Venous Thromboembolism in Children 0-18 Years — a Regional Population-Based Study from Sweden

Abstract Introduction: Venous thromboembolism (VTE) is a rare complication in childhood. Pediatric VTE is an important and increasingly frequent clinical challenge likely due to increased detection and advanced medical interventions leading to improved survival of previously fatal conditions. Objective: The principal aim of this population based study was to describe the incidence, age distribution, type/location of VTE, and acquired and genetic pro-thrombotic risk factors of VTE and recurrence of VTE in children 0-18 years. Material and Methods: The Regional Ethical Review Board in Lund approved the study. We conducted a retrospective regional study of all consecutive ICD-10 codes of VTE in children 0-18 years over a 15-year period (January 1, 2000, to December 31, 2015) in a regional catchment area of southern Sweden using an electronic diagnosis registry. Eligible subjects were defined as children under the age of 18 who presented with VTE and had imaging evidence of thrombosis. Of the 174 patients diagnosed with VTEs, 164 fulfilled the study group criteria. Data regarding subject demographics and medical history (central venous catheter, cancer, congenital heart disease, history of VTE, current infection, etc.), location of VTE and imaging method (upper, lower extremities, pulmonary embolism, renal, cardiac, cerebral sinus venous thrombosis (CSVT), etc.), coagulation studies at primary investigation which included in all cases evaluation of at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C and the genotypes FV-G1691A and FII-G20210A. In addition, plasma values for coagulation factors VIII and XI, D-dimer, PK-INR, and cardiolipin antibodies were analyzed. Results: The incidence of VTE in children in the investigated region of Sweden was found to be 0.8 per 10,000 children. Of the study group with confirmed VTE (n=164), 73/164 (45%) were males and 91/164(55%) females, with bimodal age distribution at diagnosis, 25 (15%) < 1 month, 139 (85%) >1 month-18 years. Of the children, 143/164 (87%) had DVT (deep venous thrombosis), 21/164 (13%) had PE (pulmonary embolism) and 5/164 (3%) had both DVT and PE. Of 143 patients with DVT, 50 (30%) had lower extremity DVT, 46 (28%) had upper extremity DVT and 34 (20.7%) CSVT and the remaining 13 various locations. 79/164 (59%) had acquired potential risk factors, 11/164 (11%) had genetic risk factors, 34/164 (21%) had both genetic and acquired risk factors, and 22/164 (13%) had no identified risk factors. The most frequent acquired risk factors in the cohort were the use of hormonal therapy (34%), concomitant malignancy (21%), infection at the time of thrombosis (19%) or a CVL (central venous line) (15%). Genetic thrombophilia risk factors were found in 45/164 (27.5%), the most common were Factor V Leiden (FVL) in heterozygous form in 35 (21%), FII mutation (heterozygous) in 4 (2%) and double heterozygosity for FVL and FII mutation found in 2 (1%). Plasma deficiency of Protein S was found in 5, Protein C deficiency in 6 and Antithrombin deficiency in 1 patient (who had 3 episodes of VTE). Recurrent VTE was documented in 9 (5%), of which 5 had a congenital pro-thrombotic disorder (i.e. FVL mutation (n=3), antithrombin deficiency (n=1) and a protein S deficiency (n=1). Two out of the nine with recurrent VTE had neither a genetic nor an acquired identified risk factor. Six out of a total of 45 (13.3%) with genetic risk factors had a recurrent VTE. No common acquired pro-thrombotic risk factor was found in the group with recurrent VTE. Conclusion: The incidence, age-distribution, locations and underlying disorders agree with published findings in pediatric populations. In our study, 87% of the children with VTE had either an identifiable acquired or genetic risk factor or a combination of both. Of those with a genetic risk factor, 13% had a recurrent VTE during the study period which indicates an even higher cumulative risk during childhood which emphasizes the need to consider prophylaxis in situations with increased risk of VTE. However, of those with recurrent VTE, no frequent acquired risk factor was identified. Disclosures No relevant conflicts of interest to declare.

