Heritable and Acquired Thrombophilias in Clinical Practice

2019 ◽  
Author(s):  
Hanny Al-Samkari ◽  
Nathan T. Connell

Thrombosis is common in clinical practice. Venous thromboembolism in particular raises questions of a possible underlying hereditary or acquired thrombophilic state. Despite considerable data describing the impact of various thrombophilic states on risks of initial and recurrent thromboembolic events, thrombophilia testing is not standardized. An understanding of the utility and pitfalls of clinical thrombophilia testing is necessary to employ this testing properly. When utilized appropriately, thrombophilia testing can be vital in informing an individual patient’s thrombosis risk and pursuing optimal anticoagulant management. Hereditary thrombophilia testing involves investigation for factor V Leiden, the prothrombin G202010A gene mutation, and deficiencies of the natural anticoagulants protein C, protein S, and antithrombin. Assessment for acquired thrombophilias is perhaps even more important, recognizing the possibility for myeloproliferative neoplasms, antiphospholipid antibody syndrome, occult malignancy and other important acquired thrombotic predispositions. Timing of thrombophilia testing in relation to anticoagulation, acute thrombosis, and use of hormonal agents or pregnancy is critical to ensure accurate diagnosis. This review describes each of the most important hereditary and acquired thrombophilias, explains their relationship to venous and arterial thrombosis, delineates evidence-based indications for thrombophilia testing, identifies potential testing pitfalls, and synthesizes the key points in outlining algorithms for thrombophilia testing in clinical practice. This review contains 4 figures, 4 tables, and 48 references. Key words: thrombophilia, venous thromboembolism, pulmonary embolus, deep vein thrombosis, factor V Leiden, prothrombin gene mutation, protein C deficiency, protein S deficiency, antiphospholipid antibody syndrome, hypercoagulability of malignancy

2019 ◽  
Author(s):  
Hanny Al-Samkari ◽  
Nathan T. Connell

Thrombosis is common in clinical practice. Venous thromboembolism in particular raises questions of a possible underlying hereditary or acquired thrombophilic state. Despite considerable data describing the impact of various thrombophilic states on risks of initial and recurrent thromboembolic events, thrombophilia testing is not standardized. An understanding of the utility and pitfalls of clinical thrombophilia testing is necessary to employ this testing properly. When utilized appropriately, thrombophilia testing can be vital in informing an individual patient’s thrombosis risk and pursuing optimal anticoagulant management. Hereditary thrombophilia testing involves investigation for factor V Leiden, the prothrombin G202010A gene mutation, and deficiencies of the natural anticoagulants protein C, protein S, and antithrombin. Assessment for acquired thrombophilias is perhaps even more important, recognizing the possibility for myeloproliferative neoplasms, antiphospholipid antibody syndrome, occult malignancy and other important acquired thrombotic predispositions. Timing of thrombophilia testing in relation to anticoagulation, acute thrombosis, and use of hormonal agents or pregnancy is critical to ensure accurate diagnosis. This review describes each of the most important hereditary and acquired thrombophilias, explains their relationship to venous and arterial thrombosis, delineates evidence-based indications for thrombophilia testing, identifies potential testing pitfalls, and synthesizes the key points in outlining algorithms for thrombophilia testing in clinical practice. This review contains 4 figures, 4 tables, and 48 references. Key words: thrombophilia, venous thromboembolism, pulmonary embolus, deep vein thrombosis, factor V Leiden, prothrombin gene mutation, protein C deficiency, protein S deficiency, antiphospholipid antibody syndrome, hypercoagulability of malignancy


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4720-4720
Author(s):  
Vivek Rashmikant Mehta ◽  
Uzma Khan ◽  
Aparna Basu ◽  
Asif Jan ◽  
Bolanie Gbadamosi ◽  
...  

