Laboratory Screening of Inherited Thrombotic Syndromes

1987 ◽  
Vol 57 (03) ◽  
pp. 247-251 ◽  
Author(s):  
Pier Mannuccio Mannucci ◽  
Armando Tripodi
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Laboratory Diagnosis ◽  
Heparin Cofactor Ii ◽  
C Protein ◽  
Inherited Thrombophilia ◽  
Laboratory Screening ◽  
Step Procedure ◽  
Assay Methods

SummaryThe prevalence of inherited thrombotic syndromes in the general population (1 in 2,500/5,000) appears to be higher than that of inherited bleeding disorders. The problems of their laboratory diagnosis are reviewed and a screening procedure is proposed. The most important candidates for screening are patients with unexplained venous thromboembolism at ages of less than 40-45 years, particularly when thrombotic episodes are recurrent. Screening must start from the exclusion of common acquired causes of thrombophilia. A negative family history does not exclude inherited thrombophilia, because the defects have a low penetrance and fresh mutations may have occurred in the propositi. Laboratory screening is based on a two-step procedure. The first step is aimed at detecting, preferably with specific functional assays. the most frequent and well established causes of inherited thrombophilia, i.e. deficiencies or dysfunctions of antithrombin III, protein C, protein S, plasminogen and fibrinogen. The tests included in the second step of the screening are aimed at detecting the less common or less well established causes of inherited thrombophitia (low heparin cofactor II, defective release of tissue plasminogen activator, and high plasminogen activator inhibitor). The simplest, more reliable and specific assay methods to be used in laboratory practice are recommended.

Coagulation and Fibrinolytic Profile of Paediatric Patients Undergoing Cardiopulmonary Bypass

1997 ◽  
Vol 77 (02) ◽  
pp. 270-277 ◽  
Author(s):  
Anthony K C Chan ◽  
Michael Leaker ◽  
Frederick A Burrows ◽  
William G Williams ◽  
Colleen E Gruenwald ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Plasminogen Activator ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Poor Correlation ◽  
Heparin Cofactor Ii ◽  
Paediatric Patients ◽  
Sick Children

SummaryThe haemostatic system and the use of heparin during cardiopulmonary bypass (CPB) have been studied extensively in adults but not in children. Results from adult trials cannot be extrapolated to children because of age-dependent physiologic differences in haemostasis. We studied 22 consecutive paediatric patients who underwent CPB at The Hospital for Sick Children, Toronto. Fibrinogen, factors II, V, VII, VIII, IX, XI, XII, prekallikrein, protein C, protein S, antithrombin (AT), heparin cofactor II, α2-macroglobulin, plasminogen, α2-antiplas- min, tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin-AT complexes (TAT), D-dimer, heparin (by both anti-factor Xa assay and protamine titration) and activated clotting time (ACT) were assayed perioperatively. The timing of the sampling was: pre heparin, post heparin, after initiation of CPB, during hypothermia, post hypothermia, post protamine reversal and 24 h post CPB. Plasma concentrations of all haemostatic proteins decreased by an average of 56% immediately following the initiation of CPB due to haemodilution. During CPB, the majority of procoagulants, inhibitors and some components of the fibrinolytic system (plasminogen, α2AP) remained stable. However, plasma concentrations of TAT and D-dimers increased during CPB showing that significant activation of the coagulation and fibrinolytic systems occurred. Mechanisms responsible for the activation of haemostasis are likely complex. However, low plasma concentrations of heparin (<2.0 units/ml in 45% of patients) during CPB were likely a major contributing etiology. ACT values showed a poor correlation (r = 0.38) with heparin concentrations likely due to concurrent haemodilution of haemostatic factors, activation of haemostatic system, hypothermia and activation of platelets. In conclusion, CPB in paediatric patients causes global decreases of components of the coagulation and fibrinolytic systems, primarily by haemodilution and secondarily by consumption.