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Inpatient Inherited Thrombophilia Testing at an Academic Health Center: High Cost, Low Value

Blood ◽

10.1182/blood-2020-136374 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Ruben Rhoades

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Protein C ◽

Protein S ◽

Prothrombin G20210a ◽

Antithrombin Deficiency ◽

Inherited Thrombophilia ◽

G20210a Mutation ◽

Thrombophilia Testing ◽

American Society

Testing for inherited thrombophilias following venous and arterial thrombotic events remains controversial. These conditions are associated with an increased risk of initial and recurrent venous thromboembolism (VTE) and, in some cases, arterial events such as strokes and myocardial infarctions. However, testing for them in unselected patients with thrombotic events is not associated with lower recurrence rates, and other risk factors may be more clinically useful for determining whether and for how long to anticoagulate. Further, these tests are expensive and in the setting of an acute thrombosis, many may result in false positives. As such, the American Society of Hematology and American Society for Clinical Pathology recommended in their Choosing Wisely campaigns to not test for inherited thrombophilias after a provoked VTE or in the acute setting, respectively. The AHA/ASA determined that the utility of thrombophilia screening in stroke patients was unknown in its 2014 guidelines. This single institution, retrospective study reviewed all instances of inpatient inherited thrombophilia testing in 2019 at Thomas Jefferson University Hospitals, including its 3 primary hospitals in Philadelphia, PA. Tests included those to evaluate the following conditions: Factor V Leiden (FVL); prothrombin G20210A mutation; Protein C, S, and antithrombin deficiency; hyperhomocysteinemia; and plasminogen activator inhibitor-1 (PAI-1) elevation. The study included 231 patients, among whom a total of 872 tests were sent. Tests sent for non-thrombotic indications, such as homocysteine for B12 or folate deficiency, or in patients with a known deficiency were excluded. Median age of the patients was 50.8 years (IQR 38-63) and 129 (55.8%) were female. Diagnoses for which testing was sent and predisposing risk factors are summarized in Table 1. Arterial events were most common (54.5%), followed by VTE (26.0%). 14.7% of patients had no documented thrombosis, ischemic event, or pregnancy complication. Arterial events primarily included stroke/TIA (74.6%), and 76.7% of patients had at least one documented risk factor for these conditions. VTE was associated with a major transient risk factor or cancer in 32.8% of patients. Among all inherited thrombophilia tests sent, the most common were for the evaluation of FVL (20.9%), hyperhomocysteinemia (17.0%), Protein S deficiency (16.5%), prothrombin G20210A mutation (15.1%), Protein C deficiency (14.8%), and antithrombin deficiency (14.3%) (Table 2). Overall, 83.3% of tests were normal. Tests that were most frequently abnormal included MTHFR mutation (76.0%), antithrombin (36.0%), Protein C antigen (40.0%), PAI-1 (33.3%), and total Protein S (22.2%). Given our lab's references ranges, values for antithrombin, and Protein C antigen and function, and total Protein S that fell below normal but >60% were deemed "borderline positive." The likelihood of an abnormal result was not significantly different in cases of unprovoked VTE or arterial event without a risk factor, compared to those with risk factors. All charts were reviewed, including both inpatient and outpatient notes, to determine short- and long-term clinical decision-making. Importantly, among all positive tests, clinical management was not definitively changed in response to the test result in a single case. In two patients, it was unclear whether anticoagulation was continued based upon the test result. Both patients had heterozygous FVL mutations. Most positive results were deemed by the treating clinicians to be due to the acute thrombotic episode. Last, the hospital's chargemaster was queried, showing that these tests were associated with $398,912 in total charges. This single-institution retrospective study of inpatient inherited thrombophilia tests reveals the limited benefit of thrombophilia testing in the acute setting. Arterial ischemic/thrombotic events were the most common indication for testing, yet over 3/4 of patients had at least one risk factor. Nearly a third of patients with VTE had a major provoking factor, patients in whom thrombophilia testing is not recommended. While nearly 17% of tests returned abnormal, not one was associated with a clear change in clinical management. Despite limited clinical utility, costs of these tests are high. These data justify education and pathway implementation aimed at decreasing inpatient utilization of thrombophilia tests. Disclosures No relevant conflicts of interest to declare.

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An overview of genetic risk factors in thrombophilia

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh10s1079d ◽

2010 ◽

Vol 138 (suppl. 1) ◽

pp. 79-81 ◽

Cited By ~ 2

Author(s):