Abstract Background Any inherited or acquired condition that increases the risk of developing deep venous thrombosis or pulmonary embolism is considered a thrombophilic disorder. Some examples of inherited causes of thromboembolic disorders are Factor V Leiden mutation (FVL), Prothrombin gene mutation, Protein C deficiency (low or dysfunctional), Protein S deficiency (low or dysfunctional), Anti-thrombin (AT) deficiency (low or dysfunctional). Use of these studies in clinical practice has been questioned. We attempted to identify if there are populations of patients that undergo more inpatient screening for inherited causes of venous thromboembolism (VTE). Methods Retrospective chart review of patients admitted with PE or DVT in a community teaching hospital between May 2012 and December 2014. Only patients who had DVT confirmed with ultrasound or PE confirmed with CT angiogram or had high probability of PE on V/Q scan were included in the study. Individual charts were reviewed to see if thrombophilia workup was ordered. Results A total of 704 patients with acute venous thromboembolism were identified who met our inclusion criteria for the study. Of this 111 patients (15.76%) had one or more thrombophilia screening studies ordered. Risk factors related to venous thromboembolism were evaluated for all of the 704 patients. In our patient population, patients who were smokers (31% vs 20%), had history of sleep apnea (9% vs 3%), a past medical history (PMH) of VTE (37% vs 25%) or who had a family history (FH) of VTE (11% vs 4%) were more likely to have a thrombophilia workup ordered. Table 2 shows the frequency of individual thrombophilia studies ordered among the 111 patients who had testing performed and table 3 shows distribution of positive results. Table. Test Result Abnormal Test Results ANA 1 Decreased AT III 10 Decreased Protein C 10 Decreased Protein S 7 Increased Homocysteine 6 Factor V Leiden 4 PT Gene Mutation 1 APLA 1 Conclusion The largest numbers of positive test results were noted for Protein C, Protein S and Antithrombin III and these are known to be affected by acute thrombosis and therefore could be false positives. Our study shows that those patients with PMH or FH of VTE were more likely to have thrombophilia studies. There is no consensus opinion as to whether to perform thrombophilia screenings in acute care settings. Given this and the fact that personal or family history of VTE do not usually modify future treatment decisions and that there may be significant number of false positives we do not recommend routine screening in these patient populations. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.


2003 ◽  
Vol 90 (07) ◽  
pp. 17-26 ◽  
Author(s):  
Nicole Langlois ◽  
Philip Wells

SummaryClinical equipoise exists regarding whether relatives of individuals with venous thromboembolism (VTE) and thrombophilia should be screened for thrombophilia. There have been no systematic attempts to summarize studies that have assessed the incidence of VTE in relatives. The purpose of this review was to systematically identify and review observational studies with thrombophilic relatives and to summarize their findings with respect to their risk of VTE.We conducted a systematic literature review and included nine observational studies meeting a priori inclusion criteria. Potentially eligible studies evaluated VTE incidence in relatives of index patients (probands) with symptomatic thrombophilia. In the four prospective studies, the incidence of VTE for asymptomatic family members with factor V Leiden ranged from 0.58-0.67% per year, 1.0-2.5% for protein C deficiency, 0.7-2.2% for protein S deficiency, and 4% for antithrombin deficiency. About half of all VTEs occurred during well-known risk periods but incidence rates were decreased by use of prophylaxis. No deaths from pulmonary embolism or fatal hemorrhages from anticoagulants were reported. The incidence of VTE was generally lower in the retrospective studies. The pooled relative risk from four retrospective studies for factor V Leiden carriers was 3.69 (CI 2.27, 6.00) and from two studies the pooled relative risk for deficiencies of protein C, protein S, and antithrombin was 10.58 (CI 5.38, 20.81).In conclusion, the risk of VTE events in asymptomatic relatives is low, but this may be an underestimate. Anticoagulant prophylaxis during risk periods appears to be of benefit but further research in this area is required.


1997 ◽  
Vol 78 (06) ◽  
pp. 1426-1429 ◽  
Author(s):  
M Makris ◽  
F E Preston ◽  
N J Beauchamp ◽  
P C Cooper ◽  
M E Daly ◽  
...  

