A 13-year-old white girl presents to her pediatrician to begin taking oral contraceptives. She gives a family history of deep venous thrombosis in her mother and sister. Both have had treatment with oral anticoagulants. Should she be given oral contraceptives? If so, what precautions should be considered?
A 7-year-old African American boy presents with a history of proteinuria, bilateral pedal edema, and hypoalbuminemia. The diagnosis of nephrotic syndrome is made and he begins steroid therapy. His albuminuria resolves and his overall health is starting to improve when he presents with unilateral swelling of his right thigh. An ultrasound examination shows thrombosis of the right iliac vein and the femoral vein. The family history reveals that his father has had two episodes of deep venous thrombosis and pulmonary embolism. His father is currently being treated with oral anticoagulants, but has not yet been evaluated to detennine the etiology of his recurrent deep venous thrombosis. Should this boy with nephrotic syndrome be evaluated for a hypercoagulable state?
The types of questions raised by these two cases present to pediatricians often enough to make a detailed discussion about thrombophilia in childhood worthwhile. The term thrombophilia is interchangeable with the term hypercoagulable state. It indicates an imbalance between prothrombotic and antithrombotic factors that results in intravascular thrombosis. This prothrombotic tendency may be secondary to an acquired risk factor (Table 1) or due to a congenital (inherited) thrombotic disorder (Table 2).
The clinical presentation differs depending on the site of thrombosis. In children with thrombosis related to central venous lines, presenting symptoms include the inability to draw from the central venous line; swelling, pain, and discoloration of the affected limb; superior vena cava syndrome (headache, swelling of the face, and collateral venous circulation on the chest and the neck), or all of these.
Thrombosis that is not related to central venous lines mostly occurs in the lower extremities and is usually associated with pain, swelling, and discoloration of the affected extremity. Abdominal or inguinal pain is reported less frequently. In a child with deep venous thrombosis, symptoms such as dyspnea and tachypnea suggest pulmonary embolism.
Acquired Risk Factors for Thrombosis
Inherited Thrombotic Disorders
ACQUIRED RISK FACTORS
Central Venous Lines
The incidence of thrombotic problems during childhood has steadily increased with the accelerated pace with which central venous lines and total parenteral nutrition have been used. The reported incidence of venous thromboembolic events related to central venous lines in children has ranged between 26% and 33%, whereas only 1% to 2% of thromboses in adults are related to central venous lines.1,2
In pediatric patients, most central venous lines are placed in the upper venous systems. Thrombosis presents with failure to aspirate blood through the central venous line, pain and swelling of the anterior chest, recurrent sepsis, chylothorax, superior vena cava syndrome, symptoms of pulmonary embolism, or all of these. Most cases of deep venous thrombosis related to central venous lines are "asymptomatic" and diagnosed by venography. Right atrial thrombosis occurs in infants and young children who have a central venous line tip placed into the right atrium. Impaired blood flow and increased hematocrit associated with congenital cyanotic heart disease increase the occurrence of right atrial thrombus. Several factors influence the risk of thrombosis related to central venous lines in children. These include the type of catheter, endothelial damage at insertion, and the use of potentially thrombogenic fluids such as those used for total parenteral nutrition (eg, amino acid solutions, hypertonic glucose solutions, and lipids).