Valentina Djordjevic ◽

Ljiljana Rakicevic ◽

Dragica Radojkovic

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Protein C ◽

Significant Risk ◽

Genetic Risk Factors ◽

Genetic Defects ◽

Exact Nature ◽

Factor V Leiden Mutation ◽

Thrombotic Risk ◽

Factor Ii

Thrombophilia is a multifactorial disorder, involving both genetic and acquired risk factors that affect the balance between procoagulant and anticoagulant factors and lead to increased tendency to thrombosis. The concept that thrombophilia could be associated with genetic defects was first proposed in 1965 after the discovery of familiar antihrombin III deficiency. Further family studies showed that deficiency of protein C or protein S also increased thrombotic risk. In the coming years the advent in DNA technology, especially the invention of PCR reaction, played an important role in the identification of the exact nature of these deficiencies and opened new possibilities in the genetic research of thrombophilia. The breakthrough came with the discovery of activated protein C resistance and Factor V Leiden mutation. Shortly afterwards a mutation in the 3? untranslated region of Factor II gene (FII G20210A) associated with increased concentration of factor II in plasma, was described. Large epidemiologic studies have conformed that these two common mutations represent significant risk factors for thrombophilia. In the last decade several prothrombotic genetic risk factors have been described, including genes variants associated with increased levels of coagulation factors, defects of natural coagulation inhibitors, defects of the fibrinolytic system and hyperhomocysteinemia. These genetic defects or their combination have been extensively studied in an attempt to elucidate the possible association with increased thrombotic tendency. The large-scale DNA analysis systems are now becoming available, opening a new era in the genetic studies of thrombophilia. New technology will enable many genes to be studied in a single patient bringing us closer to the ?personalized? medicine.

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Gene-Gene and Gene-Environment Interactions Determine Risk of Thrombosis in Families With Inherited Antithrombin Deficiency

Blood ◽

10.1182/blood.v94.8.2590.420k40_2590_2594 ◽

1999 ◽

Vol 94 (8) ◽

pp. 2590-2594 ◽

Cited By ~ 91

Author(s):

H.H. van Boven ◽

J.P. Vandenbroucke ◽

E. Briët ◽

F.R. Rosendaal

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Venous Thromboembolism ◽

Genetic Risk ◽

Factor V Leiden ◽

Genetic Defects ◽

Factor V ◽

Antithrombin Deficiency ◽

Gene Environment ◽

Genetic And Environmental Factors

To analyze inherited antithrombin deficiency as a risk factor for venous thromboembolism in various conditions with regard to the presence or absence of additional genetic or acquired risk factors, we compared 48 antithrombin-deficient individuals with 44 nondeficient individuals of 14 selected families with inherited antithrombin deficiency. The incidence of venous thromboembolism for antithrombin deficient individuals was 20 times higher than among nondeficient individuals (1.1% v 0.05% per year). At the age of 50 years, greater than 50% of antithrombin-deficient individuals had experienced thrombosis compared with 5% of nondeficient individuals. Additional genetic risk factors, Factor V Leiden and PT20210A, were found in more than half of these selected families. The effect of exposure to 2 genetic defects was a 5-fold increased incidence (4.6% per year; 95% confidence interval [CI], 1.9% to 11.1%). Acquired risk factors were often present, determining the onset of thrombosis. The incidence among those with exposure to antithrombin deficiency and an acquired risk factor was increased 20-fold (20.3% per year; 95% CI, 12.0% to 34.3%). In conclusion, in these thrombophilia families, the genetic and environmental factors interact to bring about venous thrombosis. Inherited antithrombin deficiency proves to be a prominent risk factor for venous thromboembolism. The increased risks among those with exposure to acquired risk factors should be considered and adequate prophylactic anticoagulant therapy in high-risk situations seems indicated in selected families with inherited antithrombin deficiency.

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Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) [see comments]

Blood ◽

10.1182/blood.v85.10.2756.bloodjournal85102756 ◽

1995 ◽

Vol 85 (10) ◽

pp. 2756-2761 ◽

Cited By ~ 226

Author(s):

T Koster ◽

FR Rosendaal ◽

E Briet ◽

FJ van der Meer ◽

LP Colly ◽

...

Keyword(s):

