Venous Thromboembolism in Heterozygotes for Factor V Leiden—The Second-Hit Hypothesis: A Report of Two Patients and a Review of the English-Language Literature

1997 ◽  
Vol 3 (3) ◽  
pp. 210-212 ◽  
Author(s):  
Ho David Pak ◽  
Augustine L. Perrotta

Resistance to activated protein C (factor V Leiden, FV-R506Q) is the most prevalent inherited hypercoagulable state with a frequency of 4.5% in the American population, but 70% of heterozygotes do not experience venous thromboembolic disease. Heterozygosity for FV-R506Q will coexist in patients with deficiencies of protein S (26.1 %), protein C (14.9%), antithrombin III (15.1%), homocystinuria/ hyperhomocysteinemia (29.6%), pregnancy or postpartum (27.9%), oral contraceptives (27.5%), trauma and surgery (18.6%), and lupus anticoagulant and/or antiphospholipid antibodies (40%). The second-hit hypothesis proposes that heterozygotes for factor V Leiden mutation who do experience venous thrombosis will have a second hypercoagulable state either hereditary or acquired. Key Words: Thromboembolism—Factor V Leiden—Heterozygotes.

2002 ◽  
Vol 8 (4) ◽  
pp. 319-324 ◽  
Author(s):  
Lothar Heilmann ◽  
Georg-Friedrich v. Tempelhoff ◽  
Kuhnhart Pollow

Preeclampsia/HELLP syndrome has been associated with a high incidence of defects in the protein C pathway and increased anticardiolipin-antibodies/lupus anticoagulants. It is also apparent that thrombophilia is responsible for other pregnancy complications, such as recurrent spontaneous abortion, fetal growth restriction, intrauterine fetal death, and abruptio placentae. ProC® Global is a new global clotting assay designed to evaluate the abnormalities in the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac®, to prolong an activated partial thromboplastin time. A total of 61 patients with a history of severe preeclampsia or HELLP syndrome and 61 normal pregnant women (controls) were evaluated, 15 of whom had factor V Leiden mutation, 12 had protein C/S deficiency, 30 had a repeated lupus anticoagulants, and 27 increased anticardiolipin antibodies (ACA). All carriers of factor V Leiden mutation (N= 15) as well as all the patients with low activated protein C (APC) resistance ratio (N= 15) had a ProC® Global normalized ratio (NR) less than 0.80 (sensitivity 100%). Twenty-four patients positive for the lupus anticoagulants (LA) and 19 patients positive for ACA (> 5.0 IgG U/mL) had a ProC® Global NR less than 0.8, while six and eight, respectively, had a ProC® Global NR greater than 0.8 (sensitivity, 70%-80%). The detection of a reduced protein C/protein S activity (<70%) was low (sensitivity, 33%-44%). In 25 cases with pathologic ProC® Global results, a thrombophilic defect (protein S/LA/ACA without APC resistance) was diagnosed in 18 women; but in 7 cases, no known thrombophilic defect was present. ProC® Global is a new screening test to identify patients with defects of the protein C system and an activated clotting system in preeclampsia but cannot correctly cover each thrombophilic component.


2002 ◽  
Vol 88 (11) ◽  
pp. 716-722 ◽  
Author(s):  
Hirohiko Kuratsune ◽  
Etsuji Suehisa ◽  
Tomio Kawasaki ◽  
Takashi Machii ◽  
Teruo Kitani ◽  
...  

SummaryAnti-phospholipid (aPL) antibodies (Abs) are well known to be associated with thromboembolic events in patients with systemic lupus erythematosus (SLE). However, the clinical relevance of aPL Abs in patients without SLE (non-SLE) who have venous thromboembolism remains unclear. We evaluated 143 non-SLE patients with a first episode of clinically suspected deep vein thrombosis (DVT) by using objective tests for diagnosing DVT and laboratory tests including the activated protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs. The prevalence of acquired APC-R, in which case there was no factor V Leiden mutation, was significantly higher in patients with DVT (15/58 cases, 25.9%, p <0.0001) than in those without DVT (3/80 cases, 3.7%), and confirmed that acquired APC-R was a strong risk factor for DVT (odds ratio [OR], 8.95; 95% confidence intervals [CI], 2.45-32.7; p <0.001). Multivariate logistic analysis revealed that the presence of LA, aCL, anti- β2-glycoprotein I, anti-prothrombin and anti-protein C Abs was not reliable as a risk factor for DVT in non-SLE patients, and that the presence of anti-protein S Abs was the most significant risk factor for DVT (OR, 5.88; 95% CI, 1.96-17.7; p <0.002). Furthermore, the presence of anti-protein S Abs was strongly associated with acquired APC-R (OR, 57.8; 95% CI, 8.53-391; p <0.0001). These results suggest that acquired APC-R may reflect functional interference by anti-protein S Abs of the protein C pathway, which action may represent an important mechanism for the development DVT in non-SLE patients.


