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Risk Factors for Venous Thromboembolism in Children

Posted on: Sunday, 23 January 2005, 03:00 CST

The incidence of venous thromboembolism (VTE) is increasing in children as a result of therapeutic advances and improved clinical outcome in primary illnesses that previously caused mortality. VTE is mostly diagnosed in hospitalized children, especially sick newborns with central venous catheters and older children with a combination of risk factors. Infants older than 3 months and teenagers are the largest groups developing VTE. The most important triggering risk factors are the presence of central venous lines, cancer and chemotherapy. Pathological conditions such as severe infection, sickle cell disease, trauma and antiphospholipid syndrome are associated with the presence of a hypercoagulable state in children. The thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be extremely low. Venous thromboembolism in pediatric patients is mainly caused by combinations of at least 2 prothrombotic risk factors for venous thromboembolic events in children are usually associated with underlying clinical conditions and a triggering risk factor. In addition, recurrence of VTE after withdrawal of anticoagulant treatment occurs in about 20% of patients after re-exposure to a triggering risk factor. A non negligible mortality and morbidity is related to VTE in childhood. This supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with VTE. Risk factor assessment for VTE in children has to be improved in order to optimize the prophylactic and therapeutic strategies. The specific evolutionary characteristics of the hemostasis in children has to be taken into consideration when a prophylactic or therapeutic strategy is applied.

[Int Angiol 2004;23:195-205]

Key words: Venous thrombosis - Thromboembolism, prevention and control - Risk factors - Child.

The physiology of the hemostatic system in children is different from that in adults. Reference ranges for components of the hemostatic system are age dependent. During early childhood, physiologic values may overlap with values observed in congenital deficiencies of acquired pathological conditions. Physiologically decreased plasma concentrations of hemostatic components also influence the response to antithrombotic therapy. The relevance of developmental hemostasis for the laboratory diagnosis and the evaluation of the risk factors for venous thromboembolism (VTE) in childhood are discussed.1

The blood coagulation and thrombin generation process in childhood

The physiological status of blood coagulation in premature infants and neonates is substantially different compared to adults.2 In the neonates the levels of vitamin-K dependent clotting factors (FVII, FX, FIX and FII) in plasma are about 30% and they are normalized after 2 to 6 months. However the kinetics of the normalization of these clotting factors' levels is substantially different for each one. The levels of FXII, FXI, precallicrein and high molecular weight kininogene are between 35% to 55% and they are normalized after 4 to 6 months. In contrast the levels of FVIII, FV and vWF are normal in neonates. The stoichiometric physiological inhibitors of blood coagulation (AT, TFPI and HcoII) as well as the dynamic anticoagulant system of protein C (protein C and protein S) are significantly reduced, at about 30% to 40%, and they are normalized within 3 months except protein C which is normalized at 6 months. Similar perturbations of the clotting factors and the natural anticoagulants are observed in prematures, but in this case the normalization is more rapid. During the first months of life, the global clotting times (PT and aPTT) are significantly prolonged and they are normalized within the next 6 months. Noteworthy the extent of aPTT prolongation strongly depends on the reagent used being more important when this test is performed with elagic acid than with kaolin.3-5 In addition, the presence of fetal fibrinogen during the first months of life further contributes to the prolongation of the global clotting times. Although in neonates and children the evolution of the quantitative aspect of blood coagulation components has been studied in details, the knowledge of thrombin generation process is limited. It has been shown that thrombin generation in children is reduced by about 25% as compared to adults. However the actual knowledge on this field is very limited.

