Laboratory Evaluation and Clinical Characteristics of 2,132 Consecutive Unselected Patients with Venous Thromboembolism – Results of the Spanish Multicentric Study on Thrombophilia (EMET*-Study)

1997 ◽  
Vol 77 (03) ◽  
pp. 444-451 ◽  
Author(s):  
José Mateo ◽  
Artur Oliver ◽  
Montserrat Borrell ◽  
Núria Sala ◽  
Jordi Fontcuberta ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Odds Ratio ◽  
Protein C ◽  
Protein S ◽  
Laboratory Evaluation ◽  
Clinical Factors ◽  
Recurrent Thrombosis ◽  
Heparin Cofactor Ii ◽  
Crude Odds Ratio ◽  
History Of

SummaryPrevious studies on the prevalence of biological abnormalities causing venous thrombosis and the clinical characteristics of thrombotic patients are conflicting. We conducted a prospective study on 2,132 consecutive evaluable patients with venous thromboembolism to determine the prevalence of biological causes. Antithrombin, protein C, protein S, plasminogen and heparin cofactor-II deficiencies, dysfibrinoge-nemia, lupus anticoagulant and antiphospholipid antibodies were investigated. The risk of any of these alterations in patients with familial, recurrent, spontaneous or juvenile venous thrombosis was assessed. The overall prevalence of protein deficiencies was 12.85% (274/2,132) and antiphospholipid antibodies were found in 4.08% (87/2,132). Ten patients (0.47%) had antithrombin deficiency, 68 (3.19%) protein C deficiency, 155 (7.27%) protein S deficiency, 16 (0.75%) plasminogen deficiency, 8 (0.38%) heparin cofactor-II deficiency and 1 had dysfib-rinogenemia. Combined deficiencies were found in 16 cases (0.75%). A protein deficiency was found in 69 of 303 (22.8%) patients with a family history of thrombosis and in 205/1,829 (11.2%) without a history (crude odds ratio 2.34, 95% Cl 1.72-3.17); in 119/665 (17.9%) patients with thrombosis before the age of 45 and in 153/1,425 (10.7%) after the age of 45 (crude odds ratio 1.81, 95% Cl 1.40-2.35); in 103/616 (16.7%) with spontaneous thrombosis and in 171/1,516 (11.3%) with secondary thrombosis (crude odds ratio 1.58, 95% Cl 1.21-2.06); in 68/358 (19.0%) with recurrent thrombosis and in 206/1,774 (11.6%) with a single episode (crude odds ratio 1.78,95% Cl 1.32-2.41). