reported symptomatic vascular accidents in hemophiliacs are,
in the majority of cases, related to central venous lines (CVLs), we
have read with interest the paper by Journeycake et al.1
Their data demonstrated that hemophiliacs with tunneled subclavian CVLs
in place for more than 48 months had abnormal venograms.1
In addition, 5 of 15 hemophiliacs (33.3%) had symptomatic deep venous
thrombosis (DVT) related to the CVLs; 3 further patients (20%) with
signs of DVT on contrast venography had no clinical problems. Because
CVLs are a common adjunct to therapy of severe hemophiliacs, we would
like to add some additional information on risk factors that, besides
the CVLs themselves, are of importance in the development of
CVL-associated vascular accidents in these patients. It has been
recently suggested that the clinical phenotype of severe HA is
influenced by coinheritance of prothrombotic risk factors.9 In addition, we have recently demonstrated that
the first symptomatic bleeding onset in children with severe HA
carrying prothrombotic risk factors is significantly later in life than in noncarriers.10 As recently described, we investigated 103 consecutively
admitted pediatric previously untreated patients (PUP) patients with hemophilia with factor levels below 1%.10 In this
cohort, factor V (FV) 1691G>A mutation, prothrombin 20210G>A variant,
MTHFR 677C>T genotype, antithrombin, protein C, protein S,
antithrombin, and lipoprotein (Lp) (a) were
determined.11,12 Of these 103 hemophilia patients, 25 (24.3%) had tunneled subclavian CVLs in place for 12 months or more.
Eight of the 25 patients with CVL (32%; inhibitor patients, n = 5;
prophylaxis, n = 3) suffered at least one vascular accident (Table
1). All 8 patients developed clinical
problems related to their catheter: symptoms ranged from
increased resistance during use of the device to acute swelling of the
arm and upper chest, followed by persistent prominence of superficial
veins over the shoulder. Contrast venography confirmed DVT in all
symptomatic cases; in 2 patients the CVL could not be completely
removed because the catheter had welded with the vessel wall. In these
2 cases, old organized thrombotic material was considered as the
pathologic background. Whereas the prevalence of prothrombotic risk
factors in children with HA was no different from that which was
previously reported,10-12 5 of 7 children with symptomatic
vascular accidents screened for prothrombotic risk factors carried at
least one genetic risk. In one other patient thrombophilia screening
awaits parental consent. Similar to patient number 2 in Journeycake et
al,1 the heterozygous factor V 20210G>A mutation was
present in 2 of our 7 patients. Additionally, 4 patients were treated
with factor (F) VIII/vWF concentrates, and 1 child each received
purified FVIII, recombinant VIIa, purified FVIII, and recombinant
FVIII, respectively.
Our data and those of Journeycake et al1 show that CVL-related vascular accidents in hemophilic patients are a common problem of multifactorial etiology. Thus in such patients, besides the duration of the CVL, the possible interaction of catheters with prothrombotic risk factors and the administration of potential thrombogenic coagulation factor concentrates without concomitant anticoagulation should be kept in mind. We would therefore recommend a general screening for prothrombotic risk factors in hemophiliacs prior to catheter implantation, continuous infusion, and immune tolerance with potential prothrombotic factor concentrates (recombinant FVIIa, FVIII/vWF).
Carmen Escuriola Ettingshausen, Karin Kurnik, Rosemarie Schobess, Wolfart D. Kreuz, Susan Halimeh, Hartmut Pollman, and Ulrike Nowak-Göttl
References
1.
Journeycake JM, Qiunn CT, Miller KL, Zajac JL, Buchanan GR.
Catheter-related deep venous thrombosis in children with hemophilia.
Blood.
2001;98:1727-1731 2. Ritchie B, Woodman RC, Poon MC. Deep venous thrombosis in hemophilia A. Am J Med. 1992;93:699-700[CrossRef][Medline] [Order article via Infotrieve]. 3. Vidler V, Richards M, Vora A. Central venous catheter-associated thrombosis in severe haemophilia. Br J Haematol. 1999;104:461-464[CrossRef][Medline] [Order article via Infotrieve].
4.
Sullivan DW, Purdy LJ, Billingham M, Glader BE.
Fatal myocardial infarction following therapy with prothrombin complex concentrates in a young man with hemophilia A.
Pediatrics.