Hypercoagulable states and risk factors for VTE in children

Frequency of VTE in children

In adults, the average annual age- and sex-adjusted incidence of in-hospital VTE is about 960.5 (95% confidence interval [CI], 795.1- 1125.9) per 10 000 person-years and is more than 100 times greater than the incidence among community residents [7.1 (95% CI, 6.5-7.6) per 10 000 personyears]. The incidence of VTE rose markedly with increasing age for both groups, with pulmonary embolism (PE) accounting for most of the agerelated increase among in-hospital cases.7 As it is expected the incidence of VTE in the general population of children is rather low but it substantially increases in pediatric patients. The incidence of VTE in the general population is 0.07 to 0.14 events per 10 000 children and 5.3 events per 10 000 pediatric hospital admissions, with a greater risk in infants less than 1 year of age and teenagers. Epidemiologie features of VTF in neonates and children have been studied in 2 registries.8,9 Neonatal VTE was almost exclusively Ccitheter related, located in the upper venous system, and asymptomatic. In older children, VTE was catheter related in approximately 1/3 and more often was located in the lower venous system. In 85% of all patients, thrombosis developed while the patient was in the hospital. Diagnosis is usually made by ultrasonography. In 98% of all patients, at least 1 risk factor was present. Congenital prothrombotic disorders were more often present in older children (21%) than in neonates (6%). A variety of treatment modalities were used. Morbidity consisted of bleeding (7%) and recurrent thrombosis (7%). Two children died as result of VTE.9 The minimum incidence of symptomatic neonatal renal venous thrombosis is reported to be 2.2 per 100 000 live births. Most of the cases (13 per 100 000 live births) occur in premature babies and leads to irreversible kidney damage in the 70% of cases.10 The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 month to 18 years with DVT/ PE for a mean of 2.86 years to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in 9 children (2.2%), all of whom had central venous line-associated thrombosis. Morbidity was substantiell, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups.11

Overview of the risk factors for VTE in neonates and children

The main risk factors for VTE in neonates and children are the catheterization of central lines, acute infection and inflammatory syndrome, cancer and chemotherapy, major trauma, sickle cell disease and congenital thrombophilia. In the following paragraphs will be presented a detailed review of the recent literature on the risk factors for VTE.

Thrombophilia

In 96% of children with objectively diagnosed VTE an acquired triggering risk factor is present. Factor V Leiden mutation is present in 13%, FII G20210A mutation in 3%, antithrombin deficiency in 1%, protein C deficiency in 1% and protein S deficiency in 1% of the studied patients. Positive family history appeared to be the only predictor for positive testing for congenital disorders (odds ratio [OR] 14.9, 95% CI 1.9-113). The overall mortality rate is 20%. The cumulative recurrence-free survival was 92% after 1 year of follow-up, and 82% after 7 years. Post-thrombotic syndrome was diagnosed in 70% patients.12

The prevalence of triggering and inherent risk factors for VTE was studied in 171 consecutive children with VTE. An underlying medical condition and a central venous line were present in 91% and 77% of the studied children respectively. A positive family history was present in 8% of children. The prevalence of factor V Leiden was 4.7%, FIIG20210A polymorphism was 2.3%, protein S deficiency was 1.2%, protein C deficiency was 0.6% and increased plasma lipoprotein (LP)(a) concentration was 7.5%. The overall frequency of inherited prothrombotic coagulation proteins was 13% (95% CI 7% to 19%) and the frequency was not significantly different between neonates and older children with VTE. Inherited prothrombotic coagulation proteins were not associated with gender, central venous line related VTE, a positive family history of thrombosis or spontaneous VTE in neonates. Increased frequency of inherited prothrombotic coagulation proteins was, however, found in older children with spontaneous VTE (60%) compared with older children with VTEs secondary to an underlying medical condition (10%) (p=0.02).13

A prospective cohort study assessed the incidence of spontaneous and risk period-related VTE in asymptomatic children, who were family members of a proband with an objectively diagnosed venous thromboembolic event and a documented single thrombophilic abnormality. A total of 1\13 children from 63 families were enrolled. Of them, 56.6% were carriers of an inherited defect, whereas the remaining were free from known genetic or acquired causes of thrombophilia. The mean observation period was 5 years (range, 1-8 years) in each group. Thirty-one risk periods occurred in the carriers group and 20 in noncarriers. Neither spontaneous nor risk period-related VTE occurred in either group during 395 and 296 observation years, respectively.14

