Mountain States Genetics Foundation

The term thrombophilia is used to describe a condition where a person is at increased risk for clot formation (hypercoagulable) in the venous or arterial system. In the late 1800s, Virchow first identified hypercoagulability as a predisposing factor for thromboembolic events. Antithrombin III deficiency was one of the first identified causes for a hypercoagulable state. Since then, several congenital abnormalities of hemostasis that predispose to thromboembolic events have been identified, and in some, the molecular defects delineated. Childhood thrombosis is receiving increased attention in the past few years. Emerging information regarding coagulation protein structure and function is adding to new understanding of an old disease. In addition, research in vascular biology and atherosclerosis is shedding light on other biochemical pathways that contribute to vascular damage and thrombogenesis. Patients with single gene defects for recognized congenital prothrombotic disorders rarely present with a first thromboembolic event during childhood, unless they also have an acquired risk factor that unmasks the defect. Patients who are homozygous or double-heterozygous for one or more genetic lesions linked to congenital prothrombotic disorder will frequently present with clinical symptoms as newborns or young children.

At the time of initial presentation, a careful history, physical examination, and laboratory evaluations are required. Interpretation of laboratory results in the infants should take into consideration the physiologic low values of coagulants and anticoagulants in this age group. Although abnormal laboratory value results frequently are linked to thromboembolic events, they may not always be causally linked – and consideration must be given to the prevalence and incidence in the general population.

Congenital Prothrombotic Disorders Established to Cause a Thromboembolic Event

Clinically significant relationships have been confirmed between thromboembolic events and deficiencies of protein C, protein S, antithrombin, presence of factor V Leiden (Arg506Gln), prothrombin mutation (G20210A), and some dysfibrinogenemias in adults. These are aberrations in the natural anticoagulant systems that occur in the plasma and at the endothelial cell level. They are usually associated with venous rather than arterial thrombosis, and commonly first occur in the presence of acquired risk factors such as pregnancy, immobilization, surgery, etc. A genetic abnormality predisposing to thromboembolic events can now be identified in up to one-third of unselected adult patients with thromboembolic events, and more than one-half of adult patients with familial thrombosis. The overall increase in risk of thromboembolic events for adults with one of these abnormalities is approximately 10-fold, compared to adults without any abnormality. There is accumulating evidence that multiple coexisting defects are present in adults with the most marked tendency to develop thromboembolic events (Table 1). Hyperhomocysteinemia is now recognized as another important etiology for thrombosis especially of the arterial side. This condition induces its prothrombotic state by adversely affecting the vessel wall, the coagulation system, and the platelet function.

Congenital Prothrombotic Disorders That Might Contribute to a Thromboembolic Event

Congenital prothrombotic disorders that might contribute to a thromboembolic event include abnormalities in the fibrinolytic system, such as plaminogen deficiency, tissue plasminogen activator deficiency, increased plasminogen activator-1, heparin cofactor II deficiency, and decreased factor XII levels (Table 1).

The true prevalence of congenital prothrombotic disorders in the general population is not known. In Caucasians, the prevalence of protein C deficiency is estimated to be 0.3%, antithrombin deficiency is 0.04%, factor V Leiden is 5%, and prothrombin gene polymorphism is 2%. There are no studies of sufficient size to estimate the prevalence of protein S deficiency among healthy adults. Additionally, the prevalence of congenital prothrombotic disorders varies in different ethnic populations; e.g., the prevalence of factor V Leiden varies from approximately 5% in the Caucasian population to <1% in the African and Asian populations. The prevalence of these abnormalities increases in unselected adults with their first thromboembolic event. In those with thrombosis and suspected thrombophilia (positive family history), the prevalences for deficiencies of protein C, protein S, and antithrombin are higher by 5% to 10%. The prevalence for factor V Leiden is approximately 50%, thus emerging as the most frequent congenital prothrombotic risk factor for a thromboembolic event (Table 2).

The incidence of thromboembolic events (DVT [deep vein thrombosis] and PE [pulmonary embolism] ) in children between 1 month and 18 years of age is estimated to be 0.07 cases and 5.3 cases/10,000 hospital admissions, respectively. Two prospective large registry studies reported the incidence of symptomatic neonatal DVT to be 0.24 to 0.26 events per 10,000 births. Comparable incidences of DVT and PE in the adult population are approximately 2.5 to 5%. The incidence in pediatric thrombosis may be increasing secondary to increased utilization of vascular access devices in the intensive care units, and increased use of indwelling catheters for intravenous antibiotics, parenteral nutrition, and chemotherapy. The inherited causes of thrombophilia in children appear to be similar to those in the adult populations. In contrast to adults, in whom thromboembolic events are idiopathic in 40% of patients, only 5% of cases are idiopathic in children. The ratio of venous to arterial thrombosis is approximately 2.5 to 1. The diagnosis of thrombosis is made at a median age of approximately 12 years, with peaks in the neonatal and adolescent periods. Children with homozygous or heterozygous factor V Leiden usually have their first vascular insult following puberty.

