Interference of factor V Leiden on protein S activity: evaluation of a new prothrombin time-based assay

2007 ◽  
Vol 18 (6) ◽  
pp. 543-546 ◽  
Author(s):  
Armando Tripodi ◽  
Daniela Asti ◽  
Veena Chantarangkul ◽  
Eugenia Biguzzi ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Prothrombin Time ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Activity Evaluation ◽  
Protein S Activity

scholarly journals Apixaban Does Not Interfere With Protein S or Activated Protein C Resistance (Factor V Leiden) Testing Using aPTT-Based Methods

2020 ◽  
Vol 144 (11) ◽  
pp. 1401-1407 ◽  
Author(s):  
Elena Maryamchik ◽  
Elizabeth M. Van Cott
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Dna Testing ◽  
Activated Protein C Resistance ◽  
S Deficiency ◽  
Free Antigen ◽  
Protein S Activity

Context.— Apixaban causes a false increase in activated protein C resistance (APCR) ratios and possibly protein S activity. Objective.— To investigate whether this increase can mask a diagnosis of factor V Leiden (FVL) or protein S deficiency in an actual population of patients undergoing apixaban treatment and hypercoagulation testing. Design.— During a 4.5-year period involving 58 patients, we compared the following 4 groups: heterozygous for FVL (FVL-HET)/taking apixaban, wild-type/taking apixaban, heterozygous for FVL/no apixaban, and normal APCR/no apixaban. Patients taking apixaban were also tested for protein S functional activity and free antigen (n = 40). Results.— FVL-HET patients taking apixaban had lower APCR ratios than wild-type patients (P < .001). Activated protein C resistance in FVL-HET patients taking apixaban fell more than 3 SD below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite apixaban. In contrast to rivaroxaban, apixaban did not interfere with the assessment of protein S activity (mean activity 93.9 IU/dL, free antigen 93.1 IU/dL, P = .39). A total of 3 of 40 patients (8%) had low free protein S antigen (30, 55, and 57 IU/dL), with correspondingly similar activity results (27, 59, and 52 IU/dL, respectively). Apixaban did not cause a missed diagnosis of protein S deficiency. Conclusions.— Despite apixaban treatment, APCR testing can distinguish FVL-HET from healthy patients, rendering indiscriminate FVL DNA testing of all patients on apixaban unnecessary. Apixaban did not affect protein S activity.

scholarly journals Rivaroxaban Causes Missed Diagnosis of Protein S Deficiency but Not of Activated Protein C Resistance (Factor V Leiden)

2017 ◽  
Vol 142 (1) ◽  
pp. 70-74 ◽  
Author(s):  
Elena Maryamchik ◽  
Matthew W. Rosenbaum ◽  
Elizabeth M. Van Cott
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Protein S Deficiency ◽  
Activated Protein C Resistance ◽  
Functional Protein ◽  
S Deficiency ◽  
Protein S Activity

Context.— Rivaroxaban causes a false increase in activated protein C resistance (APCR) ratios and protein S activity. Objective.— To investigate whether this increase masks a diagnosis of factor V Leiden (FVL) or protein S deficiency in a “real-world” population of patients undergoing rivaroxaban treatment and hypercoagulation testing. Design.— During a 2.5-year period, we compared 4 groups of patients (n = 60): FVL heterozygous (FVL-HET)/taking rivaroxaban, wild-type/taking rivaroxaban, FVL-HET/no rivaroxaban, and normal APCR/no rivaroxaban. Patients taking rivaroxaban were tested for protein S functional activity and free antigen (n = 32). Results.— The FVL-HET patients taking rivaroxaban had lower APCR ratios than wild-type patients (P < .001). For FVL-HET patients taking rivaroxaban, mean APCR was 1.75 ± 0.12, versus 1.64 ± 0.3 in FVL-HET patients not taking rivaroxaban (P = .005). Activated protein C resistance in FVL-HET patients fell more than 3 SDs below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite rivaroxaban. In contrast, rivaroxaban falsely elevated functional protein S activity, regardless of the presence or absence of FVL (P < .001). A total of 4 of 32 patients (12.5%) had low free protein S antigen (range, 58%–67%), whereas their functional protein S activity appeared normal (range 75%–130%). Rivaroxaban would have caused a missed diagnosis of all cases of protein S deficiency during the study if testing relied on the protein S activity assay alone. Conclusions.— Despite rivaroxaban treatment, APCR testing can distinguish FVL-HET from normal patients, rendering indiscriminate FVL DNA testing of all patients on rivaroxaban unnecessary. Free protein S should be tested in patients taking rivaroxaban to exclude hereditary protein S deficiency.

