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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Hematology-Oncology, Department of
Pediatrics, The University of Texas Southwestern Medical Center at
Dallas, Dallas, Texas, and the Center for Cancer and Blood Disorders at
Children's Medical Center of Dallas, Dallas, Texas.
Central venous catheters (CVCs) are a common adjunct to hemophilia
therapy, but the risk of CVC-related deep venous thrombosis (DVT) in
hemophiliacs is not well defined. In a previous study, 13 patients with
CVCs had no radiographic evidence of DVT. However, recent abstracts and
case studies demonstrate that DVT does occur. Therefore, this study
sought to determine the frequency of DVT in children with hemophilia
and long-term CVCs and to correlate venographic findings with clinical
features. All hemophilia patients with tunneled subclavian CVCs in
place for 12 months or more were candidates for evaluation. Patients
were examined for physical signs of DVT and questioned about catheter
dysfunction. Contrast venograms were obtained to identify DVT. Fifteen
boys with severe hemophilia were evaluated, including 9 from the
initially studied group of 13. Eight patients had evidence of DVT, 5 of
whom previously had normal venograms. Five of 15 patients had clinical
problems related to the CVC, all of whom had DVT. Four of 15 patients
had suggestive physical signs; 3 had DVT. The mean duration of catheter placement for all patients was 57.5 months (range, 12-102 months). For
patients with DVT, the mean duration was 66.6 ± 7.5 months, compared
to 49.5 ± 7.2 months for patients without DVT
(P = .06). No patient whose CVC was in place fewer than
48 months had an abnormal venogram. Many hemophilia patients with CVCs
develop DVT of the upper venous system, and the risk increases with
duration of catheter placement.
(Blood. 2001;98:1727-1731) Infusion of coagulation factor through peripheral
veins is simple and effective, but frequent venipuncture is often
painful and not possible for some patients with hemophilia. Central
venous catheters (CVCs) facilitate the infusion of coagulation factors, especially in demanding regimens of primary prophylaxis and induction of immune tolerance in patients with inhibitors.1-3 Many
families request CVCs for domiciliary, on-demand infusions as well.
Thus, CVCs are an increasingly common adjunct to the therapy
of hemophilia.
The CVCs can be problematic because of mechanical dysfunction and the
risk of infection and deep venous thrombosis (DVT). Published series of
hemophilia patients with CVCs have thoroughly described the risk of
infection2,4-6; however, the frequency of thrombosis is
not adequately documented. Indeed, a CVC is the greatest risk factor
for DVT in childhood.7,8 As many as two thirds of children
who receive total parenteral nutrition (TPN) or antineoplastic
chemotherapy develop catheter-related DVT.9-13
Nevertheless, investigation of CVC-related DVT in patients with
hemophilia is lacking, perhaps because it seems paradoxical that
individuals with bleeding disorders might develop DVT.
In 1998, we reported a favorable experience in 13 patients with
hemophilia who had CVCs.14 None had definitive
radiographic evidence of DVT in the upper venous system (the
subclavian, brachiocephalic, or jugular veins, or the superior vena
cava) despite having had catheters in place for 10 to 60 months (mean,
23 months). However, a recent abstract15 and several case
studies16,17 indicate that thrombosis does occur in
patients with hemophilia. Because we recently identified thrombi in
several of our patients, we further investigated this issue.
The objective of this study was to determine the frequency of DVT in
children with hemophilia whose CVCs had been implanted for 1 year or
longer. We used contrast venography to identify thrombi because it is
the "gold standard" for detection of upper venous system
thrombosis.8,14
We reviewed the records of all patients with hemophilia at our
center who had tunneled, internal CVCs (infusion ports, eg, Port-a-Cath), all of which were placed in a subclavian vein. Any patient whose CVC had been in place for more than 12 months was a
candidate to be evaluated by contrast venography for DVT involving the
subclavian, brachiocephalic, or jugular veins, or the superior vena
cava. In particular, we attempted to re-evaluate each of the 13 patients whom we had previously studied.14 The potential risks of radiation exposure and contrast injection were discussed with
the patients and their parents. No parent declined to have his or her
child evaluated, and informed consent was obtained in each case.