REDUCED TISSUE PLASMINOGEN ACTIVATOR RELEASE AND NORMAL PLASMINOGEN ACTIVATOR INHIBITOR LEVEL IN A FAMILY WITH RECURRENT VENOUS THROMBOSES

1987 ◽  
Author(s):  
J Petäjä ◽  
G Myllylä ◽  
V Rasi ◽  
E Vahtera
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Venous Occlusion ◽  
C Protein ◽  
Tissue Plasminogen ◽  
Inhibitor Level ◽  
Fast Acting ◽  
Activator Inhibitor

We have studied the fibrinolytic system in one asymptomatic and six symptomatic members of a family with recurrent DVTs in three generations. Tissue plasminogen activator activity (TPA) and fast acting inhibitor of TPA (PAI) were determined using chromogenic substrate and TPA antigen with ELISA. Measurements were made at rest and after 10 and 20 minutes of venous occlusion (VO). 17 healthy subjects served as controls. The mean TPA in the seven family members was significantly lower than in controls at 10 and 20 min VO (p< 0.01).TPA was below the lowest value of controls (<1.7 U/ml) in five of the six patients with DVT at 10 min VO and remained below the range of controls in three at 20 min VO (<3.3 U/ml). The lowered TPA activity was associated with impaired release of TPA antigen (mean level at 10 min VO 12.A ng/ml, controls 19.5 ng/ml, p<0.05; at 20 min VO 18.2 ng/ml, controls 43.2 ng/ml, p<0.01). Four .patients with and one without DVT had TPA antigen below the lowest level of controls at 10 and/or 20 min VO. The level of'PAI at rest was normal in all cases (from 0.6 to 1.7 U/ml, controls from 0 to 3.7 U/ml). In accordance with low release of TPA antigen PAI was consumed less during VO in patients than in controls (mean level at 20 min VO 0.9 U/ml, controls 0.4 U/ml, p<0.05). The levels of antithrombin III, protein C, protein S, plasminogen, fibrinogen, F V, F VIII:C, vWf:Ag, fibrinopeptide A and beta-thromboglobulin were normal . Circulating anticoagulant was not found. It is concluded that impaired release of TPA, independent of PAI, is associated with DVT in this family. The pattern of inheritance suggested autosomal dominant trait.

DIAGNOSTIC SCREENING OF CONGENITAL THROMBOTIC SYNDROMES

1987 ◽  
Author(s):  
P M Mannuccl ◽  
A Tripodl
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Antithrombin Iii ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Screening Procedure ◽  
Type I ◽  
Type Ii ◽  
Inherited Thrombophilia ◽  
Chromogenic Assay