Treatment of Leukemia With L-asparaginase
Thrombotic complications related to the treatment of leukemia have increased in recent years, especially with increased use of central venous lines and L-asparaginase during the induction of chemotherapy. An acquired deficiency of antithrombin III secondary to L-asparaginase is implicated as a causative factor, in addition to in vivo activation of the coagulation by the disease itself.3
Nephrotic syndrome is characterized by edema, proteinuria, and hypoalbuminemia and is most commonly diagnosed as due to "minimal change disease." The incidence of thromboembolic events in children with nephrotic syndrome is significantly lower than that in adults (3.3% vs 19.50%).4 Venous thromboembolic events commonly occur within the first 3 months of diagnosis. The most common abnormalities associated with venous thromboembolic events in nephrotic syndrome include elevated levels of factor VIII and fibrinogen and a 50% decrease in the levels of antithrombin III and factor XII. The site most commonly involved is the renal vein. The thrombosis is usually diagnosed by an ultrasound examination.4
The use of oral contraceptives is known to increase the risk for thrombosis.5 The greater the estrogen content of these pills, the greater the risk for thrombosis. Hemostatic changes due to taking oral contraceptives include an increase in vitamin K-dependent factors, factor VIII, and fibrinogen. Along with these increases in the procoagulant factors, fibrinolytic activity is decreased, thus creating the hypercoagulable state seen during the use of oral contraceptives. The Leiden thrombophilia study6 evaluated the thrombotic risks associated with commonly inherited disorders and reported that oral contraceptives increased these risks by 4 times in those with no other risk factors. However, the presence of the factor V Leiden heterozygous state in a young woman taking oral contraceptives increased the risk to 35 times normal, whereas the presence of the factor V Leiden homozygous state increased the risk to 80 times normal.6
These constitute a heterogenous group of antibodies that react with proteins bound to phospholipids. They can be separated into two distinct antibody types - the lupus anticoagulant (which prolongs phospholipid-dependent clotting assays such as activated partial thromboplastin time) and anticardiolipin antibodies. Antiphospholipid antibodies have been associated with thrombosis, recurrent fetal loss, and thrombocytopenia. They are frequently seen in patients with systemic lupus erythematosus, but can also occur in individuals with no underlying disorder. In vitro experiments have suggested that both prothrombotic and antifibrinolytic mechanisms are associated with these antibodies. Some of the proposed mechanisms include inhibition of prostacyclin synthesis by endothelial cells, platelet activation, and inhibition of protein C activation.7
INHERITED THROMBOTIC DISORDERS
The most common inherited disorders of coagulation that predispose to thrombosis are deficiencies of natural anticoagulants (antithrombin III, protein C, and protein S) and activated protein C resistance (factor V Leiden).
Individuals with deficiencies of protein C, protein S, and antithrombin III generally have an autosomal dominant inheritance pattern and 50% activity of the deficient factor, and are asymptomatic until early adulthood. Both quantitative (type I) and qualitative (type II) forms of these disorders can predispose mese individuals to thrombosis.8 Deep venous thrombosis and pulmonary embolism are the most common thrombotic events. Visceral involvement is rare, and arterial thrombosis is uncommon. Risk is increased by additional acquired risk factors. Clinical expression of a given deficiency is variable within the family and among unrelated families.
Proteins C and S. Proteins C and S are vitamin K-dependent proteins. They are required for inactivation of factors Va and Villa, and thus exert their anticoagulant function. The clinical presentations of these two deficiencies are so similar that it is impossible to predict the factor deficiency on the basis of history alone. Hence, once suspected, both factors must be evaluated. Homozygous deficiencies of proteins C and S present within hours of birth with purpura fulminans, cerebral or ophthalmic damage that occurred in utero, and (rarely) large venous thrombosis.
Acquired deficiencies of proteins C and S can also occur in liver disease, disseminated intravascular coagulation, a postoperative state, inflammatory disease, oral anticoagulant therapy, treatment with L-asparaginase, and newborns with an immature liver.
Antithrombin III. Antithrombin III is a protease inhibitor that inactivates thrombin by irreversibly forming a 1:1 complex. The rate of inhibinon is accelerated by heparin. Unlike protein C and S deficiencies, homozygous deficiency of antithrombin III is incompatible with life.
Activated Protein C Resistance (Factor V Leiden)
In 1993, Dahlbäck et al.9 identified activated protein C resistance as a novel mechanism for familial thrombophilia. The disorder was later shown to be due to a defect in factor V involving the mutation of arginine-506 to glutamine-506 (factor V Leiden). This molecular change makes the mutant factor V resistant to inactivation by the normal activated protein C.
Prothrombin variant as a result of guanine to adenine substitution at nucleotide 20210 is associated with an elevated plasma level of prothrombin and an increased risk for venous thrombosis. In the Dutch population, this variant is the second most common genetic risk factor for venous thrombosis.