Venograms were obtained by injection of radiocontrast medium into the
ipsilateral antecubital vein (relative to the side of CVC insertion) by
a method previously described.14 Thrombosis was defined as
2 or more of the following: (1) stenosis or occlusion (or both) of the
superior vena cava or of the subclavian, brachiocephalic, or jugular
vein; (2) poststenotic dilation; or, (3) prominent collateral veins
proximal or distal to a probable stenosis or occlusion.
Patients who underwent venography were examined carefully for dilated
veins on the chest wall and swelling, tenderness, or erythema of the
arms. Patients' parents were questioned about difficulties using the
CVC, such as resistance to infusion, absence of blood return, and pain
with accession. We recorded any episode of documented pulmonary
embolism and any history of respiratory distress or chest pain that
might indicate pulmonary embolism.
We correlated the clinical features of the patients with the results of
venography, and we compared the mean time of catheter insertion between
the groups of boys with and without DVT using a one-tailed t
test. The probability of remaining free of DVT after insertion of a CVC
was also calculated.
Patients
Three patients had more than one CVC. Patients 1 and 4 had their first
CVCs replaced because of catheter tip migration. At the time of
venography, their second CVCs had been in place for 46 and 62 months,
respectively. Patient 10 had his CVC replaced after 41 months because
of recurrent infection and mechanical dysfunction. His second CVC had
been in place for 12 months when the venogram was obtained.
Three of the 4 previously studied patients who did not have a
second venogram are no longer followed at our center. One had his CVC
removed after 5 years because of catheter migration. The other 2 have
had patent catheters for over 4 years; one of them had a normal
contrast dye study of the line to test for patency. The remaining
patient from the first study who was not re-evaluated outgrew his CVC,
and it was replaced after 57 months. He is scheduled to have a venogram
as part of his next comprehensive evaluation.
Contrast venography
Patient 10 had transferred from another physician's care. His first
CVC was in place for 41 months, but it was removed because of recurrent
infection and mechanical dysfunction. This patient did not have prior
radiographic studies. We evaluated him 12 months after insertion of a
second CVC in the opposite subclavian vein. His venogram was consistent
with DVT in his left superior venous system where his previous catheter
had been inserted. There was no evidence of DVT in the right upper
venous system, the location of the current CVC.
Clinical problems and physical examinations
Four of the 15 patients had physical signs suggestive of DVT, such as slight arm swelling or prominent chest wall veins, but no patient had a functional deficit of the affected arm. Three of these 4 patients had abnormal venograms. The patient with the normal venogram had only mild prominence of superficial veins over the ipsilateral shoulder. In contrast, 5 patients with DVT had normal physical examinations. Outcome and follow-up The mean duration of catheter placement for all patients was 57.5 months (median, 60 months; range, 12-102 months). The mean duration of CVC placement in the patients with DVT was 66.6 ± 7.5 months (SEM) compared to 49.5 ± 7.2 months for the patients without DVT (P = .06). Figure 2 depicts the probability of remaining free of DVT after CVC insertion. No patient whose catheter was in place for fewer than 48 months had an abnormal venogram associated with his current CVC, whereas all patients whose catheter was in place longer than 73 months had venographic evidence of a DVT.