The prevalence of inherited thrombotic syndromes in the general population (1 in 2,500/5,000) appears to be higher than that of inherited bleeding disorders. We have reviewed the problems of their diagnosis and propose a simple screening procedure. The most important candidates far. screening are patients with unexplained venous thromboembolism at ages ofless than 40 years, particularly when thrombotic episodes are recurrent.Screening must start from collectionof the clinical and family history of the propositus and from the exclusion of common acquired forms of thrombophilia. A negative family historydoes not exclude inherited thrombophilia, because the defects have oftena low penetrance and fresh mutationsmay have occurred in the propositi. The test chosen for laboratoryscreening of inherited thrombotic syndromes must be limited in number, easy todo and, more importantly, their results should be clinically relevent Which defects should be screened and what type of methodology should be used? The table is intended to answerthese questions by proposing a two-step screening procedure.The tests included in the .first step of the screening are aimed at evaluating Laboratory screening of inherited thrombotic syndromes the most frequent and well established causes of inherited thrombophilia, —-antithrombin III, protein C. protein S.plasminogen and fibrinogen.FIRST STEP Antithrombin III (heparin cofactorI chromogenic assay)Protein C (Francis' clotting assay)Protein S(electroimmunoassay of total proteinSantigen)Plasminogen (chromogenic assay)Fibrinogen (clotting assay)SECONSTEP(Tran's functional assay) Plasminogen activator (fibrin plate assay before and after venous stasisor DDAVP)Plasminogen activator inhibitor(chromogenic assay)The tests offirst choice that we propose (see table) are in general functional assaysdetecting both type I and type IIdeficiencies and are simple enough tobecarried out even in non specialized laboratories.For protein S, however,this goal has not been achieved yet and only type I protein S deficiencycan be currently identified with immunoassays measuring total protein S antigen. Since a number of laboratories may still not have the facilities to perform protein C functional assays, they are advised to set up at least an immunoassay, since type I deficiencies are much more frequent than type II deficiencies. The tests included in the second step of the screening are aimed at detectingthe less common or less well established causes of thrombophilia, and should be carried out when the clinical history suggests the existence of inherited thrombophilia and yet the first step has failed to reveal any laboratory abnormality. Defective plasminogen activation can be evaluated by measuring plasminogen activator activity with the simple fibrin plate assay carried out before and after stimuli such as venous occlusion and/or DDAVP infusion. The parallel measurement of plasminogen activator inhibitor allows to distinguish cases of detective plasminogen activation due to high inhibitor levels. The measurement of heparin cofactor II should also be included in this battery of second-step screening tests.Using this screening procedure in95 propositi with juvenile venous thromboembolism, we have identified 7 kindreds with antithrombin III deficiency (5 type I and 2 type II) (7.5%),7 kindreds with protein C deficiency (1 type II) (7.5%), 5 kindredswith protein S deficiency (5%), 1 withhypoplasminogenemia (1%) and 1 with dysfibrinogenemia Milano II (1). Theremaining undiagnosed cases might bedue to as yet unidentified deficiencies or abnormalities of other antithrombotic mechanisms such as,for instance, endothelial thrombomodulin or the fibrinolysis enhancing property of the protein C-protein S system.

Congenital Histidine-Rich Glycoprotein Deficiency

1993 ◽  
Vol 70 (02) ◽  
pp. 263-265 ◽  
Author(s):  
Toshio Shigekiyo ◽  
Tsutomu Ohshima ◽  
Hirofumi Oka ◽  
Akira Tomonari ◽  
Hiroyuki Azuma ◽  
...  
Keyword(s):  
Sinus Thrombosis ◽  
Clinical Signs ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Transverse Sinus ◽  
Heparin Cofactor Ii ◽  
C Protein ◽  
Liver Insufficiency ◽  
Low Levels ◽  
Activator Inhibitor

SummaryThe proband, a 43-year-old woman, suffered from right transverse sinus thrombosis during oral contraceptive treatment. A month after stopping the drug, her plasma activities of antithrombin III, protein C, protein S, heparin cofactor II, plasminogen and plasminogen activator inhibitor were normal, but her plasma histidine-rich glycoprotein (HRG) level was only 21% of the normal level of 109.5 ± 51.5% (mean ± 2 SD). The HRG concentrations in her plasma determined on four different occasions over 6 months were similar. She showed no clinical signs of liver insufficiency or sepsis. Low levels of plasma HRG (20% to 35% of normal) were also found in her aunt, uncle and two daughters. These results suggest that congenital HRG deficiency is inheritary in this family.

APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

1999 ◽  
Vol 81 (04) ◽  
pp. 527-531 ◽  
Author(s):  
U. Kjellberg ◽  
N.-E. Andersson ◽  
S. Rosén ◽  
L. Tengborn ◽  
M. Hellgren
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Reference Level ◽  
Soluble Fibrin ◽  
Prothrombin Fragment ◽  
D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 328-333 ◽  
Author(s):  
N J de Fouw ◽  
Y F de Jong ◽  
F Haverkate ◽  
R M Bertina
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Blood Platelets ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Tissue Type ◽  
Clot Lysis ◽  
Activator Inhibitor ◽  
Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

ARIC Hemostasis Study-IV. Intraindividual Variability and Reliability of Hemostatic Factors