Acquired coagulation disorders

2020 ◽  
pp. 5546-5562
Author(s):  
T.E. Warkentin
Keyword(s):  
Prothrombin Time ◽  
Protein C ◽  
Complete Blood Count ◽  
Degradation Products ◽  
Factor V Leiden ◽  
Protein S ◽  
Blood Film ◽  
Factor V ◽  
Antifibrinolytic Agents ◽  
Acquired Coagulation Disorders

Acquired disorders of coagulation may be the consequence of many underlying conditions, and although they may share abnormality of a coagulation test, for example, a prolonged prothrombin time, their clinical effects are diverse and often opposing. General clinical approach: diagnosis—most acquired disorders of coagulation can be identified by screening haemostasis tests, including (1) prothrombin time; (2) activated partial thromboplastin time; (3) thrombin clotting time; (4) fibrinogen degradation products, including (5) the cross-linked fibrin assay (D-dimer); and (6) complete blood count with examination of a blood film. Few bleeding disorders give normal results in all these tests, but disorders predisposed to thrombosis as a result of deficiency of natural anticoagulants (e.g. antithrombin, protein C, and protein S) or certain mutations (e.g. factor V Leiden) must be specifically sought. Treatment—patients with coagulopathies who are bleeding or who require surgery are usually treated with blood products such as platelets and frozen plasma. Other treatments used in particular circumstances include (1) vitamin K—required for the post-translational modification of factors II, VII, IX, and X as well as the anticoagulant factors, protein C, and protein S; (2) cryoprecipitate—used principally for the treatment of hypofibrinogenaemia; (3) concentrates of specific factors—used in isolated deficiencies (e.g. of factors VIII, IX, XI, VIIa, or fibrinogen); (4) antifibrinolytic agents (e.g. ε‎-aminocaproic acid and tranexamic acid); (5) desmopressin (1-deamino-8-d-arginine vasopressin)—increases factor VIII and von Willebrand factor.

Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

1995 ◽  
Vol 74 (05) ◽  
pp. 1255-1258 ◽  
Author(s):  
Arnaldo A Arbini ◽  
Pier Mannuccio Mannucci ◽  
Kenneth A Bauer
Keyword(s):  
Hemophilia A ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor V ◽  
Bleeding Diathesis ◽  
Mutation Site ◽  
Spontaneous Bleeding ◽  
Factor V Leiden Mutation

SummaryPatients with hemophilia A and B and factor levels less than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20–30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in amelio rating the hemorrhagic tendency in these so-called “mild severe” hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme Mnll. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.

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 Thrombophilia And Arterial Ischemic Stroke

2017 ◽  
pp. 45
Author(s):  
A.A. Abrishamizadeh
Keyword(s):  
Ischemic Stroke ◽  
Vitamin K ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Antithrombin Iii ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
C Protein

Ischemic stroke (IS) is a common cause of morbidity and mortality with significant socioeconomic impact especially when it affects young patients. Compared to the older adults, the incidence, risk factors, and etiology are distinctly different in younger IS. Hypercoagulable states are relatively more commonly detected in younger IS patients.Thrombophilic states are disorders of hemostatic mechanisms that result in a predisposition to thrombosis .Thrombophilia is an established cause of venous thrombosis. Therefore, it is tempting to assume that these disorders might have a similar relationship with arterial thrombosis. Despite this fact that 1-4 % of ischemic strokes are attributed to Thrombophillia, this   alone rarely causes arterial occlusions .Even in individuals with a positive thrombophilia screen and arterial thrombosis, the former might not be the primary etiological factor.Thrombophilic   disorders can be broadly divided into inherited or acquired conditions. Inherited thrombophilic states include deficiencies of natural anticoagulants such as protein C, protein S, and antithrombin III (AT III) deficiency, polymorphisms causing resistance to activated protein C(Factor V Leiden mutation), and disturbance in the clotting balance (prothrombin gene 20210G/A variant). Of all the inherited  thrombophilic disorders, Factor V Leiden mutation is perhaps the commonest cause. On the contrary, acquired thrombophilic disorders are more common and include conditions such as the antiphospholipid syndrome, associated with lupus anticoagulant and anticardiolipin antibodies.The more useful and practical approach of ordering various diagnostic tests for the uncommon thrombophilic states tests should be determined by a detailed clinical history, physical examination, imaging studies and evaluating whether an underlying hypercoagulable state appears more likely.The laboratory thrombophilia   screening should be comprehensive and avoid missing the coexisting defect and It is important that a diagnostic search protocol includes tests for both inherited and acquired thrombophilic disorders.Since the therapeutic approach (anticoagulation and thrombolytic therapy) determines the clinical outcomes, early diagnosis of the thrombophilic  disorders plays an important role. Furthermore, the timing of test performance of some of the  thrombophilic  defects (like protein C, protein S, antithrombin III and fibrinogen levels) is often critical since these proteins can behave as acute phase reactants and erroneously elevated levels of these factors may be observed in patients with acute thrombotic events. On the other hand, the plasma levels of vitamin K-dependent proteins (protein C, protein S and APC resistance) may not be reliable in patients taking vitamin K antagonists. Therefore, it is suggested that plasma-based assays for these disorders should be repeated3 to 6 months after the initial thrombotic episode to avoid false-positive results and avoid unnecessary prolonged   anticoagulation therapy. The assays for these disorders are recommended after discontinuation of oral anticoagulant treatment or heparin for at least 2 weeks.    