SummaryThe presence of the 20210A allele of the prothrombin (PT) gene has recently been shown to be a risk factor for venous thromboembolism. This is probably mediated through increased plasma prothrombin levels. The aim of this study was to compare the prevalence of the prothrombin 20210A allele in control subjects and in subjects with recognised thrombophilia and to establish whether the additional inheritance of the PT 20210A allele is associated with an increased risk of venous thromboembolism. 101 subjects with a history of venous thromboembolism and diagnosed as having either factor V Leiden (R506Q) or heritable deficiencies of protein C, protein S or antithrombin were studied. The prevalence of the PT 20210A allele in this group was compared with the results obtained for 150 control subjects. In addition, the relationships were examined between genetic status and the number of documented thromboembolic episodes, and between plasma prothrombin levels and possession of the PT 20210A allele. 8 (7.9%) of the 101 patients were also heterozygous for the PT 20210A allele. This compares with 0.7% in the control subjects (p = 0.005). After exclusion of patients on warfarin, the mean plasma prothrombin of 113 subjects without 20210A was 1.09 U/ml, as compared with 1.32 U/ml in 8 with the allele (p = 0.0002). Among the 101 patients with either factor V Leiden, protein S deficiency, protein C deficiency or antithrombin deficiency, the age adjusted mean (SD) number of venous thromboembolic episodes at diagnosis was 3.7 (1.5) in those with the PT 20210A allele, as compared with 1.9 (1.1) in those without (p = 0.0001). We have demonstrated that the prevalence of the PT 20210A allele is significantly greater in subjects with venous thrombosis and characterised heritable thrombophilia than in normal control subjects and that the additional inheritance of PT 20210A is associated with an increased risk of venous thromboembolism. We have also confirmed that plasma prothrombin levels are significantly greater in subjects possessing the PT 20210A compared with those who do not.


Author(s):  
Emmanuel J. Favaloro ◽  
Soma Mohammed ◽  
Ronny Vong ◽  
Kent Chapman ◽  
Priscilla Swanepoel ◽  
...  

Abstract Objectives Thrombophilia testing is commonly performed within hemostasis laboratories, and the ACL TOP 50 family of instruments represent a new ‘single platform’ of hemostasis instrumentation. The study objective was to evaluate these instruments and manufacturer reagents for utility of congenital thrombophilia assays. Methods Comparative evaluations of various congenital thrombophilia assays (protein C [PC], protein S [PS], antithrombin [AT], activated protein C resistance [APCR]) using newly installed ACL TOPs 550 and 750 as well as comparative assessments with existing, predominantly STAGO, instrumentation and reagents. Verification of manufacturer assay normal reference ranges (NRRs). Results HemosIL PC and free PS assays showed good comparability with existing Stago methods (R>0.9) and could be considered as verified as fit for purpose. HemosIL AT showed high relative bias with samples from patients on direct anti-Xa agents, compromising utility. Manufacturer NRRs for PC, PS and AT were verified with minor variance. Given the interference with direct anti-Xa agents, an alternate assay (Hyphen) was evaluated for AT, and the NRR also verified. The HemosIL Factor V Leiden (APC Resistance V) evidenced relatively poor performance compared to existing assays, and could not be adopted for use in our network. Conclusions This evaluation of HemosIL reagents on ACL TOP 50 Family instruments identified overall acceptable performance of only two (PC, free PS) of four thrombophilia assays, requiring use of third-party reagents on ACL instruments for the other two assays (AT, APCR).