In 130 consecutive children with VTE the OR for VTE was significantly increased in patients with FV Leiden mutation (OR 3.64; 95% CI: 1.14-11.6, p<0.029) whereas OR for VTE was not significantly increased in patients with FIIG20210A (OR 1.06; 95% CI: 0.24-4.73, p=0.938). Combined disorders were found in 50% of the children with the aforementioned mutations. In 19% of children without these mutations other inherited and acquired disorders were detected.15

Among 13 consecutive children with intracardiac thrombosis, diagnosed by cross-sectional echocardiography, 6 were heterozygotes for Factor V Leiden mutation whereas no carried the prothrombin 20210 G-A mutation. Other risk factors for intracardial thrombus formation are ventriculoatrial shunt for hydrocephalus, indwelling catheter for chemotherapy, cardiomyopathy, sepsis, homocystinuria and tetralogy of Fallot.16

In a cohort of 48 childhood patients with spontaneous VTE the FV Leiden mutation, the FIIG20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, the plasminogen activator inhibitor (PAI-1) promoter polymorphism, Lp(a), antithrombin, protein C, and protein S were investigated and compared with the carrier status of their first-degree family members. In 40% of patients, one prothrombotic risk factor was diagnosed, and in 56% at least 2 prothrombotic defects/alleles. In the majority of cases with spontaneous venous thrombosis, the FV Leiden G1691A mutation was involved either with a second mutated allele or combined with elevated Lp(a), the 4G/4G genotype of the PAI-1 promoter polymorphism, and the T677T MTHFR genotype. The rate of combined prothrombotic risk factors was significantly higher in childhood patients compared with their parents.17

In a cohort of 56 consecutive children with VTE prospectively studied at a single center, 89% had thrombosis in the lower venous system. Risk factors were detected in 96% of children; 38% VTE were related to central venous lines. Family history of thrombosis was positive in 23% of patients. In 46% of patients, a prothrombotic disorder was detected. In 16% a congenital disorder was present, 26% of children had acquired disorders and 4% showed combined abnormalities (association of 2 congenital disorders or 1 congenital and 1 acquired).18

In a case-control study the MTHFR C677T genotypes, FV G1691A and prothrombin G20210A were evaluated in 60 children and 80 healthy controls: 10.4% of the healthy control population showed the MTHFR TT genotype, 34.2% the CT genotype and 55.4% the CC variant. The following frequencies (patients versus controls), OR and 95% CIs were found for single defects: MTHFR 677TT genotype (10.6% vs 10.4%; OR/CI: 1.02/0.54-1.93; p=0.99) and CT genotype (43.8% vs 34.2%; OR/ CI: 2.12/1.42-3.16; p=0.0000). A combination of FV G1691A mutation and MTHFR 677CT genotype was found in 9.9% of patients and in 2.9% of the controls (OR/CI: 3.8/1.64-8.75; p=0.027). Fasting homocysteine median (range) concentrations in the patient group were significantly higher than in the controls (7 mol/l (3-23) vs 5.5 mol/ l (3-8.4): p=0.0004), and homocysteine concentrations >8.3 mol/l were found in 40% of patients vs 2.5% of the controls (OR/CI: 22/ 2.64-183; p=0.0003).