Relative Risk ◽

Venous Thrombosis ◽

Protein C ◽

Protein S ◽

Population Based ◽

Repeated Measurements ◽

Protein C Deficiency ◽

Antithrombin Deficiency ◽

Vein Thrombosis ◽

Thrombosis Risk

A deficiency of protein C (PC), antithrombin, or protein S is strongly associated with deep-vein thrombosis in selected patients and their families. However, the strength of the association with venous thrombosis in the general population is unknown. This study was a population-based, patient-control study of 474 consecutive outpatients, aged less than 70 years, with a first, objectively diagnosed, episode of venous thrombosis and without an underlying malignant disease, and 474 healthy controls who matched for age and sex. Relative risks were estimated as matched odds ratios. Based on a single measurement, there were 22 (4.6%) patients with a PC deficiency (PC activity, less than 0.67 U/mL or PC antigen, less than 0.33 U/mL when using coumarins). Among the controls, the frequency was 1.5% (seven subjects). Thus, there is a threefold increase in risk of thrombosis in subjects with PC levels below 0.67 or 0.33 U/mL [matched odds ratio, 3.1; 95% confidence interval (CI), 1.4 to 7.0]. When a PC deficiency was based on two repeated measurements, the relative risk for thrombosis increased to 3.8 (95% CI, 1.3 to 10); when it was based on DNA-confirmation, the relative risk increased further to 6.5 (95% CI, 1.8 to 24). In addition, there was a gradient in thrombosis risk, according to PC levels. The results for antithrombin are similar to those for PC, although less pronounced (relative risk, 2.2; 95% CI, 1.0 to 4.7). We could not find an association between reduced total protein S (relative risk, 0.7; 95% CI, 0.3 to 1.8) or free protein S levels (relative risk, 1.6; 95% CI, 0.6 to 4.0) and thrombosis risk. Although not very frequent, PC and antithrombin deficiency are clearly associated with an increase in thrombosis risk.

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Genetic Risk Factors of Venous Thromboembolism in the East Algerian Population

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029615600789 ◽

2016 ◽

Vol 23 (2) ◽

pp. 105-115 ◽

Cited By ~ 3

Author(s):

S. Moussaoui ◽

P. Saussoy ◽

J. Ambroise ◽

J. P. Defour ◽

R. Zouitene ◽

...

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Protein C ◽

Protein S ◽

Jak2 V617f ◽

Genetic Risk Factors ◽

Prothrombin G20210a ◽

Factor V ◽

S Deficiency ◽

Calr Mutations

Many genetic risk factors have been identified for causing venous thromboembolism (VTE). Most of them affect the function of natural anticoagulant pathways, particularly the protein C system, although recent studies suggest a role of components of the hematopoietic pathway in the etiology of venous thrombosis. In this case–control study, we aimed to determine the frequency of prothrombin G20210A and factor V Leiden (FVL) G1691A polymorphisms and protein C, protein S, and antithrombin III deficiencies in the East Algerian population and to investigate whether these genetic factors are associated with VTE. On the other hand, our study tends to evaluate the status of JAK2V617F and calreticulin (CALR) mutations among these cases. The participants consisted of 121 cases with VTE and 146 healthy controls. Polymorphisms of FVL G1691A and prothrombin G20210A were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. JAK2-V617F and calreticulin mutations were analyzed by quantitative PCR and PCR followed by capillary electrophoresis sequencing, respectively. Protein C, protein S, and antithrombin levels were determined and then hereditary deficiencies were identified. Of all cases and controls, none was a carrier of the antithrombin III deficiency, prothrombin gene G20210A, and CALR mutations. Only 1 case reported having a positive JAK2 mutation (mutant allele burden was 15%). The FVL mutation (GA/AA) was found in 14 (11.6%) cases and 2 (1.4%) controls and it was significantly different between both the groups ( P = .001). Deficiencies of protein S and protein C were detected in 17 (18.8%) cases. The univariate analysis resulted in a significant impact of FVL (odds ratio [OR] = 9.4, 95% confidence interval [CI] = 2.1-42.3; P = .003) and of protein S deficiency (OR = 16.9, 95% CI =2.1-132.8, P = .007) on the VTE status. Both factors stayed significant after adjustment for sex and age. The OR of the protein C deficiency was slightly elevated (OR = 6.4, 95% CI = 0.7-55.5), but it did not reach the level of statistical significance ( P = .091), and it was therefore not considered as a risk factor. In conclusion, coagulant factor V gene G1691A mutation and protein S deficiency constitute important genetic risk factors in patients with VTE in Eastern Algeria. The somatic mutation of JAK2 V617F and CALR mutations are less frequent causes of VTE, thus routine testing for these mutations is not recommended.

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IgA Anticardiolipin Antibodies as a Risk Factor for Arterial and Venous Thrombotic Events.

Blood ◽

10.1182/blood.v106.11.4127.4127 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4127-4127

Author(s):

