Heritable Thrombophilia in Venous Thromboembolism in Northern Pakistan: A Cross-Sectional Study

Background. Venous thromboembolism (VTE) is referred to as formation of clots in a deep vein or lodging of thrombus towards the lungs which could be fatal yet preventable. The risk of developing VTE can be increased by various factors. Where there are innumerable acquired causes, the possibility of inherited thrombophilia cannot be ignored. In view of this, we have evaluated all patients with venous thromboembolism for inherited thrombophilia. Objective. To evaluate the frequencies of antithrombin (AT) deficiency, protein C and S deficiencies, Factor V Leiden, and prothrombin gene mutations in patients harboring venous thromboembolism. Materials and Methods. A study comprising of 880 patients who were presented with manifestations of venous thromboembolism was conducted from July 2016 to June 2017. A blood sample collected from patients was screened for thrombophilia defects encompassing AT, protein C and S deficiencies, Factor V Leiden, and prothrombin gene mutations. All acquired causes of thrombosis were excluded. Results. Of 880 patients who underwent screening for thrombophilia, 182 patients demonstrated VTE history. Their age ranged from 1 to 58 years. Males constituted a predominant group. About 45 (24.7%) patients had evidence of heritable thrombophilia. Of these, 20 (10.9%) had AT deficiency, 9 (4.9%) had Factor V Leiden mutation, 6 (3.2%) had protein C deficiency, whereas protein S deficiency and prothrombin gene mutation both were found in 5 (2.7%) patients. Conclusion. Our study illustrated the highest frequency of antithrombin deficiency among other investigated thrombophilia defects.

Download Full-text

Evaluation of Direct Oral Anticoagulants in the Treatment of Venous Thromboembolism for Inherited Thrombophilia Disorders

Blood ◽

10.1182/blood.v128.22.5007.5007 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5007-5007 ◽

Cited By ~ 3

Author(s):

Ali McBride ◽

Reem Diri ◽

Ravitharan Krishnadasan ◽

Pavani Chalasani ◽

Ivo Abraham ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Protein C ◽

Factor V Leiden ◽

Secondary Prophylaxis ◽

Factor V ◽

Inherited Thrombophilia ◽

Dvt Prophylaxis ◽

Prothrombin Gene ◽

Baseline Characteristics

Abstract Background Venous thromboembolism can be classified according to the presence of either environmental or genetic risk factors. Risk factors for thrombosis can include activated protein C resistance, and heritable including deficiencies of antithrombin, protein C or protein S. Factor V Leiden deficiency and prothrombin gene mutations are some of the more common thrombophilias, with a slight increased risk for venous thromboembolism (VTE). Current guidelines suggest the use of low-molecular weight heparins for secondary prophylaxis in patients with VTE. However, there is a lack of data on the use of Direct Oral Anticoagulant (DOACs) in patients with inherited thrombophilia. We evaluated our use of rivaroxaban in patients with thrombophilia disorders treated for secondary DVT prophylaxis. Method We performed a retrospective evaluation of patients in our institution with inherited thrombophilia with an active VTE diagnosis who received DOACs for secondary prophylaxis from November 2013 until April 2016. Data collected included patient demographics, inherited thrombophilia mutation, previous history of VTE, prior treatments, and efficacy and safety of anticoagulation with DOACs. Results We had 13 patients with inherited thrombophilia mutation and 4 patients diagnosed with concomitant cancer (non-Hodgkin lymphoma, melanoma, and 2 with breast cancer) (Table 1). Out of 13 patients 3 failed warfarin, and one failed fondaparinux prior to switching to a DOAC. Mutation with heterozygous Factor V Leiden deficiency was reported in 7 patients, while mutations with Protein C and/or S deficiency were found in 4 patients. One patient had both Factor V Leiden and Protein C deficiency mutations. The prothrombin gene mutation was identified in one patient. The median of length of therapy was 2 years with 8/13 still on rivaroxaban in April 2016. The shortest treatment duration was 41 days for a patient who failed rivaroxaban with a second clot and was switched to apixaban without subsequent treatment failure. Two patients experienced 4 non-major episodes of gastrointestinal bleeding, nose bleeding and dark stool. One patient developed rash with noted bruising during their rivaroxaban therapy. Conclusion: This is the first report on outcomes for secondary DVT prophylaxis with DOACs in patients with underlying thrombophilia mutations. Safety and efficacy of DOACs for secondary VTE prophylaxis yielded favorable results; however, future prospective studies in the setting of thrombophilia are warranted. Table 1 Summary of baseline characteristics and outcomes. Table 1. Summary of baseline characteristics and outcomes. Disclosures McBride: Sanofi: Research Funding.

