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.    

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.

Inherited Prethrombotic Disorders and Infectious Purpura

1996 ◽  
Vol 75 (06) ◽  
pp. 899-901 ◽  
Author(s):  
Rudi G J Westendorp ◽  
Pieter H Reitsma ◽  
Rogier M Bertina
Keyword(s):  
Risk Factors ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Disease Course ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
C Protein ◽  
Severity Of The Disease

SummaryPatients with severe meningococcal infection are characterized by extensive microvascular thrombosis, consumption coagulopathy and secondary hemorrhages. The contribution of the inherited prethrombotic disorders to the severity of the disease course is not established yet. Here, we report on the levels of protein C, protein S, antithrombin and the presence of the factor V Leiden mutation (R506Q) in 50 patients with meningococcal disease, as determined 6 to 58 months after hospital discharge. In addition, we recalled the parents of 16 deceased patients to screen for the mutation in factor V, an abnormality which results in resistance to activated protein C. Among the patients, the prevalence of the genetic risk factors for thrombosis was not higher than expected on the basis of their prevalence in the general population. Moreover, the prevalence of the factor V Leiden mutation was not increased among the parents of the deceased patients. The individual plasma levels of protein C, protein S, and antithrombin did not differ between the patients with or without severe purpura. The present data constitute circumstantial evidence that primary defects in the natural anticoagulant systems do not play a major role in the severity of the disease course. Screening of patients with infectious purpura for inherited thrombotic risk factors is therefore not indicated.

Abstract 200: Hypercoagulabilty Panel Testing in Neonates Undergoing Cardiac Surgery

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sirisha Emani ◽  
David Zurakowski ◽  
Christopher Baird ◽  
Frank Pigula ◽  
Trenor Cameron ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Thrombin Generation ◽  
Factor V Leiden ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Coagulation Factors ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
C Protein ◽  
Cardiolipin Antibodies

Thrombosis is a crucial contributor of morbidity and mortality in neonates undergoing cardiac surgery. Although there is published data on several factors of the hemastatic system, there is no data correlating factor expression and/or function with thrombosis in neonates. We tested the hypothesis that hypercoagulability markers are predictive of thrombosis in neonates undergoing cardiac surgery. Sixty neonates undergoing cardiac surgery were tested for thrombin generation assay; coagulation factors; antithrombin III, protein C, protein S, and factor VIII; fibrinolytic inhibitors; thrombin-activatable fibrinolytic inhibitor, plasminogen activator inhibitor; and presence of cardiolipin antibodies by immunoassays. Factor V Leiden mutation was also tested in a few patients utilizing single nucleotide polymorphism assays. In this pilot study, thrombosis occurred in 15% of the neonates undergoing cardiac surgery. Significant risk factors associated with thrombosis were pre-mature birth, use of cardio pulmonary bypass, and single ventricle physiology. Hypercoagulability factors associated with thrombosis determined by univarent analysis were elevated thrombin generation, enhanced expression of thrombin-activatable fibrinolytic inhibitor and plasminogen activator inhibitor as well as presence of cardiolipin antibodies and factor V Leiden mutation. No correlation was observed between thrombosis and expression of coagulation factors antithrombin III, protein C, protein S, and factor VIII. Multivarient analysis has proven to show thrombin generation, thrombin-activatable fibrinolytic inhibitor, and presence of cardiolipin antibodies as multivariable predictors of thrombosis. These significant hypercoagulability markers are independent predictors of thrombosis. Thus thrombosis predictability can help in post-operative management and care for neonates undergoing cardiac surgery by regulating pro- and/or anti-coagulation therapy.

4g/5g Prevalence in 223 Patients with Thrombosis and in 162 Healthy Controls, from the Centre Region of Portugal.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4057-4057
Author(s):  
Rosa Maia ◽  
Emilia Cortesao ◽  
Catarina Geraldes ◽  
Luis Simoes ◽  
Carla Simoes ◽  
...  
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Factor V Leiden ◽  
Protein S ◽  
Mthfr C677t ◽  
Insertion Polymorphism ◽  
Factor V ◽  
Centre Region ◽  
History Of ◽  
Pai 1