Esther Urbaez Duran ◽

Tim Kasunic ◽

Matthew Cotant ◽

Philip Kuriakose

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Protein C ◽

Hormone Replacement ◽

Factor V Leiden ◽

Anticardiolipin Antibodies ◽

International Standards ◽

Thrombotic Risk ◽

Risk Pregnancy

Abstract Background: Many studies have concluded that the presence of anticardiolipin antibodies is associated with both venous and arterial thrombotic events. The role of IgA anticardiolipin has been studied previously with conflicting results. Some of this disparity is thought to be due in part to the lack of international standards in measuring these levels. Objective : To further evaluate the role of IgA anticardiolipin anitbody as a risk factor for thrombosis. Patients and Methods: We conducted a single institution retrospective review of all patients with elevated IgA anticardiolipin antibodies extracted from a database of 20,000 patients for whom IgA anticardiolipin had been measured. Results: One hundred forty-eight patients were identified with elevated IgA anticardiolipin antibodies as measured by semiquantitative indirect Elisa. Patients had a median age of 52.5; 52% were African American, 38% Caucasain and 9% of other ethnic background. Of these patients, 67 had associated arterial or venous thrombotic events: 15.9% were pulmonary embolisms, 47.5% were deep venous thromboses and 36.6% were arterial thrombotic events. Patients were further evaluated for other thrombotic risk factors including IgG and IgM anticardiolipin antibodies; lupus anticoagulant; pt 20210; activated protein C resistance/Factor V Leiden; hyperhomocysteinemia; antithrombin; protein C/protein S deficiency; active malignancy with or without concurrent chemotherapy; tamoxifen, oral contraceptive or hormone replacement therapy; catheter-related risk; pregnancy; myeloproliferative disorders and hyperviscosity syndromes; sickle cell disease; and surgery, trauma or immobilization within 6 weeks of the event. In 35.8% of evaluated patients with elevated IgA and thrombotic events, there was was no concommitant elevation of IgG or IgM anticardiolipin. In 33.3% of patients with thrombotic events, none of the other predetermined risk factors were present. Conclusion: IgA anticardiolipin may be an independent risk factor for development of venous and arterial thrombotic events. A large case-controlled or prospective, randomized trial with standardized measurement will likely be needed to further clarify this issue.

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Evaluation of Inherited Prothrombotic Risk Factors in Children with Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v110.11.3953.3953 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3953-3953

Author(s):

Valerie Li Thiao Te ◽

Remi Favier ◽

Jeanne-Yvonne Borg ◽

Estelle Cadet ◽

Jacqueline Reynaud ◽

...

Keyword(s):

Risk Factors ◽

Protein C ◽

Protein S ◽

Prothrombin G20210a ◽

Protein C Deficiency ◽

Antithrombin Deficiency ◽

Mthfr Genotype ◽

G20210a Mutation ◽

Family Medical History ◽

Prothrombotic Risk Factors

Abstract This retrospective study was designed to determine the prevalence of inherited prothrombotic risk factors (Factor V Leiden (FV) G1691A and prothrombin G20210A mutations, TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR), protein C, protein S, antithrombin deficiencies) in a population of children with ALL treated according to the FRALLE 2000 study Protocol (High Risk and Standard Risk groups). The study was performed in 5 French Centers including Amiens, Angers, Paris Trousseau, Rouen and Saint-Etienne. From December 2000 to March 2006, 354 children aged 1 to 18 years old were consecutively admitted for ALL and were enrolled in the FRALLE 2000 Protocol. Among them, 281 patients were investigated for hereditary prothrombotic defects at the time of ALL diagnosis. Informed parental consent was required for gene analysis. Abnormal test results for protein S (functional activity and free protein S antigen concentration), protein C and antithrombin were controlled on a second blood sample after induction. In the population studied, the prevalence of one established prothrombotic risk factor was 19,2%: the FV G1691A mutation was diagnosed in 10 patients (3.6%), all heterozygous, 10 patients (3.6%) showed the heterozygous prothrombin G20210A mutation, the TT677 MTHFR genotype was found in 34 children (12.7%), 1 patient showed protein C deficiency (0.4%). No antithrombin deficiency was detected. The prevalence of inherited protein S deficiency could not be evaluated because of missing data in the family medical history. Combined prothrombotic defects were found in 2 patients (0.71%): heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A mutation in 1 patient and combined with TT677 MTHFR genotype in the second patient. Except for TT677 MTHFR genotype, the prevalence of hereditary prothrombotic risk factors in children with ALL in France were found within the prevalence reported for children treated for ALL (table 1) and comparable to the prevalence in healthy Europeans (Junker et al. 1999, Margaglione et al 2001, Mueller et al. 2005). Comparison of the prevalence of inherited prothrombotic risk factors in children with ALL Country Population FV G1691A +/− ++ PT G20210A +/− +/+ MTHFR TT677 AT PC AT: antithrombin deficiency ; PC: protein C deficiency ; NE : non evaluated NowakGöttl et al 1999 (n=301) Germany ALL children 5.3% 0.3% 2% 0% 7.7% 0.7% 2.3% Mauz-Körholz et al. 2000 (n=108) Germany ALL children 5.6% 0% 2.8% 0% 5.6% 0% 2.7% Mitchell et al. 2002 (n=60) Canada ALL children 3.3% 0% 2% 0% NE NE NE Present study (n=281) France ALL children 3.6% 0% (n=277) 3.6% 0%(n=279) 2.7% (n=268) 0% 0.4%

