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

Blood ◽  
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.

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

Blood ◽  
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%

Risk Factors in Venous Thromboembolism

2001 ◽  
Vol 86 (07) ◽  
pp. 395-403 ◽  
Author(s):  
Ida Martinelli
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Nucleotide Substitutions ◽  
Inherited Thrombophilia ◽  
G20210a Mutation ◽  
Increased Risk

SummaryVenous thromboembolism is a serious disorder because of its potential complications, such as pulmonary embolism and the post-thrombotic syndrome. Inherited determinants of venous thromboembolism are only in part known, but in the past decades considerable progress has been made in the understanding of risk factors for the disease and their clinical impact. In particular, the development of molecular biology techniques and the increasing interest in their application, allowed an identification of two causes of inherited thrombophilia, i.e., factor V Leiden and the prothrombin G20210A mutation. Their recent discovery provided a new approach for improving the knowledge of inherited thrombophilia. In contrast to deficiencies of the naturally occurring anticoagulant proteins antithrombin, protein C and protein S, these two mutations cannot be considered true genetic defects, since they are nucleotide substitutions resulting in a more efficient coagulation process. Since they are rather common in the general populations of Caucasian descent and are associated with a moderate increased risk of venous thromboembolism, the effect of the interaction between inherited and environmental risk factors for venous thromboembolism has become an even greater field of interest. Prevention of first events and recurrences of venous thromboembolism can be optimized only through a knowledge of the main risk factors, their effect, and their interaction with environmental factors.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3805-3805
Author(s):  
Bader Allahyani ◽  
Rolf Ljung
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Genetic Risk ◽  
Protein C ◽  
Age Distribution ◽  
Protein S ◽  
Population Based ◽  
Antithrombin Deficiency ◽  
Thrombotic Risk ◽  
Recurrent Vte

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.

Prevalence and Financial Impact of Inappropriate Thrombophilia Testing in the Inpatient Hospital Setting: A Retrospective Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2330-2330 ◽  
Author(s):  
Eric Mou ◽  
Henry Kwang ◽  
Jason Hom ◽  
Lisa Shieh ◽  
Neera Ahuja ◽  
...  
Keyword(s):  
Protein C ◽  
Hospital Setting ◽  
Factor V Leiden ◽  
Protein S ◽  
Financial Impact ◽  
Prothrombin G20210a ◽  
Factor V ◽  
G20210a Mutation ◽  
Thrombophilia Testing ◽  
Test Ordering

Abstract Introduction Thrombophilia diagnostics are frequently ordered in the inpatient hospital setting, but their impact on patient care is often equivocal. Thrombophilia testing is expensive, and many results are subject to confounding when ordered in the context of an acute hospitalization. Furthermore, these tests are frequently lost to follow-up or wastefully repeated after the patient is discharged. In this study, we conducted a retrospective chart review to determine the rate and financial impact of inappropriate thrombophilia test ordering across all inpatient services at Stanford Hospital over one calendar year. Methods Utilizing data from our finance department, we obtained a list of all inpatient thrombophilia testing ordered at Stanford Hospital from June 2014 through June 2015. Thrombophilia testing was defined as ordering any of the following: factor V Leiden, prothrombin G20210A mutation, antithrombin III, lupus anticoagulant, beta-2 glycoprotein 1 IgM/IgG, anticardiolipin IgM/IgG, dilute Russell viper venom time, protein C or protein S levels, and JAK2 V167F mutation. The criteria for defining a test as 'inappropriate' were guided by utilizing major society guidelines and current evidence, placing an emphasis upon the ordered tests' clinical relevance and reliability in the context of the patient's admission diagnosis. The criteria were formulated by a senior hematologist with specific expertise in thrombophilia evaluations. Two internal medicine resident physician data reviewers independently evaluated the ordered tests to determine their appropriateness. To ensure consistency between reviewers, identical test datasets were evaluated and compared, demonstrating satisfactory concordance (>0.85). When the appropriateness of a test was unclear, joint evaluation was performed with the entirety of the study team to arrive at a final conclusion. Each test was linked to the ordering primary service. Charge data for each individual test was obtained through our financial department. Aggregate data were evaluated manually. Results In total, we reviewed 889 individual orders involving 167 patients across 20 ordering specialties. Of the 889 total orders, 331 were deemed inappropriate (37.2%), translating into a cumulative hospital charge of $152,923 (Figure 1). The tests most frequently inappropriately ordered included antithrombin III (94.4%), factor V Leiden (93.2%), protein C (92.7%), protein S (92.2%), and the prothrombin G20210A mutation (89.3%). Ordering individual tests in the setting of clearly provoked thrombotic events, during the acute thrombotic period, while patients were on concurrent anticoagulation, or when results failed to impact management represented the most common reasons testing was deemed inappropriate. Ordering practices were then stratified across the hospital's different primary services. Of services with the highest volume of test ordering, General Medicine (38.1%) and Neurology (34.9%) ordered testing inappropriately at the highest rates, while Rheumatology (12.8%) and Hematology (15.9%) ordered inappropriately at the lowest rates. Notably, the non-teaching services ordered testing inappropriately at one of the highest rates (62.2%), though their volume of ordering was lower in comparison with the aforementioned groups. Discussion Our results illustrate the high prevalence and significant financial impact of inappropriate or unnecessary thrombophilia testing conducted in the inpatient setting at our institution. Factors confounding test validity were frequently present at the time of ordering. Furthermore, stratifying ordering practices by specialty illustrated the differential rates of inappropriate ordering between services. Even when thrombophilia testing results fail to impact short term decision-making, misappropriated labeling of patients as 'thrombophilic' can have a lasting negative impact on future anticoagulation decisions. Combined with the high cost of errant ordering, these serve as a strong impetus to reduce the rate of thrombophilia testing during inpatient hospitalizations. Our baseline data demonstrate a need for institution-wide changes such as implementing electronic best practice advisories or potential ordering restrictions, and of tantamount importance, service-specific educational interventions in order to reduce unnecessary expenditures and improve patient care. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The APC-independent anticoagulant activity of protein S in plasma is decreased by elevated prothrombin levels due to the prothrombin G20210A mutation

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1686-1692 ◽  
Author(s):  
Rory R. Koenen ◽  
Guido Tans ◽  
René van Oerle ◽  
Karly Hamulyák ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Factor V Leiden ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Healthy Population ◽  
Factor V ◽  
Thrombotic Risk ◽  
G20210a Mutation

AbstractProtein S exhibits anticoagulant activity independent of activated protein C (APC). An automated factor Xa–based one-stage clotting assay was developed that enables quantification of the APC-independent activity of protein S in plasma from the ratio of clotting times (protein S ratio [pSR]) determined in the absence and presence of neutralizing antibodies against protein S. The pSR was 1.62 ± 0.16 (mean ± SD) in a healthy population (n = 60), independent of plasma levels of factors V, VIII, IX, and X; protein C; and antithrombin, and not affected by the presence of factor V Leiden. The pSR strongly correlates with the plasma level of protein S and is modulated by the plasma prothrombin concentration. In a group of 16 heterozygous protein S–deficient patients, the observed mean pSR (1.31 ± 0.09) was significantly lower than the mean pSR of the healthy population, as was the pSR of plasma from carriers of the prothrombin G20210A mutation (1.47 ± 0.21; n = 46). We propose that the decreased APC-independent anticoagulant activity of protein S in plasma with elevated prothrombin levels may contribute to the thrombotic risk associated with the prothrombin G20210A mutation.

scholarly journals Genetic Risk Factors of Venous Thromboembolism in the East Algerian Population

2016 ◽  
Vol 23 (2) ◽  
pp. 105-115 ◽  
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.

Hereditary Thrombophilia as a Model for Multigenic Disease

1999 ◽  
Vol 82 (08) ◽  
pp. 662-666 ◽  
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.