2002 ◽  
Vol 126 (5) ◽  
pp. 577-582 ◽  
Author(s):  
Elizabeth M. Van Cott ◽  
Britt L. Soderberg ◽  
Michael Laposata

Abstract Objectives.—To present the current understanding of factor V Leiden and activated protein C resistance, and to propose a laboratory testing algorithm. Data Sources.—Publications on MEDLINE with the terms factor V Leiden or activated protein C resistance through mid 2001, as well as publications in the authors' files, were screened for inclusion in this report. Study Selection.—Original studies that report a novel finding on testing or clinical features of activated protein C resistance or factor V Leiden are included. Data Extraction.—The novel or key findings from the selected studies are analyzed. Data Synthesis.—Protein C and protein S are the integral components of an anticoagulation pathway that limits fibrinogen conversion to fibrin through the degradation of factors Va and VIIIa. When factor Va is resistant to degradation by activated protein C, this anticoagulation pathway does not operate properly, and patients have an increased risk for thrombosis. This report describes the protein C/protein S pathway, the significance of activated protein C resistance and the factor V Leiden mutation, and the clinical testing used to detect activated protein C resistance and the factor V Leiden mutation. A proposed laboratory testing algorithm is also provided. Conclusions.—Factor V Leiden is a risk factor for venous thrombosis and it is particularly common in white populations. A laboratory testing algorithm is proposed.


2001 ◽  
Vol 7 (4) ◽  
pp. 259-268 ◽  
Author(s):  
Yale S. Arkel ◽  
De-Hui W. Ku

The association of thrombophilia with pregnancy complications has received increasing attention. It is now apparent that thrombophilia is respernsihle for a large number of the serious complications of pregnancy such as venous thrombosis, pulmonary embolism, fetal loss, pregnancy loss, intrauterine fetal demise, and preeclampsia. The inherited thrombophilia abnormalities, factor V Leiden mutation, prothrombin gene mutation 20210A, and antithrombin III, protein C, and protein S deficiency, and the acquired disorders, the anticardiolipin syndrome and lupus inhibitor, are responsible for a large share of the incidences of premature termination of pregnancy and many of the above complications. The normal physiology of pregnancy may be prothrombotic, with evidence for increased markers of activated coagulation and coagulation factors. There is a decrease in protein S and resistance to activated protein C occurs in a significant number of pregnancies in the absence of the factor V Leiden mutation. In the following article, we review some of the major studies that have correlated the thrombophilia and other acquired disorders that adversely impact pregnancies.


1998 ◽  
Vol 80 (08) ◽  
pp. 344-345 ◽  
Author(s):  
Pasra Arnutti ◽  
Motofumi Hiyoshi ◽  
Wichai Prayoonwiwat ◽  
Oytip Nathalang ◽  
Chamaiporn Suwanasophon ◽  
...  

1996 ◽  
Vol 75 (03) ◽  
pp. 422-426 ◽  
Author(s):  
Paolo Simioni ◽  
Alberta Scudeller ◽  
Paolo Radossi ◽  
Sabrina Gavasso ◽  
Bruno Girolami ◽  
...  

SummaryTwo unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F. V defect and F. V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F. V Leiden mutation, the measurement of the responsiveness of patients plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so-called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F. V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F. V, instead of protecting from thrombotic risk due to heterozygous F. V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F. V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F. V Leiden mutation based on the APC-resi-stance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged.


1997 ◽  
Vol 77 (06) ◽  
pp. 1154-1155 ◽  
Author(s):  
Gary D Sinclair ◽  
Sandra Low ◽  
Man-Chiu Poon

SummaryWe describe a novel hemi-nested, allele specific whole blood PCR assay for detection of the factor V Leiden mutation associated with the plasma defect, activated protein C resistance. This assay utilizes 5 μl of whole blood without prior DNA extraction. The hemi-nested design, employing an outer primer pair in combination with nested, allele specific primers obviates the need for restriction enzyme digestion. PCR reactions are analysed directly on agarose or polyacrylamide minigels. The assay confirmed the genotypes of 50 individuals previously categorized by PCR and Mnll digestion, and has been subsequently utilized in the genotyping of 445 individuals referred for thrombosis studies.


Author(s):  
A.A. Abrishamizadeh

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.    


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