Pediatric Thromboembolism 

  • Author: Scott C Howard, MD; Chief Editor: Robert J Arceci, MD, PhD   more...
 
Updated: Nov 2, 2011
 

Background

Thromboembolism, or the development of a clot within blood vessels, can occur in arteries or veins. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in adults. Although the incidence of venous thromboembolism is lower in children than in adults, the morbidity associated with venous thromboembolism is clinically significant when it occurs. Arterial thromboembolism is also an important cause of morbidity in adults but is less common in children and is only briefly addressed in this article.

The diagnosis and treatment of thrombosis in children were initially based on standards of care for adults. However, since the early 1990s, pediatric data have emerged, stressing differences in the etiology, pathophysiology, and drug pharmacokinetics of thromboembolism in children.

In 1845, Virchow postulated that 3 factors were important in the development of thrombosis: (1) impairment of blood flow (stasis), (2) vascular injury, and (3) alterations of the blood (hypercoagulability).

Virchow triad for the pathophysiology of thrombus Virchow triad for the pathophysiology of thrombus formation.

These factors also play a role in pediatric thrombosis. Developmental differences are discussed in this article.

Next

Pathophysiology

The physiology of hemostasis is remarkably complex and reflects a fine balance between uninterrupted flow of blood (ie, fluid) and a rapid, localized response to vascular injury (ie, clotting).

The process of hemostasis is traditionally divided into a cellular phase and a fluid phase. The former involves platelets and the vascular wall, and the latter plasma proteins.

The fluid phase is divided into 3 processes: (1) the multiple-step zymogen pathway that leads to thrombin generation, (2) thrombin-induced formation of a fibrin clot, and (3) complex fibrinolytic mechanisms aimed at limiting clot propagation (see Media file 2). Abnormalities in any of these steps can contribute to hypercoagulable or hypocoagulable states.

Regarding the fluid phase, many age-dependent differences are present in the hemostatic system of infants and children. Adult levels of the vitamin-K–dependent coagulation factors II, IX, and X, as well as contact factors, are not achieved until age 3-6 months. Levels of thrombin inhibitors, such as antithrombin and heparin cofactor II, are similarly low at birth. That is, they are in the ranges that may cause heterozygous adults to develop thromboembolism.

Levels of alpha-2-macroglobulin are higher in infants and children than in adults. Conversely, levels of protein C and S are low at birth. Protein S levels approach adult values by age 3-6 months, but protein C levels remain low even into childhood. Plasminogen levels are low in newborns and infants, which has implications for treatment of thromboembolism in newborns. Thrombin generation is decreased (probably because of low prothrombin levels) and delayed in newborns, who have a higher risk for bleeding relative to adults.

Previous
Next

Epidemiology

Frequency

United States

Deep venous thrombosis (DVT) or pulmonary embolism (PE) develops in approximately 2.5-5% of adults in the United States.

In 2004, The National Hospital Discharge Survey demonstrated an annual incidence of 4.2 cases of DVT and 0.9 cases of PE per 100,000 population.[1] PE has been found in 3.7% of children at autopsy. Strokes occur with an annual incidence of approximately 2.5 per 100,000 children.

International

In the Canadian Registry, the incidence of venous thromboembolism was estimated at 0.07 cases per 10,000 children and 5.3 cases per 10,000 hospital admissions in 1994.[2]

In a German study by Nowak-Gottl et al (2004), the incidence of symptomatic neonatal thromboembolism was 5.1 cases per 100,000 births.[3]

Mortality/Morbidity

Pulmonary embolism

In adults, the mortality rate associated with untreated PE is 18-30%. Even if PE is diagnosed early, the mortality rate is 8%.

In the Canadian Registry, the mortality rate in children was 2.2%, and deaths were mainly due to PE or direct extension of DVT into the heart.[2] In the Canadian Pediatric Ischemic Stroke Registry, 6% of children died after ischemic stroke, 72% had residual neurologic deficits, and 22% fully recovered.

A high index of suspicion for thromboembolism is required for timely diagnosis; indeed, many early reports were based on autopsy data. Symptoms can be nonspecific and include tachypnea, tachycardia, fever, pleuritic chest pain, cough, shortness of breath, and (less commonly) hemoptysis. DVT is absent in children with PE more often than it is in adults. Risk factors include the presence of a central venous catheter (CVC), immobility, heart disease, a ventriculoatrial shunt, trauma, cancer, surgery, infection, dehydration, shock, and obesity.