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Inherited Pro-Thrombotic Risk Factors in Children of South Moravia Region, Czech Republic

Blood ◽

10.1182/blood.v120.21.5136.5136 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5136-5136

Author(s):

Ondrej Zapletal ◽

Jan Blatny ◽

Eva Janousova

Keyword(s):

Risk Factors ◽

Protein C ◽

Thrombotic Event ◽

Protein S ◽

Study Cohort ◽

Global Test ◽

Thrombotic Risk ◽

Mthfr C677t Polymorphism ◽

Thrombophilia Screening ◽

Fv Leiden

Abstract Abstract 5136 Introduction: Pro-thrombotic risk factors are associated with increased risk of thrombosis. Some of them are inherited, but clinical manifestation of thrombosis in childhood is rare. It is most likely to appear in the adulthood. When leading to thrombosis during childhood, risk factors must be either very strong (e. g. homozygous deficiency of natural coagulation inhibitors), or must act together with other, usually acquired factors. Aims: - To analyse data of children referred for thrombophilia screening to Thrombosis Haemostasis centre, Dpt. of Paediatric Haematology University Hospital Brno, Czech Republic in years 2005–09. - To specify the characteristics of that cohort and identify the reasons for referral. -To determine prevalence of respective risk factors (RF) in children within study cohort. -To analyse possible correlation between related RF findings (ProC Global and FV Leiden, Protein C, Protein S; homocystein and MTHFR C677T polymorphism). Methods: We have collected data of all consecutive children aged from 0 to 18 years referred to our out-patient clinic for assessment of inherited thrombophilia in years 2005–2009 for any reason. Data recorded for each patient were as follows: age, gender, reason for assessment, thrombotic event and its type (if applicable) and vascular anomalies. Laboratory examinations done: FV Leiden mutation, Prothrombin gene mutation G20210A, MTHFR C677T polymorphism, protein C, protein S and Antithrombin levels, coagulation activity of F VIII, ProC Global test, homocystein and lipoprotein (a) level. Data were statistically analyzed to reach the aims of the study. Results: Data of 849 Caucasian children aged 0–18 years were available for analysis, 475 girls (55. 9 %) and 374 boys (44. 1 %). Median age was 11 years at the time of referral, boys 10 years, girls 13 years. Reasons for thrombophilia screening were as follows: family history of thrombosis/thrombophilia (70. 6 %), vascular anomaly (10. 8 %), thrombotic event (8 %) and others (10. 6 %). Thrombophilia screening was in more than 70 % of children performed before 15 years of age. Thrombotic event has been recorded in 79 patients (9. 3 %), both arterial (37. 6 %) and venous (63. 3 %). Adolescent patients had significantly more thrombotic events than younger children. Most of them were venous thromboses. Ischemic strokes and other arterial events were relatively more frequent in younger children. Frequency of “positive” laboratory findings in the studied cohort were as follows: MTHFR 60. 3 %, positive ProC Global test findings 58. 1 %, FV Leiden (heterozygous)37 %, hyperlipoproteinemia (a) 28. 5 %, protein S deficiency 11. 3 %, high FVIII activity 9. 4 %, Prothrombin gene mutation (heterozygous) 7. 7 %, Antithrombin deficiency 2. 7 %, elevation of homocystein 1. 6 % and protein C deficiency 1 %. Findings have confirmed high sensitivity of ProC Global test to the pathology in protein C pathway, particularly to FV Leiden mutation (sensitivity 98. 4 %). There was no statistically significant relation between homocystein level and MTHFR polymorphism status. Prevalence of RF in study cohort was found to be similar to the literature data. Deficiencies of natural coagulation inhibitors (AT, PC and PS) were rare, pro-thrombotic mutations were more frequent. Data suggest, that role of inherited pro-thrombotic risk factors in the development of thrombotic event in children is not the major one. It is very likely, that more potent risk factors, often acquired ones, are often important for development of thrombotic event during childhood. Conclusions: In our centre, we assessed proximately 170 children referred for thrombophilia screening per year. The incidence is thus 8 children per 10000. During 2005–09the main reason for referral was positive family history, but children were often referred in younger age, than recommended. The evidence available to date suggests that it is neither necessary nor useful to examine asymptomatic children before they reach puberty. Finding of inherited thrombophilia, and thus possibility to use measures preventing eventual thrombotic event, are more important in adolescence and adulthood rather than in younger age. In children with thrombotic event, however, it is recommended to screen for inherited risks. Diagnosis and treatment of thrombotic event in children requires a specialised care and relevant expertise of the Paediatric Thrombosis Haemostasis centre. Disclosures: No relevant conflicts of interest to declare.