Prothrombin G20210A mutation and oral contraceptive use increase upper-extremity deep vein thrombotic risk

2003 ◽  
Vol 89 (03) ◽  
pp. 452-457 ◽  
Author(s):  
Yolanda Mira ◽  
Jose Mateo ◽  
Cristina Falco ◽  
Piedad Villa ◽  
Amparo Estelles ◽  
...  
Keyword(s):  
Oral Contraceptive ◽  
Upper Extremity ◽  
Protein C ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Protein S Deficiency ◽  
Factor V Leiden Mutation ◽  
G20210a Mutation ◽  
S Deficiency ◽  
Deep Vein

SummaryThe role played by a hypercoagulable state, either inherited or acquired, in the pathogenesis of upper-extremity deep vein thrombosis (UEDVT) remains a question of debate. We performed a case-control study including 79 patients with a first objectively confirmed episode of UEDVT, 31 secondary and 48 primary, and 165 healthy controls. Nine patients (11.4%) with UEDVT were carriers of the prothrombin G20210A mutation vs. six (3.7%) in controls; P = 0.025, OR: 3.39 (95% CI 1.16 to 9.88). No statistical difference was observed between cases and controls for the factor V Leiden mutation, AT, protein C or protein S deficiency and anticardiolipin antibodies (ACAs). Thirteen (35.1%) UEDVT patients were oral contraceptive (OC) users vs. 12 (16%) controls; P = 0.020, OR: 2.89 (95% CI 1.16-7.21). When secondary UEDVT patients were compared with controls, no differences were observed in any of the risk factors analysed. On the other hand, when primary UEDVT was considered, six (12.5%) patients were carriers of the prothrombin G20210A mutation vs. six (3.7%) controls; P = 0.031, OR: 3.76 (95% CI 1.15-12.26). Regarding ACAs, a borderline statistical significance was observed when primary UEDVT was compared with controls, P = 0.048; OR: 4.88 (95% CI 1.05-22.61). In primary UEDVT, 52% of the fertile women were OC users vs. 16% of controls; P = 0.001, OR:5.78 (95% CI 2.13-15.67). When the interaction of both factors, i.e. prothrombin G20210A mutation and OC intake, were considered, the risk increased markedly, indicating a synergistic effect as observed with other thrombotic locations. In patients with primary UEDVT screening for antithrombin, protein C and protein S deficiency and APC resistance would not be justified, although it might be reasonable to determine the carrier status of the prothrombin G20210A mutation only in OC users.

Effects of Hereditary and Acquired Risk Factors of Venous Thrombosis on a Thrombin Generation-Based APC Resistance Test

2002 ◽  
Vol 88 (07) ◽  
pp. 5-11 ◽  
Author(s):  
Joyce Curvers ◽  
M. Christella Thomassen ◽  
Janet Rimmer ◽  
Karly Hamulyak ◽  
Jan van der Meer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Thrombin Generation ◽  
Contraceptive Use ◽  
Hormone Replacement ◽  
Protein S ◽  
Resistance Test ◽  
Prothrombin G20210a ◽  
Apc Resistance

SummarySeveral hereditary and acquired risk factors for venous thromboembolism (VTE) are associated with impaired down-regulation of thrombin formation via the protein C pathway. To identify individuals at risk, functional tests are needed that estimate the risk to develop venous thrombosis.We determined the effects of hereditary and acquired risk factors of venous thrombosis on an APC resistance test that quantifies the influence of APC on the time integral of thrombin formation (the endogenous thrombin potential, ETP) initiated in plasma via the extrinsic coagulation pathway. APC sensitivity ratios (APCsr) were determined in plasma from carriers of factor VLeiden (n = 56) or prothrombin G20210A (n = 18), of individuals deficient in antithrombin (n = 9), protein C (n = 7) or protein S (n = 14) and of women exposed to acquired risk factors such as hormone replacement therapy (n = 49), oral contraceptive use (n = 126) or pregnancy (n = 35). We also analysed combinations of risk factors (n = 60).The thrombin generation-based APC resistance test was sensitive for the factor VLeiden and prothrombin G20210A mutation, to protein S deficiency, hormone replacement therapy, oral contraceptive use and pregnancy. The assay was not influenced by antithrombin-or protein C deficiency. The presence of more than one risk factor of venous thrombosis resulted in more pronounced APC resistance. The APCsr of individuals with a single or combined risk factors of VTE correlated well with reported risk increases.The thrombin generation-based APC resistance test identifies individuals at risk for venous thrombosis due to acquired risk factors and/or hereditary thrombophilic disorders that affect the protein C pathway.