Recurrent thromboembolism

Thromboembolism recurs in 4-7% of adults. In the Canadian Registry, 19% of children developed recurrent thromboembolism.

Recurrent thromboembolism might be secondary to inadequate anticoagulation because of a concern about bleeding and/or the persistence of underlying risk factors, such as use of a CVC.

A study in Germany showed that the number of underlying genetic risk factors affected recurrence rates. Children with no genetic risk factors had a 4.8% recurrence rate, whereas those with one genetic risk factor had a 17.6% recurrence rate. In children with 2 or more genetic risk factors, the risk of recurrence was almost 50%.

Goldenberg et al (2004) noted an increased recurrence rate in children with venous thromboembolism and elevated levels of factor VIII and/or D-dimer after 3-6 months of anticoagulation therapy.[4]

Postthrombotic syndrome

Postthrombotic syndrome (PTS) consists of chronically swollen, painful extremities with induration of the skin, ulceration, and pigmentary changes secondary to chronic venous stasis. About 20-67% of adults with DVT develop PTS.

According to the Canadian Registry, PTS occurs in 21-25% of children with venous thrombosis.

Using a standardized score, investigators in a study from the Hospital for Sick Children in Toronto, Canada, observed PTS in 63% of 153 children. Cases were mild in 83% and moderate in 17%.

Treatment of PTS consists of the use of elastic compression stockings, elevation of the extremity above the level of the heart, and administration of analgesics or narcotics as necessary.

Race

Although some prothrombotic risk factors are more common in particular racial groups, overall no evidence suggests that children of any particular race are at higher risk for thromboembolism.

Sex

Male and female children are equally affected by thromboembolism.

Age

The incidence of thromboembolism peaks in newborns and infants younger than 1 year, then remains very low until adolescence, when incidence begins to increase.

Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

Scott C Howard, MD  Associate Member, Department of Oncology, Director of Clinical Trials, International Outreach Program, St Jude Children's Research Hospital; Associate Professor, University of Tennessee Health Science Center College of Medicine

Scott C Howard, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, and International Society of Paediatric Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

J Martin Johnston, MD  Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Hematology/Oncology, The Children's Hospital at Memorial University Medical Center; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital

J Martin Johnston, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

James L Harper, MD  Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Samuel Gross, MD  Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University

Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD  King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Philip M Monteleone, MD, to the development and writing of this article.

References

  1. Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr. 2004;145(4):563-5. [Medline].

  2. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83(5):1251-7. [Medline].

  3. Nowak-Gottl U, Kosch A. Factor VIII, D-Dimer, and thromboembolism in children. N Engl J Med. Sep 9 2004;351(11):1051-3. [Medline].

  4. Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med. Sep 9 2004;351(11):1081-8. [Medline].

  5. Nuss R, Hays T, Chudgar U, et al. Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary emboli. J Pediatr Hematol Oncol. May-Jun 1997;19(3):202-7. [Medline].

  6. Goldenberg NA, Bernard TJ. Venous thromboembolism in children. Pediatr Clin North Am. Apr 2008;55(2):305-22, vii. [Medline].

  7. Sandoval JA, Sheehan MP, Stonerock CE, Shafique S, Rescorla FJ, Dalsing MC. Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk. J Vasc Surg. Apr 2008;47(4):837-43. [Medline].

  8. Kosch A, Koch HG, Heinecke A, et al. Increased fasting total homocysteine plasma levels as a risk factor for thromboembolism in children. Thromb Haemost. 2004;91(2):308-14. [Medline].

  9. Altinisik J, Ates O, Ulutin T, et al. Factor V Leiden, prothrombin G20210A, and protein C mutation frequency in Turkish venous thrombosis patients. Clin Appl Thromb Hemost. Oct 2008;14(4):415-20. [Medline].

  10. Athale U, Siciliano S, Thabane L, Pai N, Cox S, Lathia A. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer. Dec 2008;51(6):792-7. [Medline].

  11. Athale UH, Nagel K, Khan AA, Chan AK. Thromboembolism in children with lymphoma. Thromb Res. 2008;122(4):459-65. [Medline].