In 27 consecutive childhood patients with inferior caval vein thrombosis and 100 healthy age-matched controls were investigated for the presence of prothrombotic risk factors with respect to the first thrombotic onset. In 19 out of 27 patients, thrombosis occurred during infancy; the remaining vascular accidents were diagnosed during puberty. In 13 out of the 19 infants, vascular occlusion occurred spontaneously, 5 times associated with renal venous thrombosis; 68.4% of patients in the first year of life (n=13) showed at least one prothrombotic risk factor. The incidence of heterozygous FV mutation was 15% and homozygous FV mutation was 3%. Increased levels of Lp(a) were found in 15%, MTH FR TT677 with mild hyperhomocysteinemia was found in 11% and antithrombin deficiency type II was found in 3%. In the adolescent group, genetic risk factors were found in 50% of patients (FV mutation 3%, and FIIG20210A 11%). Remarkably, during puberty and adolescence the predominant defect diagnosed was the PT G20210A variant, whereas the FV Leiden mutation had a higher incidence during infancy.20

In 119 children with spontaneous venous thrombosis and controls (n=100) the frequencies, OR, 95%-CIs and p-values were FV Leiden 19.3% vs 5%, (OR/CI 4.55/1.66-12.5, p=0.0038) and FIIG20210A, 8.4% vs 3%, (OR/CI 2.96/0.8-11, p=0.17). A combination of the FV Leiden mutation with the FIIG20210A variant was found in 3 children (2.5% of cases) but only once in the controls. With a median (range) age of 2 years (0-17), carriers of the FV Leiden mutation were significantly younger compared with patients carrying the FIIG20210A variant (16 years: 0-18, p<0.001). Vascular accidents in carriers of the FV Leiden mutation occurred in deep veins of the leg, cerebral veins, renal veins and portal veins. Patients with the FIIG20210A mutation showed spontaneous thrombosis in the majority of cases in the deep veins of the leg (n=5) and in the central nervous system (n=2). Combined defects were found in a neonate with renal venous thrombosis and in 2 adolescents with deep vein thrombosis. These data suggest that the heterozygous FV Leiden mutation is the most commonly found prothrombotic risk factor responsible for spontaneous thrombosis during infancy and early childhood. In contrast, the FIIG20210A variant is likely to be more important during puberty and adolescence.21

In a cohort of 38 children with VTE or arterial thrombosis and FIIG20210A mutation was found that children with arterial thrombosis were younger. Less than half of the studied children had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and thrombosis occurred most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there.22

Two studies investigated the association between the presence of FV Leiden and an hypercoagulable state in children. Both studies included a sufficient number of affected and normal children and demonstrated the presence of an hypercoagulable state, documented with increased plasma levels of D-dimers and thrombin generation markers, in children carrying the FV Leiden mutation.23,24 In addition, infants and children with the Arg506-to-Gln mutation in the factor V gene showed significantly increased thrombomodulin concentrations along with normal protein C activities compared with relatives and healthy controls. No difference was recorded in these studies between heterozygous infants and children without vascular occlusion and patients who previously had suffered from thromboembolism.

The risk of recurrent VTE among children in relation to the presence of single or combined-inherited and/or acquired causes of thrombophilia has been evaluated in a total of 301 children with an objectively confirmed first episode of spontaneous VTE. The patients were followed prospectively for a median time of 7 years (range: 6 months to 15 years) after withdrawal of anticoagulation. In 58% of children was found one single prothrombotic risk factor was whereas combined defects were found in 20.6%. Recurrent VTE occurred in 21% of patients within a median time of 3.5 years (range: 7 weeks to 15 years) after withdrawal of anticoagulation, with a significantly shorter cumulative thrombosis-free survival in children carrying combined defect. The FV G1691A mutation was present in the majority of patients with recurrent VTE. Only the presence of prothrombotic defects increases the risk of recurrent VTE (single defect: OR 4.6; 95% CI, 2.3-9.0; p<0.0001; combined defect: OR 24.0; 95% CI: 5.3- 108.7; p<0.0001).25

Cancer and chemotherapy related hypercoagulable state

Pediatric patients with acute lymphoblastic leukemia (ALL) are at an increased risk of thromboembolic events. Potentially responsible mechanisms include the disease process itself, treatment with chemotherapeutic agents (particularly L-asparaginase), or a combination of the disease and treatment. A prospective study in 66 children with ALL showed that DVT of the upper venous system, diagnosed with bilateral venography and ultrasound occurred in 29% patients.26