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Hereditary Thrombophilia as a Model for Multigenic Disease

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615894 ◽

1999 ◽

Vol 82 (08) ◽

pp. 662-666 ◽

Cited By ~ 27

Author(s):

Sandra J. Hasstedt ◽

Mark F. Leppert ◽

George L. Long ◽

Edwin G. Bovill

Keyword(s):

Risk Factors ◽

Protein C ◽

Antithrombin Iii ◽

Factor V Leiden ◽

Protein S ◽

Factor V ◽

Antithrombin Deficiency ◽

Factor V Leiden Mutation ◽

The Past ◽

S Deficiency

IntroductionNearly 150 years ago, Virchow postulated that thrombosis was caused by changes in the flow of blood, the vessel wall, or the composition of blood. This concept created the foundation for subsequent investigation of hereditary and acquired hypercoagulable states. This review will focus on an example of the use of modern genetic epidemiologic analysis to evaluate the multigenic pathogenesis of the syndrome of juvenile thrombophilia.Juvenile thrombophilia has been observed clinically since the time of Virchow and is characterized by venous thrombosis onset at a young age, recurrent thrombosis, and a positive family history for thrombosis. The pathogenesis of juvenile thrombophilia remained obscure until the Egeberg observation, in 1965, of a four generation family with juvenile thrombophilia associated with a heterozygous antithrombin deficiency subsequently identified as antithrombin Oslo (G to A in the triplet coding for Ala 404).1,2 The association of a hereditary deficiency of antithrombin III with thrombosis appeared to support the hypothesis, first put forward by Astrup in 1958, of a thrombohemorrhagic balance.3 He postulated that there is a carefully controlled balance between clot formation and dissolution and that changes in conditions, such as Virchow’s widely encompassing triad, could tip the balance toward thrombus formation.The importance of the thrombohemorrhagic balance in hypercoagulable states has been born out of two lines of investigation: evidence supporting the tonic activation of the hemostatic mechanism and the subsequent description of additional families with antithrombin deficiency and other genetically abnormal hemostatic proteins associated with inherited thrombophilia. Assessing the activation of the hemostatic mechanism in vivo is achieved by a variety of measures, including assays for activation peptides generated by coagulation enzyme activity. Activation peptides, such as prothrombin fragment1+2, are measurable in normal individuals, due to tonic hemostatic activity and appear elevated in certain families with juvenile thrombophilia.4 In the past 25 years since Egeberg’s description of antithrombin deficiency, a number of seemingly monogenic, autosomal dominant, variably penetrant hereditary disorders have been well established as risk factors for venous thromboembolic disease. These disorders include protein C deficiency, protein S deficiency, antithrombin III deficiency, the presence of the factor V Leiden mutation, and the recently reported G20210A prothrombin polymorphism.5,6 These hereditary thrombophilic syndromes exhibit considerable variability in the severity of their clinical manifestations. A severe, life-threatening risk for thrombosis is conferred by homozygous protein C or protein S deficiency, which if left untreated, leads to death.7,8 Homozygous antithrombin III deficiency has not been reported but is also likely to be a lethal condition. Only a moderate risk for thrombosis is conferred by the homozygous state for factor V Leiden or the G20210A polymorphism.9,10 In contrast to homozygotes, the assessment of risk in heterozygotes, with these single gene disorders, has been complicated by variable clinical expression in family members with identical genotypes.11 Consideration of environmental interactions has not elucidated the variability of clinical expression. Consequently, it has been postulated that more than one genetic risk factor may co-segregate with a consequent cumulative or synergistic effect on thrombotic risk.12 A number of co-segregating risk factors have been described in the past few years. Probably the best characterized interactions are between the common factor V Leiden mutation, present in 3% to 6% of the Caucasian population,13,14 and the less common deficiencies of protein C, protein S, and antithrombin III. The factor V Leiden mutation does not, by itself, confer increased risk of thrombosis. The high prevalence of the mutation, however, creates ample opportunity for interaction with other risk factors when present.The G20210A prothrombin polymorphism has a prevalence of 1% to 2% in the Caucasian population and, thus, may play a similar role to factor V Leiden. A number of small studies have documented an interaction of G20210A with other risk factors.15-17 A limited evaluation of individuals with antithrombin III, protein C, or protein S deficiency revealed a frequency of 7.9% for the G20210A polymorphism, as compared to a frequency of 0.7% for controls.18 The G20210A polymorphism was observed in only 1 of the 6 protein C-deficient patients.18 In the present state, the elucidation of risk factors for venous thromboembolic disease attests to the effectiveness of the analytical framework constructed from the molecular components of Virchow’s triad, analyzed in the context of the thrombohemorrhagic balance hypothesis. Two investigative strategies have been used to study thromobophilia: clinical case-control studies and genetic epidemiologic studies. The latter strategy has gained considerable utility, based on the remarkable advances in molecular biology over the past two decades. Modern techniques of genetic analysis of families offer important opportunities to identify cosegregation of risk factors with disease.19 The essence of the genetic epidemiologic strategy is the association of clinical disease with alleles of specific genes. It is achieved either by the direct sequencing of candidate genes or by demonstration of linkage to genetic markers.