  12. Biss TT, Brandao LR, Kahr WH, Chan AK, Williams S. Clinical features and outcome of pulmonary embolism in children. Br J Haematol. Sep 2008;142(5):808-18. [Medline].

  13. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):887S-968S. [Medline].

  14. Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res. 2003;109(2-3):85-92. [Medline].

  15. Skinner R, Koller K, McIntosh N, McCarthy A, Pizer B. Prevention and management of central venous catheter occlusion and thrombosis in children with cancer. Pediatr Blood Cancer. Apr 2008;50(4):826-30. [Medline].

  16. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):887S-968S. [Medline].

  17. Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. Oct 25 2011;343:d6423. [Medline]. [Full Text].

  18. Agnelli G, Verso M. Epidemiology of cerebral vein and sinus thrombosis. Front Neurol Neurosci. 2008;23:16-22. [Medline].

  19. Aissaoui N, Martins E, Mouly S, et al. A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep vein thrombosis, or both. Int J Cardiol. Aug 6 2008;[Medline].

  20. Akar N, Akar E, Deda G, et al. Coexistence of two prothrombotic mutations, factor V 1691 G-A and prothrombin gene 20210 G-A, and the risk of cerebral infarct in pediatric patients. Pediatr Hematol Oncol. Nov-Dec 1999;16(6):565-6. [Medline].

  21. Akl EA, Rohilla S, Barba M, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer: a systematic review. Cancer. Oct 1 2008;113(7):1685-94. [Medline].

  22. Alioglu B, Avci Z, Tokel K, et al. Thrombosis in children with cardiac pathology: analysis of acquired and inherited risk factors. Blood Coagul Fibrinolysis. Jun 2008;19(4):294-304. [Medline].

  23. Andrew M. Developmental hemostasis: relevance to hemostatic problems during childhood. Semin Thromb Hemost. 1995;21(4):341-56. [Medline].

  24. Andrew M, David M, deVeber G, et al. Arterial thromboembolic complications in paediatric patients. Thromb Haemost. Jul 1997;78(1):715-25. [Medline].

  25. Andrew M, deVeber G. Low molecular weight heparin. In: Pediatric Thromboembolism and Stroke Protocols. Hamilton, Ontario: BC Decker; 1997:6-10.

  26. Athale U, Siciliano S, Thabane L, et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer. Dec 2008;51(6):792-7. [Medline].

  27. Babyn PS, Gahunia HK, Massicotte P. Pulmonary thromboembolism in children. Pediatr Radiol. Mar 2005;35(3):258-74. [Medline].

  28. Barnes C, Newall F, Ignjatovic V, et al. Reduced bone density in children on long-term warfarin. Pediatr Res. 2005;57(4):578-81. [Medline].

  29. Bick RL. Therapy for venous thrombosis: guidelines for a competent and cost-effective approach. Clin Appl Thromb Hemost. Jan 1999;5(1):2-9. [Medline].

  30. Billett HH. Antiplatelet agents and arterial thrombosis. Cardiol Clin. May 2008;26(2):189-201, vi. [Medline].

  31. Dentali F, Gianni M, Agnelli G, et al. Association between inherited thrombophilic abnormalities and central venous catheter thrombosis in patients with cancer: a meta-analysis. J Thromb Haemost. Jan 2008;6(1):70-5. [Medline].

  32. deVeber G, Monagle P, Chan A, et al. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol. Dec 1998;55(12):1539-43. [Medline].

  33. Goldenberg NA, Bernard TJ. Venous thromboembolism in children. Pediatr Clin North Am. Apr 2008;55(2):305-22, vii. [Medline].

  34. Hagstrom JN, Walter J, Bluebond-Langner R, et al. Prevalence of the factor V leiden mutation in children and neonates with thromboembolic disease. J Pediatr. Dec 1998;133(6):777-81. [Medline].

  35. Helmerhorst FM, Bloemenkamp KW, Rosendaal FR. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost. Jul 1997;78(1):327-33. [Medline].

  36. Ignjatovic V, Barnes C, Newall F, et al. Point of care monitoring of oral anticoagulant therapy in children: comparison of CoaguChek Plus and Thrombotest methods with venous international normalised ratio. Thromb Haemost. Oct 2004;92(4):734-7. [Medline].