In patients suffering ALL an hypercoagulable state, documented by increased levels of thrombin generation markers (TAT, F1+2) has been shown.27 Administration of L-asparaginase alone or in combination with chemotherapeutic drugs induces a decrease of antithrombin levels but this does not modify the already existing hypercoagulable state.28 A study in a group of 32 children with ALL proposed that the immunophenotypic subgroup of ALL thromboembolic episodes or even disseminated intravascular coagulation (DIC) may occur during treatment with L-asparaginase.29

In a longitudinal, prospective, non-randomized study, 27 children with ALL treated according to the protocol ALL-BFM-90 received substitution with antithrombin concentrate, when AT levels were below than 60% of the normal with a concomitant increase of D- dimers. Although the ad\ministration of AT decreased plasma levels of hypercoagulability markers at the end of the treatment course, a causative association between replacement treatment with AT and decreasing of D-dimers could not be strongly supported.30

In an open label randomized, controlled study in children with ALL being treated with L-asparaginase the efficacy and safety of prophylactic antithrombin replacement was evaluated. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28%, compared to 37% in the non treated arm (p>0.05). The tolerance was similar in both groups. In addition the prophylactic replacement with antithrombin concentrate did not improve the hypercoagulable state in the treated group since the surrogate plasma markers of thrombin generation were similar in both groups.31

Comments

The frequency of VTE in children with ALL depends on the chemotherapeutic protocol used.32,33 The L-asparaginase induced transitory reduction of AT levels to 50-60% of normal seems to make the hemostatic equilibrium more unstable. However isolated L- asparaginase and the reduction of AT levels does not seem to be the most important risk factor for thrombosis. The manifestation of VTE or DIC is probably due to the coexistence of several other inherent (i.e. presence of FV Leiden mutation, FII20210 mutation) and triggering risk factors (the cancer per se, central venous line, bacterial, viral or fungal infection, inflammatory syndrome, desydratation, lysis syndrome and chemotherapy).34,35 The use of prednisone and L-asparaginase concomitantly administered in a leukemic patient suffering from a prothrombotic risk factor triggers venous thrombosis in the majority of cases.36 There are no controlled trials on the potential benefit of prophylactic antithrombotic treatment at the diagnosis of leukemia and during the chemotherapy. The initiation of prophylactic antithrombotic treatment has to be proposed after careful evaluation of the risk factors.

Central venous catheters

Indwelling central venous catheters (CVC) are essential devices in the management of children with oncologic/hematologic diseases or following bone marrow transplantation.

The Canadian Childhood Thrombophilia Registry monitored 244 consecutive patients with objectively diagnosed central venous line related DVT for a median duration of 24 months The incidence of DVT was 3.5 per 10 000 hospital admissions. Venous thrombosis was more frequent in the upper venous system. Thirty-nine children held pulmonary emboli, but most were not investigated for pulmonary emboli. Nine (3.7%) children died as a consequence of their thromboembolic disease. Recurrent DVT occurred in 16 (6.5%) children, and postphlebitic syndrome occurred in 23 (9.5%) children. Currently no uniform guidelines exist for the prevention and management of central line related DVT in children. The frequency and clinical consequences of CVL-related DVTs justify controlled trials of primary prophylaxis in children requiring central venous access.37