Thrombophilia Testing Practices: The Mayo Clinic Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Caleb J Scheckel ◽  
Rajiv K. Pruthi ◽  
Ariela L. Marshall ◽  
Aneel A. Ashrani ◽  
Dong Chen ◽  
...  
Keyword(s):  
Mayo Clinic ◽  
Protein C ◽  
Factor V Leiden ◽  
Choosing Wisely ◽  
Prothrombin G20210a ◽  
Reference Laboratory ◽  
Factor V ◽  
Clinic Staff ◽  
G20210a Mutation ◽  
Thrombophilia Testing

Introduction: The 2013 ASH Choosing Wisely campaign recommends against thrombophilia testing in patients with major transient risk factors for venous thromboembolism (VTE). Our Special Coagulation Laboratory (SCL) offers an algorithmic approach to thrombophilia testing which includes assays for lupus anticoagulant, dysfibrinogenemia, anticoagulant proteins (protein C, protein S, antithrombin), activated protein C resistance with reflex to factor v Leiden (if indicated), and prothrombin G20210A mutation. Samples are received through Mayo Clinic Laboratories (MCL), national and international reference laboratory (often with limited or no clinical information) and from internal Mayo Clinic practice. We hypothesized that thrombophilia testing would decline in cases where it was recommended against following the publication of testing guidelines. Methods: We audited the external thrombophilia testing samples between2013-2019 and internal samples between 2014-2019 (periods during which they were available). For the internal samples, complete test volumes were only available 2014-2019. Because external clients may either adopt internal testing or contract with a different reference laboratory, many clients may not have been retained over the entire observed period. To better understand the ordering practices of consistent clients, external clients which did not have thrombophilia testing sent to MCL each year of the observed period were excluded. We separated internal ordering practices by hematology and oncology or thrombophilia clinic staff and trainees contrasted with those of other specialties. Results: MCL received 18,529 external thrombophilia testing samples from 322 external healthcare systems during the observed period. From 37 clients, 5,878 (38.2%) samples met inclusion criteria. Annual volume of samples ranged from 890 in 2013 to 861 in 2019 (861-1046). Special coagulation lab processed 11,639 internal thrombophilia tests during the observed periods. There was a consistent small annual increase in testing with 1,398 performed in 2014 and 2,430 in 2019. Of 11651 tests ordered, only 18.6% (2167) were ordered by people most likely to be familiar with ASH choosing wisely campaign. Annual thrombophilia testing ordered by hematology and oncology or thrombophilia clinic staff increased from 307 in 2014 to 387 in 2019 (307-432). However, the ordering practices of these providers as a proportion of overall practices declined from 22.0% (307/1398) in 2014 to 15.9 % (387/2430) in 2019. Table Discussion: Our preliminary data showed no significant trend in thrombophilia ordering practices among included external clients since publication of the ASH Choosing Wisely guidelines on thrombophilia testing. Internally we found a consistent small rise in numbers of thrombophilia tests ordered since 2014 but this may reflect changes in patient volume. We observed that the majority of internal thrombophilia testing was ordered by non-hematology/oncology or thrombophilia providers who are perhaps less likely to be familiar with ASH Choosing Wisely guidelines. The proportion of testing ordered by hematology & oncology or thrombophilia providers declined during the observed period. Our findings are limited by lacking information on the indication and appropriateness for testing as well as possibility of change in patient population. However the overall trend in test volumes and specialty of ordering providers deserves attention and highlight the value in educating other medical societies on ASH Choosing Wisely recommendations for thrombophilia testing. Future work will focus on appropriateness for thrombophilia testing including the indication and time (remote from anticoagulation and acute thrombotic episode), location of testing (inpatient vs. outpatient), as well as investigating if testing has changed patient management, which may help in creating new Choosing Wisely recommendations for thrombophilia testing. Figure 1. Disclosures Pruthi: HEMA Biologics: Honoraria; Bayer Healthcare: Honoraria; Merck: Honoraria; Instrumentation Laboratory: Honoraria; Genentech Inc.: Honoraria; CSL Behring: Honoraria.

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