Abstract A deletion/insertion polymorphism (4G or 5G) in the promoter of the PAI-1 gene has been suggested to be involved in regulation of the synthesis of the inhibitor, the 4G allele being associated with enhanced gene expression, and therefore related with thrombosis. In the present work we studied the prevalence of 4G/5G polymorphism in 223 unrelated patients with history of objectively confirmed thromboembolism, and in 162 healthy unrelated controls, both groups natural from all centre regions of Portugal. In this normal cohort, the prevalence of 4G/4G is 23%, 4G/5G is 38% and 5G/5G is 39%; in the affected population is, respectively, 47%, 21.5% and 30%, which means that 4G/4G is twice more frequent in the patients with thrombosis. When we relate the age of the first thrombosis episodes in the three groups, we find no significative difference, as the respective media is 36.8; 38.6 and 35.5 years in the 4G/4G, 4G/5G and 5G/5G group, respectively. This data suggest that this polymorphism by itself, even in homozygosity, is not associated with earlier thrombosis. In our patients, we studied the presence of Lupus Anticoagulant, Factor V Leiden, Factor IIG20210A, MTHFR C677T, and also Antithrombin III, Protein S and Protein C levels. We analyse the prevalence of the three mutations in patients with DVP, PTE, ischemic and venous CVA and we only find a significative difference in the 4G/4G group: 46.2% patients with DVP and 48.2% patients with PTE (23% in normal cohort). In conclusion, in the centre region of Portugal, the prevalence of 4G/4G is 23%, 4G/5G is 38% and 5G/5G is 39%; in our cohort of unrelated patients the only significative difference is in the 4G/4G group (47%); this variation maintain in the DVP and PTE group. We did not find difference at the age of the first thrombotic episode, in the three groups.

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

1996 ◽  
Vol 76 (04) ◽  
pp. 505-509 ◽  
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.

scholarly journals Clinical profile, common thrombophilia markers and risk factors in 85 young Indian patients with arterial thrombosis

2013 ◽  
Vol 131 (6) ◽  
pp. 384-388 ◽  
Author(s):  
Mahendra Narain Mishra ◽  
Ravi Kalra ◽  
Shalesh Rohatgi
Keyword(s):  
Myocardial Infarction ◽  
Family History ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Positive Family History ◽  
Protein S ◽  
Factor V ◽  
C Protein ◽  
Indian Patients ◽  
Low Levels

CONTEXT AND OBJECTIVE: Arterial thrombosis may occur consequent to hereditary thrombophilia and increased lipoprotein(a) [Lp(a)] and fibrinogen. Our aim was to study the prevalence of common thrombophilia markers in 85 consecutive cases of arterial thrombosis. DESIGN AND SETTING: A retrospective study was conducted from 85 consecutive young patients treated as outpatients or admitted due to stroke or myocardial infarction at a tertiary care hospital. METHODS: Eighty-five Indian patients (age < 45 years) presenting ischemic stroke (n = 48) or myocardial infarction (n = 37) and 50 controls were studied for seven thrombophilia markers including antithrombin (AT), factor V, protein C, protein S, activated protein C resistance (APC-R), fibrinogen and Lp(a). Functional assays for protein C, protein S, factor V and APC-R were performed using clotting-based methods. Semi-quantitative estimation of fibrinogen was done using Clauss's method and Lp(a) using immunoturbidimetry. Statistical analysis was done using the Epi Info 6 software. RESULTS: Thirty-three samples (38.8%) tested positive for one or more thrombophilia markers. The three commonest abnormalities were elevated Lp(a) (20%), fibrinogen (17.6%) and low APC-R (14.2%). Low levels of protein C, protein S and AT were present in 4.7, 9.4 and 7% of the patients, respectively. Overall, the risk factor profile was: smoking (33%), positive family history (15.3%), hyperlipidemia (7%), hypertension, diabetes mellitus and obesity (2.3% each). CONCLUSIONS: An association was found between low levels of protein C, protein S and AT and arterial thrombosis, but only elevated fibrinogen levels, smoking, positive family history and hyperlipidemia showed statistical significance.

scholarly journals Inherited Hypercoagulable States

1997 ◽  
Vol 2 (4) ◽  
pp. 313-320 ◽  
Author(s):  
A Koneti Rao ◽  
Sunita Sheth ◽  
Robert Kaplan
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Thromboembolic Events ◽  
Heparin Cofactor Ii ◽  
Predisposing Factor ◽  
Inherited Thrombophilia ◽  
Prothrombin Gene

Hypercoagulable states are a group of conditions associated with increased predisposition to thromboembolic events. Most of the inherited abnormalities recognized to date are associated with venous thromboembolism (VTE) rather than arterial thrombosis. The well-recognized inherited hypercoagulable states are the deficiencies of antithrombin, protein C and protein S, and the resistance to APC (factor V Leiden). These entities represent aberrations in the natural anticoagulant systems that exist in plasma. Other causes of inherited thrombophilia include abnormalities in the proteins of the fibrinolytic system, dysfibrinogenemias, deficiency of heparin cofactor II, abnormal thrombomodulin, elevated levels of histidine-rich glycoprotein, and the recently described variation in the prothrombin gene. One entity that has become firmly established as a predisposing factor for recurrent VTE is hyperhomocysteinemia. About half of VTE episodes in patients with inherited thrombophilias occur in relation to events that are generally recognized as predisposing states, such as surgery, pregnancy (particularly puerperium) and immobilization. In this review, the risks of VTE associated with inherited risk factors are discussed, and guidelines for the diagnosis and management are presented.

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