A retrospective analysis of clinical records of 482 patients in whom 567 indwelling central venous catheters had been inserted showed an 4% incidence of catheter obstruction due to thrombosis.38 In a retrospective cohort study in pediatric intensive care unit in children with diabetic cetoxeosis the placement of femoral central venous catheter was associated with an increased risk for symptomatic VTE. Femoral central venous catheter was placed in 6 out of 113 patients and DVT occurred in 3 of them (2.6% of the studied population and 50% of the patients with central femoral catheter). Children who developed DVT were younger than the other without thrombosis. They also had significantly higher glucose, corrected sodium concentrations, and lower pH and serum bicarbonate than did age-matched patients with femoral central venous catheter and shock.39,40 In a cohort of 42 children with cancer and central venous catheter 44% developed thrombosis of the catheterized vein diagnosed with ultrasonography. In 29% an additional hereditary abnormality was present.41 In another cohort of 93 children requiring central venous catheter in a pediatric intensive care unit, the incidence of DVT was 18.3%. Thromboses were diagnosed within the first 4 days of catheter placement. Risk factors most predictive of DVT were presence of a cancer (OR=17.23, 95% CI=1.5 to 194) and young age (OR for age 0.72, 95% CI=0.54 to 0.96).42

Critically ill neonates and children

The sick neonate may develop spontaneous or catheter-related thromboses. An hypercoagulable state, documented by increased levels of in vivo thrombin generation markers (thrombin/antithrombin complex) and of impaired in vitro inhibition of thrombin generation is present in critically ill neonates hospitalized in intensive care units,43, 44 in preterm infants with neonatal respiratory distress syndrome (RDS)45 in children with neisseria meningitides or meningococcal infection, which cause meningitis, fulminant septicemia or mild meningococcemia.46,47

Sickle call disease

In sickle cell disease, loss of erythrocyte membrane phospholipid asymmetry occurs with the exposure of phosphatidylserine (PS), which provides a docking site for coagulation proteins. In vivo sickling/ desickling, with resulting red cell membrane changes and microvesicle formation, appears to be one of the factors responsible for PS exposure. In children with sickle cell disease homozygous for sickle hemoglobin (SS disease) high levels of fetal hemoglobin are associated with the presence of procoagulant microparticles and in vivo thrombin generation.48 In patients with the SC genotype, the hypercoagulable state, although present, is of a lesser magnitude than in SS disease.49 In addition children with sickle cell disease present reduced levels of vitamin K dependent clotting factors, FV as well as a moderated decrease of PC and a slight decrease of PS levels whereas AT levels are usually normal and FVIII levels are increased.50-52 Both hemostatic abnormalities and hepatic dysfunction contribute to low levels of natural coagulation inhibitors.

In patients suffering major β-thalassemia increased in vivo thrombin generation and platelet activation has been also reported. This is due to increased exposure of procoagulant phospholipids on the membrane of the affected red cells.53

Antiphospholipid syndrome

Antiphospolipid syndrome is present in the childhood and is also a triggering risk factor for VTE. Antiphospholipid antibodies and antiphospholipid syndrome was present in 75% of 57 children and adolescents with systemic lupus erythematosus (anticardiolipin 70.2% and lupus anticoagulant 29.1%). Arterial thrombosis occurred in 7% of the patients, DVT occurred in 1.7% and 5% 3 patients had involvement of small calibre vessels. Recurrences were observed in 37.5% of the affected patients, with a mean interval of 13 months between the events.54 Vascular lesion and alterations of the fibrinolytic system associated with the Kawasaki disease predispose to thrombosis during childhood.55

A cross-sectional cohort study of 59 consecutive, nonselected children with systemic lupus erythematosus (SLE) showed that thromboembolisms diagnosed with objective radiographic tests occurred in 17% of patients. Acquired activated protein C resistance (APCR) was present in 31% of the studied patient and it was significantly associated with theromboembolic episodes, with the presence of lupus anticoagulants but not anticardiolipin antibodies. The presence of both APCR and lupus anticoagulants was associated with the highest risk of a thromboembolism.56