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Hereditary Deficiencies of Protein C or Protein S Confer Increased Risk of Arterial Thromboembolic Events at Young Age. Results from a Large Family Cohort Study

Blood ◽

10.1182/blood.v112.11.422.422 ◽

2008 ◽

Vol 112 (11) ◽

pp. 422-422

Author(s):

Bakhtawar Khan Mahmoodi ◽

Jan-Leendert P. Brouwer ◽

Nic J.G.M. Veeger ◽

Jan van der Meer

Keyword(s):

Risk Factors ◽

Protein C ◽

Protein S ◽

Thromboembolic Events ◽

Antithrombin Deficiency ◽

Increased Risk ◽

Atherosclerosis Risk ◽

History Of ◽

Arterial Thromboembolic Events ◽

Atherosclerosis Risk Factors

Abstract Introduction: Hereditary deficiencies of protein S, protein C or antithrombin are strong risk factors for venous thromboembolism (VTE). Whether these deficiencies are associated with arterial thromboembolism (ATE) and whether history of VTE in these subjects predisposes to subsequent ATE has yet to be determined. Methods: Based on pedigree analysis we enrolled a total 552 subjects (52% women; mean age, 46±17 years), belonging to 84 different kindreds, in this retrospective family-cohort study. Detailed information on previous episodes of VTE, ATE, anticoagulants use and atherosclerosis risk factors (i.e. diabetes, hypertension, hyperlipidemia, and smoking) were collected. In addition to the index deficiencies participants were also tested for other thrombophilic defects; including factor V Leiden, prothrombin G20210A, increased FVIII and lupus anticoagulants. Primary study outcome was objectively verified symptomatic ATE. As the assumption for proportional hazards for the final model was not met over the entire observation period, we opted for a piecewise Cox model with a cut off point set at 55 years of age. Results: Of 552 subjects (mean age±SD, 46±17 years; 52% women), 308 had either protein S (35%), protein C (39%) or antithrombin deficiency (26%). Age, atherosclerosis risk factors and other thrombophilic defects were similar (P>0.23) between deficient and non-deficient subjects. A total of 44 arterial thromboembolic events had occurred, corresponding to an overall annual incidences of 0.34% (95% CI, 0.23–0.49) in deficient and 0.17% (0.09–0.28) in non-deficient subjects, hazard ratio 2.3 (1.2–4.5; P=0.01). However, the risk hazards varied over lifetime; while risk of ATE conferred by these deficiencies was 5.4 (1.6–18.4; P=0.006) before age 55 years, it was 1.3 (0.6–2.9; P=0.51) thereafter. After adjusting for atherosclerosis risk factors and clustering of ATE within families, deficient subjects had 4.7-fold (1.5–14.2; P=0.007) higher risk of ATE before age 55 years, versus 1.1 (0.5–2.6; P=0.84) thereafter, compared to non-deficient family members. For separate deficiencies these were 4.6 (1.1 – 18.3), 6.9 (2.1 – 22.2) and 1.1 (0.1 – 10.9) in protein S-, protein C- and antithrombin-deficient subjects, respectively, before age 55 years. History of VTE was not related to subsequent ATE, hazard ratio 1.1 (0.5 – 2.2). Conclusions: Compared to non-deficient family members, subjects with protein S or protein C deficiencies but not antithrombin deficiency have an increased risk for ATE before age 55 years, independent of prior VTE. After age 55 years conventional atherosclerosis risk factors accounted for ATE. In thrombophilic families, deficiencies of protein S and protein C should be considered in atherothrombotic risk assessment before age 55 years.

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