We removed the CVCs from 6 of the 8 patients with DVT because they no longer functioned or had migrated out of the subclavian vein. We discussed the risks of continued use of an apparently functional CVC associated with a DVT with the parents of the remaining 2 boys (patients 7 and 10). Patient 10 had his CVC removed. The family of patient 7 preferred to keep the CVC for frequent prophylactic infusions until they were comfortable with peripheral venous administration. None of the 8 patients with DVT was treated with systemic fibrinolytic agents or anticoagulants. No patient presented with clinical signs suggestive of pulmonary thromboembolism. No patient had a catheter-related infection, except for patient 10 described previously. We did not prospectively assay for inherited thrombophilic states in all patients. However, we did test patient 2 because his parents strongly desired placement of a second CVC. He had no demonstrable abnormalities of protein C, protein S, antithrombin, or prothrombin, but he was heterozygous for the factor V Leiden mutation. Because of this finding we discouraged replacement of the CVC and taught the family how to use peripheral veins instead.
Regimens of primary prophylaxis beginning in the first year of life can prevent hemophilic arthropathy,1,18,19 and immune tolerance programs can eliminate inhibitors.1 Reliable venous access is needed for these treatments, but repeated peripheral venipuncture can be difficult or impossible in very young children. CVCs can make these intensive and effective treatment approaches more feasible and more convenient.20-22 However, the widespread use of CVCs is now being re-evaluated because of complications such as infection and thrombosis. Five recent series describing more than 100 hemophilia patients with CVCs have documented the risk of catheter-related infection and mechanical dysfunction.2-6,19 Four of the studies mention catheter occlusion in a total of 8 patients, but only Blanchette and coworkers described venographic evidence of DVT in a single patient.19 We report herein a specific investigation for DVT using contrast venography in a cohort of unselected patients with hemophilia and long-term CVCs. Although we initially reported that catheter-related thrombosis is rare in hemophilia patients,14 with longer follow-up we now realize that DVT is indeed common. Approximately half of our patients with CVCs in place for more than 1 year now have evidence of DVT. We found that the risk of DVT increased with time and was highest when CVCs had been in place 4 years or longer. Three of 8 patients with DVT in this series had suggestive physical signs, and 5 had evidence of catheter dysfunction. Yet, despite the common occurrence of thrombosis, no patient has had clinically apparent pulmonary embolism or symptomatic postphlebitic syndrome. This study corroborates the findings of other observers reported in abstract form.15,16 Koerper and colleagues performed bilateral venograms on 11 asymptomatic children with hemophilia who had tunneled catheters in place for 1 to 6 years.16 Two patients (22%) had complete occlusion of the left brachiocephalic vein with development of collateral vessels. Blanchette and coworkers evaluated 16 patients with hemophilia who had indwelling catheters for 1 to 40 months using Doppler ultrasonography, dye studies of the central line testing for patency, and venograms.15 Ten of 16 patients (63%) had evidence of a DVT. The site of catheter insertion was not mentioned. Venography identified thrombi in the subclavian and brachiocephalic veins or involving the superior vena cava, but only ultrasonography identified thrombi in the internal jugular vein. These investigators concluded that both ultrasound and radiocontrast studies should be used to evaluate adequately the entire upper venous system. Our patients had only subclavian CVCs, and because it would be unlikely to have jugular venous thrombosis without DVT in contiguous veins, venography alone was deemed sufficient. Thrombosis in patients with bleeding disorders is seemingly paradoxical. Young patients with hemophilia should not be prone to DVT. They have defective coagulation but are otherwise healthy, and they have no increased risk of concomitant