In contrast, the presence of lupus anticoagulants in children not affected by a systemic disease does not seem to be a risk factor for VTE. A retrospective study of 95 consecutive children, diagnosed with presence of lupus anticoagulants (LA) at a hemostasis referral center; showed that at diagnosis, 84% of children were free of symptoms, and that the presence of LA was found incidentally. A 10% of patients had bleeding symptoms, 55% had thrombotic events and 1.5% had systemic lupus erythematosus. None of the children who were initially free of symptoms had bleeding, thrombotic complications, or autoimmune disease subsequently. At follow-up, 58% of patients had normal activated partial thromboplastin time values after 1.9 years, 38% still had activated partial thromboplastin time elevations but did not fulfill all criteria for presence of LA after 3.2 years and 4% patients, who had presented with thrombosis, had persistent positive lupus anticoagulant, anticardiolipin, and antinuclear antibodies after 1.4, 2.8, and 7.5 years, respectively. One of these had recurrent thrombosis.57

Some rare cases of Budd-Chiari syndrome have been reported in children with familial polycythemia vera, and antiphospholipid antibody syndrome.58, 59

Nephrotic syndrome

In children the hemolytic-uremic syndrome is a thrombotic complication of Escherichia coli (E. coli) O157:H7 infection. In 53 children infected with E. coli O157:H7 markers of in vivo thrombin generation and fibrinolysis were prospectively measured. The children in whom the hemolytic-uremic syndrome subsequently developed (n=16) had significantly higher median plasma concentrations of prothrombin fragment 1+2, tissue plasminogen activator (t-PA) antigen, t-PA-plasminogen-activator inhibitor type 1 (PAI-1) complex, and D-dimer than children with uncomplicated infection. These abnormalities preceded the development of azotemia and thrombocytopenia. Thus an hypercoagulable state and an inhibition of fibrinolysis in children with E. coli infection preceeds and probably has a causative role to the manifestation of hemolytic-uremic syndrome.60 Neither peritoneal dialysis nor administration of blood products down regulate the hypercoagulable state and norma\lise fibrinolysis.61 Cardiac ischemia has also been reported during hemolytic uremic syndrome.62

It is of great interest to have the best evaluation of the thromboembolic risks in nephrotic children. The criteria that are commonly used are: albuminuria, and plasma levels of fibrinogen and antithrombin. One can suggest adding to these criteria the D-dimer assay, a molecular marker of coagulation activation, and the factor V Leiden workup because it represents a genetic predisposition for thromboembolic complications. As far as prevention of thromboembolic complications is concerned, the standard but basic guidelines of nephrotic patients must be followed. Furthermore, vitamin K antagonists should be administered as soon as the risk criteria are gathered, but only after a careful evaluation of the benefits/risks ratio. As to the treatment of thromboembolic events, one should follow the present recommendations for children. A better future regarding prevention of thromboembolic accidents is based not only on the necessity of multicentric prospective studies but also on basic research that will allow to discover thh primum movens of childood nephrotic syndrome.63

Cushing syndrome and metabolic abnormalities

An hypercoagulable state has been described in patients with active Cushing's syndrome. Primary prophylaxis with anticoagulants is recommended in these patients when they are exposed to a thrombophilic condition such as surgery.64

Trauma

Although the incidence and risk factors for VTE after trauma in adults have been well described, similar data regarding pediatric patients are lacking. Risk of VTE increases with age and injury severity scores. VTE is associated with head, thoracic, abdominal, lower extremity, and spinal injuries. Craniotomy, laparotomy, and spinal operations are also associated with VTE. The greatest risk of VTE was in children with venous catheters.65