1984;74:279-281 5. Karayalcin G, Goldberg B, Cherrick I, Kurer C, Bierman F, Lanzkowsky P. Acute myocardial infarction complicating prothrombin complex concentrate therapy in an 8-year-old boy with hemophilia A and factor VIII inhibitor. Am J Pediatr Hematol Oncol. 1993;15:416-419[Medline] [Order article via Infotrieve]. 6. Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (Novo Seven) in a patient with haemophilia A and inhibitor. Thromb Haemost. 1999;82:1775-1776[Medline] [Order article via Infotrieve]. 7. Escuriola Ettingshausen C, Martinez Saguer I, Kreuz W. Portal vein thrombosis in a patient with severe haemophilia A and F V G1691A mutation during continuous infusion of factor VIII after intramural jejunal bleeding - successful thrombolysis under heparin therapy. Eur J Pediatr. 1999;158:S180-S182. 8. Olcay L, Gurgey A, Toplaoglu H, Altay S, Parlak H, Firat M. Cerebral infarction associated with factor Leiden mutation in a boy with hemophilia A. Am J Hematol. 1997;56:189-190[CrossRef][Medline] [Order article via Infotrieve].
9.
Nichols WC, Amano K, Cacheris PM, et al.
Moderation of hemophilia A phenotype by the factor V R506Q mutation.
Blood.
1996;88:1183-1187 10. Escuriola Ettingshausen C, Halimeh S, Kurnik K, et al. Hemophilia phenotype is dependent on the presence of prothrombotric risk factors: a multicenter cohort study. Thromb Haemost. 2001;85:218-220[Medline] [Order article via Infotrieve].
11.
Junker R, Koch HG, Auberger K, Münchow N, Ehrenforth S, Nowak-Göttl U.
Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia.
Arterioscler Thromb Vasc Biol.
1999;19:2568-2572
12.
Nowak-Göttl U, Junker R, Hartmeier M, et al.
Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood.
Circulation.
1999;100:743-774
Response:Catheter-related thrombosis in children with hemophilia AWe read with interest the letter by Ettingshausen et al. In-dwelling catheters facilitate the long-term care of pediatric patients in a variety of clinical situations, including cancer, chronic infection, and hemophilia. But these patients are at risk of developing deep venous thrombosis (DVT) of the upper venous system. Factors influencing thrombotic potential of central venous catheters include caustic agents that are administered through the line, inflammatory states conferred by the condition itself, duration of catheter use, and inherited hypercoagulable disorders.1,2 The cumulative effect of these risk factors is not known. As well, we do not know which inherited factors add the greatest risk. Factor V Leiden places patients older than 15 years of age at an annual risk for DVT of 0.58%.3 Methylenetetrahydrofolate reductase mutations are common, with homozygous (MTHFR TT) mutations being present in 5%-12% of persons studied in cohorts, but they do not cause thrombosis unless associated with increased plasma homocysteine levels.4,5 Prospective trials in patients who have known thrombophilia and require central lines are needed to determine the incidence of DVT related to these events. A large percentage of patients with central venous catheters have radiographic evidence of DVT, but only a few of these patients are symptomatic.6,7 Acute upper venous system occlusion is associated with catheter malfunction, pulmonary embolism, extremity swelling, and superior vena cava syndrome. But long-term complications of catheter-related DVT identified by imaging studies in asymptomatic patients have yet to be defined. Ideally, catheters should be removed as early as possible prior to the development of any occlusive symptoms. Physicians should be alert to the signs of underlying DVT, including pain or difficulty with accession of the catheter, swelling of the arm, or dilated superficial chest wall veins. In the event of documented DVT, inherited thrombophilia should be considered prior to the placement of a second catheter and before the continued use of agents such as recombinant factor VIIa. The efficacy and safety of DVT prophylaxis in children with catheters have not been proven. Until we have alternative therapeutic options for patients who require catheters and treatment with agents such as recombinant factor VIIa and prothrombin complex concentrates, general screening prior to catheter insertion is not practical.
Janna M. Journeycake and George R. Buchanan
References 1. Manco-Johnson MJ. Disorders of hemostasis in childhood: risk factors for venous thromboembolism. Thromb Haemost. 1997;78:710-714[Medline] [Order article via Infotrieve]. 2. David M, Andrew M. Venous thromboembolic complications in children. J Pediatr. 1993;123:337-345[CrossRef][Medline] [Order article via Infotrieve].
3.
Middeldorp S, Meinardi JR, Koopman MMW, van Pampus ECM, et al.
A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.
Ann Intern Med.
2001;135:322-327
4.
Deloughery TG, Evans A, Sadeghi A, McWilliams J, et al.
Common mutation in methylenetetrahydrofolate reductase: correlation with homocysteine metabolism and late onset vascular disease.
Circulation.
1996;94:3074-3078
5.
Bauer KA.
The thrombophilias: well-defined risk factors with uncertain therapeutic implications.
Ann Intern Med.
2001;135:367-373 6. De Cicco M, Matovic M, Balestreri L, Panarello G, et al. Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter: a prospective study. Thromb Res. 1997;86:101-113[CrossRef][Medline] [Order article via Infotrieve]. 7. Glaser D, Meideros D, Rollins N, Buchanan GR. Catheter-related thrombosis in children with cancer. J Pediatr. 2001;138:255-259[CrossRef][Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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