Download Full-text

A Heparin Cofactor II Mutation (HCII Rimini) Combined with Factor V Leiden or Type I Protein C Deficiency in Two Unrelated Thrombophilic Subjects

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650612 ◽

1996 ◽

Vol 76 (04) ◽

pp. 505-509 ◽

Cited By ~ 11

Author(s):

F Bernardi ◽

C Legnani ◽

F Micheletti ◽

B Lunghi ◽

P Ferraresi ◽

...

Keyword(s):

Protein C ◽

Antithrombin Iii ◽

Factor V Leiden ◽

Type I ◽

Factor V ◽

Protein C Deficiency ◽

Heparin Cofactor Ii ◽

Factor V Leiden Mutation ◽

Heterozygous Condition ◽

Inherited Thrombophilia

Summary305 patients with juvenile thromboembolic episodes were screened for the presence of heparin cofactor II deficiency. The heterozygous deletion of two bases was found in the exon 5 of the heparin cofactor II gene in two unrelated patients, very likely due to a founder effect. This molecular lesion, causing a frameshift and elongated translation, affects the core of the molecule and should cause the complete unfolding of the protein, which is in accordance with the observed type I deficiency. The corresponding region of antithrombin III gene is affected by a cluster of frameshift mutations suggesting that heparin cofactor II and antithrombin III could share similar mutational patterns.The heparin cofactor II gene alteration was associated with, in one patient, the factor V Leiden mutation and, in the other, type I protein C deficiency. The tracing of the single defects in several family members indicated that the mutations became clinically manifest only when present in the doubly heterozygous condition. This study provides two examples, based on molecular findings, of the interplay of risk factors which is potentially useful to define a role for heparin cofactor II deficiency in inherited thrombophilia.

Download Full-text

In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband

Thrombosis and Haemostasis ◽

10.1160/th11-02-0080 ◽

2011 ◽

Vol 106 (10) ◽

pp. 646-654 ◽

Cited By ~ 23

Author(s):

Elena Rossi ◽

Angela Ciminello ◽

Tommaso Za ◽

Silvia Betti ◽

Giuseppe Leone ◽

...

Keyword(s):

Venous Thromboembolism ◽

Universal Screening ◽

Protein C ◽

Clinical Phenotype ◽

Hormonal Contraception ◽

Factor V Leiden ◽

Factor V ◽

Inherited Thrombophilia ◽

At Deficiency ◽

Increase In Risk

SummaryThe utility of laboratory investigation of relatives of individuals with inherited thrombophilia is uncertain. To assess the risk of venous thromboembolism (VTE) among the carriers, we investigated a family cohort of 1,720 relatives of probands with thrombophilia who were evaluated because of VTE (n=1,088), premature arterial thrombosis (n=113), obstetric complication (n=257), or universal screening before pregnancy or hormonal contraception or therapy (n=262); 968 relatives were carriers of thrombophilia. A first deep venous thrombosis (DVT) occurred in 44 carriers and 10 non-carriers during 37,688 and 29,548 observationyears from birth, respectively. The risk of DVT among the carriers compared with non-carriers was estimated as a hazard ratio (HR). If the proband had VTE and factor V Leiden (FVL) and/or prothrombin (PT)20210A, the HR for DVT was 2.77 (95%CI 1.21–4.82) in the carriers overall, and 5.54 (95%CI 3.20–187.00) in those homozygous or double heterozygous for FVL and PT20210A. If the proband had VTE and a deficiency of antithrombin (AT), protein C or S, the HR for DVT was 5.14 (95%CI 0.88–10.03) in the carriers overall, and 12.86 (95%CI 2.46–59.90) in those with AT deficiency. No increase in risk was found among the carriers who were relatives of the probands who were evaluated for reasons other than VTE. In conclusion, familial investigation for inherited thrombophilia seems justified for probands with previous VTE, but appears of doubtful utility for the relatives of probands without VTE. This should be taken with caution regarding families with deficiency of natural anticoagulants, given the low number of cases analysed.

Download Full-text

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

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613594 ◽

2003 ◽

Vol 90 (07) ◽

pp. 17-26 ◽

Cited By ~ 33

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.

Download Full-text

THROMBOPHILIC RISK FACTORS IN PATIENTS WITH CRANIAL AND SPINAL DURAL ARTERIOVENOUS FISTULAE

Neurosurgery ◽

10.1227/01.neu.0000325730.77263.7e ◽

2008 ◽

Vol 63 (4) ◽

pp. 693-699 ◽

Cited By ~ 18

Author(s):

Rüediger Gerlach ◽

Martina Boehm-Weigert ◽

Joachim Berkefeld ◽

Judith Duis ◽

Andreas Raabe ◽

...