Two other inherited disorders with predilection for thrombosis are dysfibrinogenemia and plasminogen deficiency. Thrombosis is seen in 11% of cases of dysfibrinogenemia, whereas bleeding is associated with 31%.10 This variability in clinical presentation is due to the different types of functional defects. Since the first report in 1958, more than 300 abnormal fibrinogens have been reported. The mode of inheritance is autosomal dominant. This is also one of the disorders associated with arterial thrombosis.11 Mechanisms behind thrombotic risk include (1) fibrin formed from the abnormal fibrinogen resisting plasmin proteolysis; (2) decreased fibrin-mediated plasminogen activation; and (3) decreased thrombin binding to fibrin.
Defects in fibrinolysis due to either plasminogen deficiency12 or an increase in plasminogen activation inhibitor-1 have been considered a major cause of thrombotic disorders in adults, but have not been extensively studied in children. Plasminogen deficiency is an autosomal dominant disorder, and both qualitative and quantitative abnormalities of plasminogen have been reported. Although reports suggest that decreased fibrinolysis can cause thrombosis, the fibrinolytic system is not investigated routinely because we lack standardized tests for fibrinolytic proteins.
The homocysteine level in plasma is regulated by two enzymes, cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase. A reduction in either enzyme may result in increased levels of homocysteine with associated risk for arterial thrombotic events. Other factors that can induce elevated homocysteine levels include deficiencies of vitamin B12, vitamin B6, or folate, renal failure, and poor diet. The mechanism by which hyperhomocystinemia contributes to thrombogenesis is endothelial injury induced by homocysteine.13
Complications of Venous Thromboembolic Events
Serious immediate complications include death from extension into the heart or pulmonary embolism (2%). Long-term complications are related to either recurrent thrombosis (19%) or post-phlebitic syndrome (21% to 25%).4
Deep Venous Thrombosis
Although the venogram is the "gold standard" test for the diagnosis of deep venous thrombosis, pediatricians may have to accept an ultrasound because the patient is usually a sick newborn or child. To detect pulmonary embolism, one has to resort to a spiral computed tomography scan, which has not been validated in children. Magnetic resonance imaging, magnetic resonance arteriograph, and magnetic resonance venograph offer alternate testing modalities for the diagnosis of deep venous thrombosis.
The goals of diagnosis are to correctly identify the factors involved in a particular individual and asymptomatic individuals at risk for thrombosis. But what are the guidelines regarding screening for these inherited disorders? Guidelines are not well established, especially for children. Recommendations of the British Society of Hematology indicate screening when the following conditions exist:
1. Venous thrombosis in the absence of a triggering event at a young age. For pediatricians, this implies any patient with thrombosis.
2. Recurrent venous thrombosis.
3. Thrombosis at an unusual site.
4. Arterial thrombosis before 30 years of age.
5. Familial thrombosis.
6. Unexplained neonatal thrombosis.
7. Recurrent fetal loss.
Preferred Diagnostic Tests
Functional assays are preferable to immunologic methods and have shorter waiting periods for results. Children with thrombosis should be evaluated in a thrombophilia clinic at a children's hospital. This allows appropriate measures to be used to collect blood from very young children. Laboratory evaluation is not recommended immediately after an acute thrombotic event because some factors may be reduced after a major thrombosis. It is thus preferable to evaluate the patient in a stable state (ie, 15 to 30 days postthrombosis). If the patient has to begin anticoagulation therapy before laboratory testing, it is best to wait until 2 weeks after anticoagulation therapy is discontinued. If that is not possible, the best time is during a stable period of long-term anticoagulation. Another alternative is to study symptomatic family members who are not taking anticoagulants.
Standard heparin is the most widely used anticoagulant for pediatric patients. Heparinization should be attempted in an inpatient hospital setting. Because heparin is more rapidly cleared in young children, frequent monitoring and several dose adjustments may be required. Standard heparin may be continued for a minimum of 5 days in most patients. An initial bolus of 75 to 100 U /kg of heparin is given during 10 minutes followed by a maintenance dose of 20 U /kg/ h for children older than 1 year and 28 U /kg/ h for infants younger than 1 year.