  37. Journeycake JM, Manco-Johnson MJ. Thrombosis during infancy and childhood: what we know and what we do not know. Hematol Oncol Clin North Am. 2004;18(6):1315-38, viii-ix. [Medline].

  38. Kuhle S, Koloshuk B, Marzinotto V, et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res. 2003;111(4-5):227-33. [Medline].

  39. Male C, Chait P, Ginsberg JS, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase. Thromb Haemost. 2002;87(4):593-8. [Medline].

  40. Male C, Lechner K, Eichinger S, et al. Clinical significance of lupus anticoagulants in children. J Pediatr. Feb 1999;134(2):199-205. [Medline].

  41. Manco-Johnson MJ. Disorders of hemostasis in childhood: risk factors for venous thromboembolism. Thromb Haemost. Jul 1997;78(1):710-4. [Medline].

  42. Michelson AD, Bovill E, Monagle P, Andrew M. Antithrombotic therapy in children. Chest. Nov 1998;114(5 Suppl):748S-769S. [Medline].

  43. Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest. Jan 2001;119(1 Suppl):344S-370S. [Medline].

  44. Morgan J. Perioperative venous thrombosis in children: is it time for primary prophylaxis?. Paediatr Anaesth. Feb 2007;17(2):99-101. [Medline].

  45. Nowak-Gottl U, Schobess R, Kurnik K, et al. Elevated lipoprotein(a) concentration is an independent risk factor of venous thromboembolism. Blood. May 1 2002;99(9):3476-7; author reply 3477-8. [Medline].

  46. Nowak-Gottl U, von Kries R, Gobel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. May 1997;76(3):F163-7. [Medline].

  47. Price VE, Chan AK. Arterial thrombosis in children. Expert Rev Cardiovasc Ther. Mar 2008;6(3):419-28. [Medline].

  48. Price VE, Chan AK. Venous thrombosis in children. Expert Rev Cardiovasc Ther. Mar 2008;6(3):411-8. [Medline].

  49. Rivkin MJ, Volpe JJ. Strokes in children. Pediatr Rev. Aug 1996;17(8):265-78. [Medline].

  50. Sifontes MT, Nuss R, Hunger SP, et al. Activated protein C resistance and the factor V Leiden mutation in children with thrombosis. Am J Hematol. 1998;57(1):29-32. [Medline].

  51. Streif W, Andrew M, Marzinotto V, et al. Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients. Blood. 1999;94(9):3007-14. [Medline].

  52. van Beynum IM, Smeitink JA, den Heijer M, et al. Hyperhomocysteinemia: a risk factor for ischemic stroke in children. Circulation. Apr 27 1999;99(16):2070-2. [Medline].

  53. Vu LT, Nobuhara KK, Lee H, et al. Determination of risk factors for deep venous thrombosis in hospitalized children. J Pediatr Surg. Jun 2008;43(6):1095-9. [Medline].

  54. Wasay M, Dai AI, Ansari M, et al. Cerebral venous sinus thrombosis in children: a multicenter cohort from the United States. J Child Neurol. Jan 2008;23(1):26-31. [Medline].

  55. [Best Evidence] Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. Sep 23 2008;118(13):1373-82. [Medline].

  56. Young G, Manco-Johnson M, Gill JC, et al. Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study. J Thromb Haemost. May 2003;1(5):958-62. [Medline].

 
Previous
Next
 
Virchow triad for the pathophysiology of thrombus formation.
Coagulation cascade. Solid arrows represent activation events, dashed arrows represent inhibition events, and dotted lines with circles represent inactivation events. a = active; APC = activated protein C; F = factor; FDP= fibrin degradation products; HMW = high molecular weight; PAI-1 = plasminogen activator inhibitor-1; PL = phospholipid; TM = thrombomodulin; t-PA = tissue type plasminogen activator; u-PA = urokinase plasminogen activator; XL= crosslinked.
Nomogram for adjusting the dosage of heparin. Reproduced with permission from Michelson et al (1998). APTT = activated partial thromboplastin time.
Dosing of low-molecular-weight heparins (LMWHs) in children. Reproduced with permission from Michelson et al (1998).
Warfarin dosing in children. INR = international normalized ratio. Reproduced with permission from Michelson et al (1998).
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.