The acquired causes of thrombophilia in children include the antiphopholipid antibody syndrome, use of oral contraceptives, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), malignancy and its treatment, especially use of the agent L-Asparaginase in patients with leukemia, dehydration from any cause, malnutrition, and sickle cell disease. The antiphospholipid antibodies (APA) are observed very frequently in children, especially after viral infections, varicella being a very common culprit. But it is infrequent to see thrombosis in children after every viral infection. The APA can be associated with both arterial and venous thromboembolic events, especially stroke. Platelet hyperaggregability as seen in patients with PNH and throbotic thrombocytopenic purpura (TTP) also confers an increased thrombotic risk. In newborns, there are certain conditions that predispose to neonatal thrombosis, including maternal diabetes mellitus, hypoxia/asphyxia, polycythemia, infections, and the indwelling catheters. Less than 1% of cases of thromboembolic events in neonates are idiopathic. Over 50% of cases in children and over 80% of cases in newborns occur in the upper venous system secondary to the use of indwelling catheters

Venous thromboembolic events are the most common clinical presentation of single gene congenital prothrombotic disorders and occur in the presence or absence of other acquired risk factors. The most suggestive features for the presence of a congenital prothrombotic disorder include a positive family history, recurrent thromboembolic events, an early age for the first event, the absence of a significant acquired insult, and occurrence in an unusual site. Thromboses in children affect large, central vessels including the atria of the heart, the vena cava, hepatic, renal, and pulmonary vessels. Proximal vessels affected include the subclavian, axillary, jugular, and iliofemoral. Distal thromboses of the calf and arm vessels are uncommon in children.

Diagnosis should include use of imaging studies, including, but not limited to ultrasound/doppler, venograms, radionuclide studies and magnetic resonance arteriography/venography. Measurement of d-dimers is gaining importance in the initial screen for the diagnosis of a pulmonary embolus.

Complications of childhood thrombosis include death from thrombosis in 3-5% of patients, pulmonary embolism in about 20%, and the post-phlebitic syndrome in 10-20% of patients.

The management of childhood thrombosis follows treatment guidelines in the adult population. These remain the primary source for recommendations in children until more studies in children are completed. The first guidelines for antithrombotic treatment in pediatric patients occurred in 1995, based primarily on adult studies and case studies in children. Data from recent pediatric studies show, however, that extrapolation of adult guidelines to infants and children is suboptimal. But until large scale studies are completed, treatment will follow some of the modified adult guidelines. Treatment includes use of anticoagulation and thrombolytic agents. Indefinite anticoagulation is suggested for patients with 2 or more episodes of spontaneous thromboses, one spontaneous life threatening thrombosis, one spontaneous thrombosis at an unusual site (cerebral, mesenteric vessels) and one spontaneous thrombosis in the presence of more than a single biologic defect. In those with a prothrombotic stimulus, vigorous prophylaxis during high risk situations (e.g. immobilization) is suggested. For venous thromboembolic disease, a minimum of 3-6 months of treatment with anticoagulation is suggested. For a recurrent thromboembolic event that is not related to a central venous catheter, indefinite anticoagulation is suggested. Use of unfractioned heparin in the management of these patients has given way to use of low molecular weight heparins, due to their ease of administration and less frequent monitoring of levels.

Oral anticoagulation with use of oral warfarin is still used in some patients after initial heparinization. Fibrinolytic agents like tPA (tissue plasminogen activator) are used at times to manage clots located in areas that be accessed locally or for those situated in dangerous situations like the atrial walls of the heart.

Andrew M, David M, Adams M, et al.. Venous thromboembolic complications (VTE) in children: first analysis of the Canadian registry of VTE. Blood 83:1251-1257; 1994.Andrew M, Monagle PT, Brooker L. Thromboembolic complications during infancy and childhood. Hamilton, ON, BC Decker Inc, 2000.Bonudel M, Hepner M, Sciuccati G, et al.. Prothrombotic abnormalities in children with venous thromboembolism. J Pediatr Hemat Oncol 22: 66-72, 2000.Hirsh J. Approach to patients with inherited thrombophilia. Hamilton, ON, BC Decker Inc, 1998Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 119 (Suppl):344S-370S; 2001Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatr 96:292-294, 1995Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 78:297-301, 1997

Sutor A, Masicotte P, Leaker M, Andrew M. Heparin therapy in pediatric patients. Sem Thromb Hemost 23:303-319, 1997

Table 1: Odds ratio for prevalence of thrombotic disease in adults
with various heterozygotic abnormalities

Type of abnormality	Number of families	Prevalence of history of thrombosis Heterozygous (%) Normal (%) Odds ratio
Antithrombin Def	28	44	2	13.7
Protein C Def	13	44	9	9.8
Protein S Def	15	56	4	10
Dysfibrinogenemia	10	40	0	18
Plaminogen Def	20	1	0	2.6
Impaired fibrinolysis	18	54	33	1.7
Heparin Cofactor II	4	20	13	0.8

Table 2: Summary of prevalence of inherited thrombophilic disorders
in different populations

Population	Pro C Def (%)	Prot S Def (%)	Anti-thrombin Def (%)	FVLeiden (%)	Pro-thrombin mutation (%)	Hyper- homo-cyteinemia
Normal	0.3	-	0.04	3-8	1	0.3-1.4
Unselected pts with thrombosis	3	1.5	1	13-20	-	4 -10
Pts with thrombosis and thrombophilia	7.9	7.2	5.3	52	7	-