Stroke and arterial thrombosis in children

The incidence of stroke in children exceeds 8 per 100 000 per year. Patients with sickle cell dis ease are known to have an ill- defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. Hematological or prothrombotic conditions are also associated with AIS in children, and include sickle cell disease and prothrombotic disorders. The latter have been identified in from 1/ 3 to one half of children with AIS, are usually acquired, and frequently act in concert with other risk factors for stroke. The most common embolie source is congenital heart disease, which is present in 25% of children with AIS. Risk factors include vascular, intravascular, and embolic disorders; frequently, there are multiple risk factors in a given child, necessitating thorough investigations. More than 50% have a vasculopathy including postvaricella angiopathy, dissection, moyamoya, or vasculitis. Intravascular mechanisms are frequently present, including dehydration. Congenital Human cytomegalovirus (HCMV) infection should also be included among the causes of neonatal aortic thrombosis.66 Outcomes include death in 6% and neurological deficits in 2/3 of children. Given that no clinical trials have been completed in pediatric stroke to date, treatment is empiric. Initial neuroprotective strategies aim to reduce the size of the infarct. For older children antithrombotic agents (antiplatelet drugs and anticoagulants) are given to reduce the 20% to 30% risk of recurrence.67

Conclusions

Venous thromboembolic events are being increasingly diagnosed in systemic and cerebral vessels in children. Systemic VTE are increasing in children as a result of therapeutic advances and improved clinical acumen in primary illnesses that previously caused mortality. The epidemiology of systemic VTE has been studied in international registries. VTE is mostly diagnosed in hospitalized children, especially sick newborns with central venous catheters and older children with a combination of risk factors. Children older than 3 months and teenagers are the largest groups developing VTE. The most important triggering risk factors are the presence of central venous lines, cancer and chemotherapy.

There is evidence showing that pathological conditions such as severe infection, sickle cell disease, trauma, antiphospholipid syndrome induce are associated with the presence of an hypercoagulable state in children, documented with increased plasma concentration of thrombin generation markers. These conditions probably are triggering risk factors for VTE, but their impact needs to be evaluated in prospective and case control studies.

Factor V Leiden is a risk factor for VTE whereas FIIG20210A does not seem to be a less potent risk factor. In children with VTE and FIIG20210A mutation almost always an additional triggering factor exists at the time of the event and VTE occur in older age. Unlike factor V Leiden and deficiencies of proteins C and S which cause VTE, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. Early- onset spontaneous VTE in childhood patients is mainly caused by combinations of at least 2 prothrombotic risk factors. Venous thromboembolic events in children are usually associated with underlying clinical conditions and a triggering risk factor. The added contribution of prothrombotic conditions to the occurrence of VTE in children is not clear. Recurrence of VTE after withdrawal of anticoagulant tretment occurs in about 20% of patients after re- exposure to a triggering risk factor. The probability of recurrence of the thromboembolic event increases when 2 inherent risk factors are present.

The thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be extremely low. Common triggering conditions for VTE in thrombophilic adults do not seem to increase the thrombotic risk in children carrying the same inherited defect. Accordingly, screening for thrombophilia in otherwise healthy children younger than 15 years who belong to families with inherited defects predisposing to thrombosis seems unjustified.

There is a non negligible mortality and morbidity related to VTE in childhood. This supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with VTE.

Prophylaxis and treatment studies for VTE consist of inadequately powered randomized controlled trials or prospective cohort studies (discussed in another chapter). Properly designed clinical trials are urgently required in children with VTE to define the best methods of diagnosis, treatment and long-term management.68

The specific evaluation of the impact of risk factors for VTE in children has to be studied in order to adapt the prophylactic and therapeutic strategies to the characteristics of the children. The specific evolutionary characteristics of the hemostasis in children has to be taken in consideration when a prophylactic or therapeutic strategy is applied.

Received April 19, 2004; accepted for publication October 19, 2004.

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G. T. GEROTZIAFAS

Unit of Biologic Hematology, Robert Debr Hospital, Paris, France

Address reprint requests to: G. Gerotziafas, MD, Service d'Hmatologie Biologique, Hpital Robert Debr, 48 Boulevard Serrurier, 75935 Paris, CEDEX 19, France.

E-mail: grigoris.gerotziafas@rdb.ap-hop-paris.fr gerotzialfasgrigoris@hotmail.com

Copyright Edizioni Minerva Medica Sep 2004

Source: International Angiology

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