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2318-2318
Author(s):  
Junghyun Park ◽  
Marc Rodger

Introduction Thrombophilia testing in unprovoked venous thromboembolism patients (VTE) is controversial. Common thrombophilias such as Factor V Leiden or prothrombin gene variant appear to not importantly increase the risk of VTE recurrence, and thus are not considered in anticoagulation management decisions. However, patients with potent thrombophilias such as antiphospholipid antibodies (APLA), antithrombin deficiency, protein C and S deficiency, and homozygous genetic thrombophilias or combined defects are at higher risk of recurrence and it is recommended that they receive long-term anticoagulation. If the proportion of patients with "potent" thrombophilia is high then thrombophilia testing should be conducted. We sought to determine the proportion of unprovoked VTE patients with "potent" thrombophilia. Methods All patients with managed in our oral anticoagulation management system in the period from 1998 to 2015 were potentially eligible for the study. Inclusion criteria were: 1) symptomatic, objectively confirmed VTE unprovoked proximal deep vein thrombosis or pulmonary embolism. Exclusion criteria were: 1) cancer or myeloproliferative disease at the time of VTE diagnosis; 2) no cast, surgery, trauma or immobilization (>3 days in bed 90% of waking hours) in the 90 days prior to diagnosis. We selected unprovoked VTE patients diagnosed between 2002 and 2010, as thrombophilia testing was relatively universal and available in our electronic system in that time frame (N=1344). We then selected a convenience sample of N=1165. The primary outcome measure was the proportion of patients with "potent" thrombophilia (potent= homozygous Factor V Leiden, homozygous Prothrombin gene variant, APLA, protein C, protein S or anti-thrombin deficiency or combined deficiencies). Results In 1165 patients with unprovoked VTE, complete screening was done in 470 patients (40.34%) and 976 (83.78%) had at least one thrombophilia test. Complete thrombophilia testing was defined as a screen including testing for factor V Leiden, prothrombin gene defect, APLA, anti-thrombin deficiency, protein C, and protein S. Potent thrombophilias were demonstrated in 103/1165 patients (8.84%; 95% CI, 7.34 to 10.61) (Table 2) in the total study population, and 103/976 (10.55%; 95% CI, 9.62-14.47) in patients with at least one thrombophilia test. Conclusion The proportion of unprovoked VTE patients with "potent" thrombophilia is high. Given a high proportion of "potent' thrombophilia patients who likely benefit from indefinite anticoagulation, complete thrombophilia testing appears warranted in patients with unprovoked VTE in whom anticoagulants maybe discontinued. Thrombophilia testing is warranted for a selected group of patients to detect high-risk thrombophilias that could impact anticoagulation management. Table 1. Thrombophilia screening Complete screening 470 (40.3%) No screening 189 (16.2%) At least one thrombophilia test 976 (83.8%) Table 2. Thrombophilia All patients (n=1165) Tested for individual thrombophilia % 95% CI % 95% CI FVL Heterozygous 162/1165 (13.9%) 12.0-16.0% 162/883 (18.4%) 15.9-21.0% FVL Homozygous 4/1165 (0.3%) 0.1-0.9% 4/883 (0.5%) 0.2-1.2% Prothrombin Heterozygous 63/1165 (5.4%) 4.3-6.9% 63/831 (7.6%) 6.0-9.6% Prothrombin Homozygous 1/1165 (0.0%) 0.0-0.5% 1/831 (0.1%) 0.0-0.7% Antithrombin deficiency 10/1165 (0.9%) 0.5-1.6% 10/815 (1.2%) 0.7-2.2% Protein C deficiency 18/1165 (1.6%) 1.0-2.4% 18/639 (2.8%) 1.8-4.4% Protein S deficiency 13/1165 (1.1%) 0.7-1.9% 13/635 (2.1%) 1.2-3.5% Lupus anticoagulant 24/1165 (2.1%) 1.4-3.1% 24/849 (2.8%) 1.9-4.2% Anticardiolipin IgM 16/1165 (1.4%) 0.9-2.2% 16/886 (1.8%) 1.1-2.9% Anticardiolipin IgG 20/1165 (1.7%) 1.1-2.6% 20/885 (2.2%) 1.5-3.5% β-2 microglobulin IgM 10/1165 (0.9%) 0.5-1.6% 10/333 (3.0%) 1.6-5.4% β-2 microglobulin IgG 8/1165 (0.7%) 0.4-1.4% 8/333 (2.4%) 1.2-4.7% Homocysteine 50/1165 (5.7%) 4.3-7.4% 50/668 (7.5%) 5.7-9.7% Factor VIII elevated 11/1165 (0.9%) 0.5-1.7% 11/646 (1.7%) 1.0-3.0% At least one or more of the above 331/1165 (28.4%) 25.9-31.1% 331/976 (33.9%) 31.0-36.9% Potent thrombophilia 103/1165 (8.8%) 7.34-10.6% 103/976 (10.6%) 9.6-14.5% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2330-2330 ◽  
Author(s):  
Eric Mou ◽  
Henry Kwang ◽  
Jason Hom ◽  
Lisa Shieh ◽  
Neera Ahuja ◽  
...  