1995 ◽  
Vol 73 (02) ◽  
pp. 256-260 ◽  
Author(s):  
Nghia D Nguyen ◽  
Habib Ghaddar ◽  
Valarie Stinson ◽  
Lloyd E Chambless ◽  
Kenneth K Wu ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Coagulation Factors ◽  
Total Variance ◽  
Intraindividual Variability ◽  
Plasminogen Activator Inhibitor 1 ◽  
Platelet Factor ◽  
Hemostatic Factors ◽  
R Value

SummaryWe have recently reported the short-term intraindividual variability of several coagulation factors and inhibitors included in the ARIC study (Chambless et al. Ann Epidemiol 1992; 2:723). In this paper, we reported the intraindividual variability results of additional hemostatic factors. Blood samples were collected for hemostatic assays three times at 1-2-week intervals from 39 subjects recruited from 4 ARIC field centers. The contributions of within-person, processing and assay (designated “method”) and between-person variances to the total variance were estimated and from them the reliability coefficient, R, was computed as the proportion of total variance in the between-person component. The R value was high for (β-thromboglobulin and tissue- plasminogen activator: 0.83 and 0.81, respectively; and intermediate for D-dimer and plasminogen activator inhibitor-1: 0.73 and 0.72, respectively. Protein S (total and free) and platelet factor 4 had low repeatability (R<0.50) derived mostly from “method” variability while low R value (0.03) for fibrinopeptide A was attributed to high “method” and “within-person” variability. Gender, age and the level of hemostatic factors did not influence the intraindividual variability.

scholarly journals The Impact of the Gene Variants FV Leiden, FII G20210A, MTHFR C677T and PAI-1 4G/5G on Pregnancy Loss in Women from Central Serbia

2020 ◽  
Vol 21 (1) ◽  
pp. 19-25
Author(s):  
Gordana M. Sosic ◽  
Snezana Sretenovic ◽  
Danijela Radivojevic ◽  
Nikola Jovic ◽  
Mirjana Varjacic
Keyword(s):  
Plasminogen Activator ◽  
Pregnancy Loss ◽  
Methylenetetrahydrofolate Reductase ◽  
Plasminogen Activator Inhibitor ◽  
Gene Variants ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inherited Thrombophilia ◽  
Factor Ii ◽  
The Impact ◽  
Activator Inhibitor

AbstractThrombophilia is a condition of enhanced functionality of the haemostatic system with an increased tendency for thrombosis, and it can be a congenital, acquired, or complex defect. Pregnancy can be the cause of acquired transitory thrombophilia, which may lead to complications if inherited thrombophilia is also present.The aim of this study was to determine the genetic structure of the population based on the frequency of the gene variants factor V Leiden G1691A, factor II G20210A, methylenetetrahydrofolate reductase C677T, and plasminogen activator inhibitor-1 4G/5G, as well as to investigate the predictive value of these gene variants in repeated miscarriages.The study included 87 female patients from Central Serbia with an average age of 32.7±4.5 years with inherited thrombophilia and previous miscarriages, with or without intrauterine foetal death. The exclusion criteria included the existence of gynaecological and infectious aetiology and the deficit of factors important for the coagulation process.The resulting genotypes were in Hardy-Weinberg equilibrium. The frequency of genotypes with mutated alleles was significantly higher in this group of patients than in the control group for all variants except factor II G20210A. The most commonly mutated alleles were the plasminogen activator inhibitor-1 4G allele (0.61) and methylenetetrahydrofolate reductase T allele (0.47). Double mutation of plasminogen activator inhibitor-1 4G/5G and methylenetetrahydrofolate reductase C677T was dominant in patients with recurrent pregnancy loss (46.15%).The presence of a combination of genetic variants of the plasminogen activator inhibitor-1 4G/5G and methylenetetrahydrofolate reductase C677T is a significant predictor of spontaneous abortions in women with inherited thrombophilia in Central Serbia.