inherited thrombophilia.23,24 Accordingly, Arbini and coworkers tested 21 patients with severe hemophilia but with mild bleeding symptoms for prothrombotic disorders. Only one was heterozygous for the factor V Leiden mutation, and none had an hereditary deficiency of antithrombin, protein C, or protein S.24 Patients with debilitating diseases such as cancer and short-gut syndrome also require tunneled catheters to facilitate the infusion of chemotherapy, blood products, or TPN. These conditions and their treatments can injure the endothelium and promote DVT within months of catheter insertion. As many as 50% of these patients develop CVC-related DVT.11,13,25 We have shown that this risk is ultimately the same for hemophilia patients, but we did not detect thrombosis until CVCs had been in place 4 years or longer. This suggests that thrombi form more slowly in patients with hemophilia, perhaps because hemostasis is only intermittently normalized by factor infusions. Why so many patients develop DVT is not known. Vidler and colleagues reported 2 patients with severe hemophilia and an inhibitor who had CVC-related DVT.17 Both were treated with high-dose factor infusions and one with an activated prothrombin complex concentrate (PCC). The authors speculated that high-dose factor and procoagulant PCC therapy might have promoted thrombus formation. Three patients in our study received PCC; 2 did not develop DVT. The patient with DVT received PCC only through his first CVC, which was removed after 3 months because of migration of the catheter tip. His DVT occurred approximately 5 years after the insertion of a second CVC. Thus, exposure to a PCC is not a necessary antecedent of thrombosis in hemophilia patients. Perhaps the only requisites are chronic irritation of the vessel wall by a catheter tip and intermittent normalization of coagulation. Although patients with hemophilia may develop catheter-related DVT, the benefits of CVCs, especially in young patients, likely outweigh the risks. However, caution is urged, and physicians should specifically monitor for DVT. Surveillance should include attention to difficulties with the infusion of factor and examination of the patient for physical signs of DVT. Patients should also be evaluated intermittently for the feasibility of peripheral venipuncture, and families should understand that a CVC is a temporary adjunct to therapy. Removal of catheters within 4 years might prevent thrombosis. Screening venography may be warranted for patients who require CVCs longer. If DVT occurs, one should strongly consider removal of the CVC and the use of peripheral veins instead. Further studies of CVC-related DVT are needed to define the adverse sequelae, the utility of routine screening, and the appropriateness of anticoagulant therapy.
Submitted January 18, 2001; accepted May 15, 2001.
Supported in part by National Institutes of Health Training Grant T32-CA09640, and grants from Maternal and Child Health Bureau (5 H30 MC00029-11), Centers for Disease Control and Prevention (U27/CCU613189-05), and the Children's Cancer Fund of Dallas.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: George R. Buchanan, Division of Hematology-Oncology, Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9063; e-mail: George.Buchanan{at}UTSouthwestern.edu.
1. Ljung R, Lindgren A, Tengborn L, Petrini P. The feasibility of long-term venous access in children with hemophilia. Semin Hematol. 1994;31(suppl. 2):16-18. 2. Miller K, Buchanan G, Zappa S, et al. Implantable venous access devices in children with hemophilia: a report of low infection rates. J Pediatr. 1998;132:934-938[Medline] [Order article via Infotrieve]. 3. Bollard CM, Teague LR, Berry EW, Ockelford PA. The use of central venous catheters (portacaths) in children with haemophilia. Haemophilia. 2000;6:66-70[Medline] [Order article via Infotrieve]. 4. Ljung R, van den Berg M, Petrini P, et al. Port-a-cath usage in children with haemophilia: experience of 53 cases. Acta Paediatr. 1998;87:1051-1054[Medline] [Order article via Infotrieve]. 5. Collins PW, Khair KS, Liesner R, Hann M. Complications experienced with central venous catheters in children with congenital bleeding disorders. Br J Haematol. 