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.


2005 ◽  
Vol 93 (02) ◽  
pp. 306-310 ◽  
Author(s):  
Andrea Gerhardt ◽  
Cornelis Kluft ◽  
Rüdiger Scharf ◽  
Rainer Zotz

SummaryWomen who are using oral contraceptives can acquire APC resistance, measured by the effect of APC on the endogenous thrombin potential (ETP). The objective of our study was to examine whether persistentAPC resistance determined with an ETP-based normalized APC sensitivity ratio (nAPCsr) is a risk marker for venous thromboembolism in women with pregnancy-associated thromboembolism. We determined the activities of antithrombin, protein C, protein S, and performed a genetic analysis of factor V Leiden G1691A, prothrombin mutation G20210A, and methylenetetrahydrofolate reductase mutation (MTHFR C677T) in 65 women with venous thromboembolism during pregnancy or the puerperium and in 114 normal women. A significantly (p<0.05) higher nAPCsr was present in normal women using hormones, in younger women (≤ 45 yrs), and in women with carrier status of factorV Leiden. In normal women without factor V Leiden a significant (p< 0.05) negative correlation of nAPCsr with age (r= –0.39),antithrombin activity (r= –0.38),protein S activity (r= –0,26),and a significant positive correlation with hormone intake (r= 0.36) was present. nAPCsr is influenced by several coagulation parameters, which are modified by the use of oral contraceptives. Consequently, a multivariate analysis of our data did not show a significant association of nAPCsr to venous thromboembolism, neither as a continuous variable (odds ratio 0.8, 95% CI 0.6–1.1, p=0.10) nor using a cutoff value (nAPCsr cut-off 3.1: odds ratio 1.2, 95% CI 0.3–5.3, p=0.77). Our study demonstrates that nAPCsr is not a risk marker for pregnancy-associated venous thromboembolism.


2020 ◽  
Vol 46 (08) ◽  
pp. 872-886
Author(s):  
Jonathan Douxfils ◽  
Laure Morimont ◽  
Céline Bouvy

AbstractCombined oral contraceptives (COCs) induce several changes in the levels of coagulation factors. The levels of procoagulant factors are often increased, while levels of anticoagulant factors are decreased. Fibrinolysis is also affected, even if the effect seems to be more counterbalanced by opposite regulation of profibrinolytic and antifibrinolytic factors. These effects on hemostasis are more pronounced with third- or fourth-generation COC compared with second-generation COC. Venous thromboembolism (VTE) risk increases when multiple risk factors, including genetic and environmental, are present simultaneously. COC use causes changes in coagulation that modify the prothrombotic state induced by preexisting hemostatic alterations in a supra-additive manner. Therefore, testing appears to be of importance not only before implementing COC but also to monitor any potential thrombogenicity induced by COC therapy. Inherited genetic factors, such as factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C or protein S deficiencies, non-O blood group, as well as CYP2C9*2 and the rs4379368 mutations, have all been identified as genetic predictive risk factors of VTE in women. Nevertheless, the screening of these genetic biomarkers is not capable of assessing the phenotypic expression of the risk. This review will focus on the different options for screening the thrombogenic status in this population. Specific attention will be given to the endogenous thrombin potential-based activated protein C resistance, a test aiming at assessing the thrombogenicity induced by hormonal therapies and inherited or acquired thrombophilia.


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