The experience with low-molecular-weight heparin in young children is limited. However, several studies of adults have demonstrated that low-molecular-weight heparin is as effective and safe as standard heparin.8 Potential advantages of low-molecular-weight heparin for pediatric patients include predictable pharmacokinetics, less but more accurate monitoring, twice daily dosing, subcutaneous administration, less effect on bone metabolism, a lower incidence of heparin-induced thrombocytopenia, and safety. The recommended dose is 1.5 mg /kg subcutaneously every 12 hours for neonates and infants younger than 2 months and 1 mg /kg subcutaneously every 12 hours for children older than 2 months. The duration of therapy may include the entire period of anticoagulation (3 to 6 months).
Warfarin is the only oral anticoagulant used in children. It exerts its anticoagulant effect by inhibiting vitamin K, an essential cofactor for synthesis of factors II, VII, IX, and X. Laboratory monitoring is by prothrombin time and is reported as an international normalized ratio. The international normalized ratio corrects the variabilities seen with different thromboplastin reagents. Warfarin therapy can be initiated with a loading dose of 0.2 mg/ kg and the dose is adjusted to give an international normalized ratio between 2 and 3.
Associated problems include warfarininduced skin necrosis (due to decreased protein C), hemorrhagic risk, growth retardation, and frequent dose adjustments according to seasonal dietary changes and concomitant medications.
For a newborn with homozygous protein C deficiency with purpura fulminane, plasma infusion is started after obtaining plasma for protein C assays. Plasma infusion is continued every 12 hours until the lesion is healed and coumadinization is accomplished. This may take 4 to 6 weeks.
Thrombolytic therapy with tissue plasminogen activator is used in small doses to reestablish patency of central lines and in high doses systemically for arterial thrombosis, extensive deep venous thrombosis, or massive pulmonary embolism. The safety and efficacy of thrombolytic therapy have not been well evaluated in children and studies to determine efficacy and safety are urgently needed.
Regarding the cases described at the beginning of this article, the girl should be evaluated for thrombophilia before oral contraceptives are prescribed and the boy should be tested for a hypercoagulable state.
Thromboembolic events seen in pediatric patients require the involvement of a pediatric specialist for diagnosis and management. The greatest risk for thrombosis is in the neonatal period, and placement of central venous lines is probably a major factor. Because the hemostatic system of children differs from that of adults, one has to understand the specific differences before recommending diagnostic evaluation and subsequent anticoagulation therapy.
1. Andrews M, David M, Adams K, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83:1251-1257.
2. Streif W, Andrews ME. Venous thromboembolic events in pediatric patients: diagnosis and management. Hematol Oncol Clin North Am. 1998;12:1283-1312.
3. 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.
4. Andrew M, Montgomery RR. Acquired disorders of hemostasis. In: Nathan DG, Orkin SH, eds. Nathan and Oski's Hematology of Infancy and Childhood, 5th ed. Philadelphia: W. B. Saunders; 1998:1692-1693.
5. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348:977-980.
6. Vandenbroucke JP, Koster T, Briet E, Reítsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453-1457.
7. Shapiro SS. Lupus anticoagulants and antiphospholipid antibodies focus on hemostasis. Clinical Hemostasis Review. 1993;3:1-3.
8. Andrew M, Michelson AD, Bovili E, Leaker M, Massicote MP. Guidelines for anti-thrombotic therapy in pediatric patients. J Pediatr. 1998;32:575-588.
9. Dahlbäck B, Carlsson M, Svevsson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA. 1993;90:1004-1008.
10. Beck EA. Congenital abnormalities of fibrinogen. Clin Haematol. 1979;8:169-181.
11. Rodgers GM, Chandler VVL. Laboratory and clinical aspects of inherited thrombotic disorders. Am J Hematol. 1992;41:113-122.
12. De Stefano V, Firiazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes and management. Blood. 1996;87:3531-3544.
13. Leebeek WG, Knot EA, Ten Cate JW, Traas DW. Severe thrombotic tendency associated with a type I plasminogen deficiency. Am J Hematol. 1989;30:32-35.
Acquired Risk Factors for Thrombosis
Inherited Thrombotic Disorders