Keyword(s):

Risk Factors ◽

Protein C ◽

Factor V Leiden ◽

Factor V ◽

Arteriovenous Fistulae ◽

Factor V Leiden Mutation ◽

Exact Test ◽

G20210a Mutation ◽

Cardiolipin Antibodies ◽

Prothrombin Gene

ABSTRACT OBJECTIVE Numerous studies have reported the technical aspects and results of surgical and/or endovascular treatment of cranial dural arteriovenous fistulae (cDAVF) and spinal dural arteriovenous fistulae (sDAVF). Only a few of them have addressed the question of thrombophilic conditions, which may be relevant as pathogenetic factors or can increase the risk for venous thromboembolic events. Therefore, the objective of this study is to compare thrombophilic risk factors in patients with cDAVF and sDAVF with no history of trauma. METHODS A total of 43 patients (25 with cDAVF and 18 with sDAVF) were included in this study. Blood samples were analyzed for G20210A mutation of the prothrombin gene and factor V Leiden mutation. In all patients, prothrombin time, international normalized ratio, fibrinogen, antithrombin, protein C and S activity, von Willebrand factor antigen, ristocetin cofactor activity, D-dimer, coagulation factor VIII activity, and tissue factor pathway inhibitor were determined. Screening was performed for the occurrence of lupus antiphospholipid and cardiolipin antibodies. RESULTS The prevalence of G20210A mutation of the prothrombin gene was significantly higher in patients with cDAVF (n = 6) compared with patients with sDAVF (n = 0; P < 0.05, Fisher's exact test). A factor V Leiden mutation was found in 3 patients with sDAVF and in 1 patient with cDAVF (P = 0.29, Fisher's exact test). No significant difference was found for other parameters, except for fibrinogen, but decreased protein C activity was more frequent in patients with cDAVF compared with patients with sDAVF (4 versus 1). Decreased protein S activity was encountered in 3 patients (2 with sDAVF and 1 with cDAVF). Cardiolipin antibodies were found in 2 patients with cDAVF but in none with sDAVF, whereas only 1 patient with sDAVF had lupus antiphospholipid antibodies. CONCLUSION In both groups of patients with dural arteriovenous fistulae, genetic thrombophilic abnormalities occurred in a higher percentage than in the general population. The differences of the genetic abnormalities may be involved in different pathophysiological mechanism(s) in the development of these distinct neurovascular entities.

Download Full-text

Factor V Leiden (G1691A) and Prothrombin Gene G20210A Mutations as Potential Risk Factors for Venous Thromboembolism after Total Hip or Total Knee Replacement Surgery

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613052 ◽

2002 ◽

Vol 87 (04) ◽

pp. 580-585 ◽

Cited By ~ 59

Author(s):

G. Larson ◽

T. L. Lindahl ◽

C. Andersson ◽

L. Frison ◽

D. Gustafsson ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Factor V Leiden ◽

Composite Endpoint ◽

Factor V ◽

Factor V Leiden Mutation ◽

G20210a Mutation ◽

Symptomatic Pulmonary Embolism ◽

Increased Risk ◽

Prothrombin Gene

SummaryPatients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

Download Full-text

Influence of factor VIII/von Willebrand complex on the activated protein C-resistance phenotype and on the risk for venous thromboembolism in heterozygous carriers of the factor V Leiden mutation

Blood Coagulation & Fibrinolysis ◽

10.1097/00001721-199910000-00002 ◽

1999 ◽

Vol 10 (7) ◽

pp. 416 ◽

Cited By ~ 11

Author(s):

V. De Mitrio ◽

R. Marino ◽

F. A. Scaraggi ◽

L. Di Bari ◽

F. Giannoccaro ◽

...

Keyword(s):

Venous Thromboembolism ◽

Factor Viii ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Activated Protein C Resistance ◽

Factor V Leiden Mutation ◽

Heterozygous Carriers ◽

Von Willebrand

Download Full-text

Co-inheritance of the 20210A Allele of the Prothrombin Gene Increases the Risk of Thrombosis in Subjects with Familial Thrombophilia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665427 ◽

1997 ◽

Vol 78 (06) ◽

pp. 1426-1429 ◽

Cited By ~ 114

Author(s):

M Makris ◽

F E Preston ◽

N J Beauchamp ◽

P C Cooper ◽

M E Daly ◽

...

Keyword(s):

Venous Thromboembolism ◽

Protein C ◽

Factor V Leiden ◽

Protein S ◽

Factor V ◽

Protein C Deficiency ◽

Antithrombin Deficiency ◽

Control Subjects ◽

Increased Risk ◽

Venous Thromboembolic

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.

Download Full-text