THROMBOPHILIA:ITS CAUSES AND A ROUGH ESTIMATE OF ITS PREVALENCE

1987 ◽  
Author(s):  
E Briët ◽  
L Engesser ◽  
E J P Brommer ◽  
A W Broekmans ◽  
R M Bertina
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Antithrombin Iii ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Factor Vii ◽  
Type I ◽  
Factor V ◽  
Protein C Deficiency ◽  
Familial Cases

Idiopathic venous thrombosis and embolism have gained widespread interest since the discovery that, deficiencies of antithrombin III, protein C, and protein S are associated with familial venous thrombophilia. The purpose of our study was to obtain an estimate of the prevalence of this syndrome and to establish the etiology in as many cases as possible.We collaborated with specialists from 37 Dutch hospitals, covering about 10% of the Dutch population. A history as well as blood samples were obtained from 113 unrelated cases with familial thrombophilia and from 90 isolated cases. Assuming that each proband in a family with thrombophilia has an average of four affected relatives, a rough estimate of the prevalence of familial thrombophilia in The Netherlands is 40 cases per 100.000. The prevalence of non-familial thrombophilia is probably lower.In 35 out of the 113 familial cases we established a diagnosis of hereditary antithrombin III deficiency (n=5), protein C deficiency (type I: n=9; type II: n=4), protein S deficiency (n=15) and dysfibrinogenemia (n=2). In 36 cases we found no abnormality at all and in the remaining 42 cases abnormalities were found in one or more of the following: heparin cofactor II, factor V, factor VII, factor VIII, von Willebrand factor, plasminogen, tissue plasminogen activator, plasminogen activator inhibitor, alpha 2 antiplasmin and histidine rich glycoprotein. In most of these cases, however, the hereditary nature of the abnormalities could not be demonstrated and the causal relationships remain to be established.In the 90 isolated cases, we diagnosed hereditary deficiencies of anti thrombin III, protein C and protein S each in one case and a lupus anticoagulant in two cases. In 54 cases no abnormality was found and in the remaining 31 cases various abnormalities were found in one or more of the proteins mentioned above.We conclude that the syndrome of thrombophilia is not rare but its true prevalence needs to be established by more rigorous means. An etiological diagnosis can be made with confidence in only one third of the familial cases and in less than 10 percent of the isolated cases.

scholarly journals Continuous Active State of Coagulation System in Patients With Nonthrombotic Inflammatory Bowel Disease

2011 ◽  
Vol 17 (6) ◽  
pp. 600-604 ◽  
Author(s):  
Huseyin Alkim ◽  
Selime Ayaz ◽  
Canan Alkim ◽  
Aysel Ulker ◽  
Burhan Sahin
Keyword(s):  
Plasminogen Activator ◽  
Degradation Products ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inflammatory Bowel ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Activator Inhibitor ◽  
D Dimer

This study was planned for searching possible changes of the total coagulation and fibrinolysis system in inflammatory bowel disease (IBD) in order to obtain some clues for explaining the relation between IBD and hypercoagulability. A total of 24 patients with ulcerative colitis, 12 patients with Crohn disease, and 20 healthy controls were studied. Platelets; prothrombin time (PT); partial thromboplastin time (PTT); fibrinogen; d-dimer; fibrinogen degradation products; protein C; protein S; antithrombin; thrombin time; von Willebrand factor; coagulation factors V, VII, VIII, IX, XI, and XIII; plasminogen; antiplasmin; tissue plasminogen activator; plasminogen activator inhibitor 1; and prothrombin fragments 1 + 2 were studied. Most of the procoagulants (platelets, fibrinogen, von Willebrand factor, coagulation factor IX, and plasminogen activator inhibitor 1) were found increased together with decreases in some anticoagulants (protein S and antithrombin) in IBD. Also the activation markers of coagulation (d-dimer, fibrinogen degradation products, and prothrombin fragments 1 + 2) were all increased. The parameters of the total coagulation–fibrinolysis system were increased in IBD, regardless of the form and the activity of the disease.

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