1997;99:206-208[Medline] [Order article via Infotrieve]. 6. Liesner RJ, Vora AJ, Hann IM, Lilleyman JS. Use of central venous catheters in children with severe congenital coagulopathy. Br J Haematol. 1995;91:203-207[Medline] [Order article via Infotrieve]. 7. Nuss R, Manco-Johnson MJ. Venous thrombosis: issues for the pediatrician. Contemp Pediatr. 2000;17:75-94. 8. Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr. 1998;133:770-775[CrossRef][Medline] [Order article via Infotrieve]. 9. Andrew M, Marzinotto V, Pencharz P, et al. A cross sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. J Pediatr. 1995;126:358-63[CrossRef][Medline] [Order article via Infotrieve]. 10. Ross P Jr, Ehrenkranz R, Kleinman CS, Seashore JH. Thrombus associated with central venous catheters in infants and children. J Pediatr Surg. 1989;24:253-256[CrossRef][Medline] [Order article via Infotrieve]. 11. Mitchell LG, Sutor AH, Andrew M. Hemostasis in childhood acute lymphoblastic leukemia: coagulopathy induced by disease and treatment. Semin Thromb Hemost. 1995;21:390-401[Medline] [Order article via Infotrieve]. 12. Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP. Guidelines for antithrombotic therapy in pediatric patients. J Pediatr. 1998;132:575-588[CrossRef][Medline] [Order article via Infotrieve]. 13. Glaser DW, Medeiros D, Rollins N, Buchanan GR. Catheter-related thrombosis in children with cancer. J Pediatr. 2001;138:255-259[CrossRef][Medline] [Order article via Infotrieve]. 14. Medeiros D, Miller KL, Rollins NK, Buchanan GR. Contrast venography in young haemophiliacs with implantable central venous access devices. Haemophilia. 1998;4:10-15[Medline] [Order article via Infotrieve]. 15. Blanchette VS, Al-Trabolsi H, Stain AM, et al. High risk of central venous line-associated thrombosis in boys with hemophilia [abstract]. Blood. 1999;94:818a. 16. Koerper MA, Esker S, Cobb L. Asymptomatic thrombosis of innominate vein in hemophiliac children with subcutaneous venous access devices (ports) [abstract]. National Hemophilia Foundation 48th Annual Meeting; 1996; San Diego, CA. 17. 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]. 18. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992;232:25-32[Medline] [Order article via Infotrieve]. 19. Blanchette VS, Al-Musa A, Stain AM, Filler RM, Ingram J. Central venous access catheters in children with haemophilia. Blood Coagul Fibrinolysis. 1996;7(suppl 1):539-544. 20. Perkins JL, Johnson VA, Osip JM, et al. The use of implantable venous access devices (IVADs) in children with hemophilia. J Pediatr Hematol Oncol. 1997;19:339-344[Medline] [Order article via Infotrieve]. 21. Schultz WH, Ware R, Filston HC, Kinney TR. Prolonged use of an implantable central venous access system in a child with severe hemophilia. J Pediatr. 1989;114:100-101[Medline] [Order article via Infotrieve]. 22. Vora AJ, Lilleyman JS. Vascular access in young haemophiliacs: use of indwelling central venous catheters. Int J Pediatr Hematol Oncol. 1994;1:521-527. 23. Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost. 2000;83:387-391[Medline] [Order article via Infotrieve]. 24. Arbini AA, Mannucci PM, Bauer KA. Low prevalence of the factor V Leiden mutation among "severe" hemophiliacs with a "milder" bleeding diathesis. Thromb Haemost. 1995;74:1255-1258[Medline] [Order article via Infotrieve]. 25. Beck C, Dubois J, Grignon A, Lacroix J, David M. Incidence and risk factors of catheter-related deep vein thrombosis in pediatric intensive care unit: a prospective study. J Pediatr. 1998;133:237-241[CrossRef][Medline] [Order article via Infotrieve].
© 2001 by The American Society of Hematology.
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  L. Raffini Thrombophilia in Children: Who to Test, How, When, and Why? Hematology, January 1, 2008; 2008(1): 228 - 235. [Abstract] [Full Text] [PDF]
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 C. E. Ettingshausen, K. Kurnik, R. Schobess, W. D. Kreuz, S. Halimeh, H. Pollman, U. Nowak-Gottl ;, J. M. Journeycake, and G. R. Buchanan Catheter-related thrombosis in children with hemophilia A: evidence of a multifactorial disease Blood, February 15, 2002; 99(4): 1499 - 1499. [Full Text] [PDF]
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Abstract
Introduction