Fundamentals and Patient Evaluation

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
General Population ◽  
Venous Thrombosis ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Incidence Rates ◽  
Factor V ◽  
Inherited Thrombophilia ◽  
Occult Malignancy ◽  
History Of

Thrombophilia is the term used to describe a tendency toward developing thrombosis. This tendency may be inherited, involving polymorphism in gene coding for platelet or clotting factor proteins, or acquired due to alterations in the constituents of blood and/or blood vessels. An inherited thrombophilia is likely if there is a history of repeated episodes of thrombosis or a family history of thromboembolism. One should also consider an inherited thrombophilia when there are no obvious predisposing factors for thrombosis or when clots occur in a patient under the age of 45. Repeated episodes of thromboembolism occurring in patients over the age of 45 raise suspicion for an occult malignancy. A summary of inherited thrombophilias are summarized in Table 24.1. This list continues to grow, as new genetic polymorphisms and combined mutations are being detected. The prevalence of common thrombophilias is shown in Figure 24.1. Factor V Leiden (FVL) mutation and hyperhomocysteinemia are present in nearly 5% of the general population and are often found in patients with venous thrombosis, while deficiencies of antithrombin (AT), protein C, and protein S are relatively uncommon. Elevated levels of factor VIII (FVIII) are uncovered frequently in the general population and in patients with thrombosis. This is not surprising as FVIII is an acute-phase reactant that increases rapidly after surgery or trauma; however, prospective studies have shown that FVIII elevation in some patients cannot be attributed to a stress reaction and probably represents mutations in the genes regulating FVIII synthesis or release (Kyrle et al., 2000). The same may be true for factors IX and XI. The relative risks for thrombosis among patients with inherited thrombophilias have been determined. While AT mutations are the least common, they are associated with a substantial risk of venous thrombosis; similar risk is seen with protein C and S deficiency. In contrast, the lifetime risk of having a thromboembolic event in an individual heterozygous for FVL is comparatively low (Martinelli et al., 1998). Incidence rates markedly increase with age, and are highest among those with AT deficiency, followed by protein C and protein S, and least with FVL.

scholarly journals Different Risks of Thrombosis in Four Coagulation Defects Associated With Inherited Thrombophilia: A Study of 150 Families

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2353-2358 ◽  
Author(s):  
Ida Martinelli ◽  
Pier Mannuccio Mannucci ◽  
Valerio De Stefano ◽  
Emanuela Taioli ◽  
Valentina Rossi ◽  
...  
Keyword(s):  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Superficial Vein ◽  
Protein S Deficiency ◽  
Vein Thrombosis ◽  
S Deficiency ◽  
Superficial Vein Thrombosis ◽  
Coagulation Defects

AbstractDeficiency of the naturally occurring anticoagulant proteins, such as antithrombin, protein C and protein S, and activated protein C resistance due to the factor V Leiden gene mutation is associated with inherited thrombophilia. So far, no direct comparison of the thrombotic risk associated with these genetic defects is available. In this study, we wish to compare the lifetime probability of developing thrombosis, the type of thrombotic symptoms, and the role of circumstantial triggering factors in 723 first- and second-degree relatives of 150 index patients with different thrombophilic defects. We found higher risks for thrombosis for subjects with antithrombin (risk ratio 8.1, 95% confidence interval [CI], 3.4 to 19.6), protein C (7.3, 95% CI, 2.9 to 18.4) or protein S deficiency (8.5, 95% CI, 3.5 to 20.8), and factor V Leiden (2.2, 95% CI, 1.1 to 4.7) than for individuals with normal coagulation. The risk of thrombosis for subjects with factor V Leiden was lower than that for those with all three other coagulation defects (0.3, 95% CI, 0.1 to 1.6), even when arterial and superficial vein thromboses were excluded and the analysis was restricted to deep vein thrombosis (0.3, 95% CI, 0.2 to 0.5). No association between coagulation defects and arterial thrombosis was found. The most frequent venous thrombotic manifestation was deep vein thrombosis with or without pulmonary embolism (90% in antithrombin, 88% in protein C, 100% in protein S deficiency, and 57% in factor V Leiden), but a relatively mild manifestation such as superficial vein thrombosis was common in factor V Leiden (43%). There was a predisposing factor at the time of venous thromboembolism in approximately 50% of cases for each of the four defects. In conclusion, factor V Leiden is associated with a relatively small risk of thrombosis, lower than that for antithrombin, protein C, or protein S deficiency. In addition, individuals with factor V Leiden develop less severe thrombotic manifestations, such as superficial vein thrombosis.

Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review

2003 ◽  
Vol 90 (07) ◽  
pp. 17-26 ◽  
Author(s):  
Nicole Langlois ◽  
Philip Wells
Keyword(s):  
Venous Thromboembolism ◽  
Relative Risk ◽  
Observational Studies ◽  
Protein C ◽  
Retrospective Studies ◽  
Factor V Leiden ◽  
Protein S ◽  
Clinical Equipoise ◽  
Factor V ◽  
Protein C Deficiency

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.

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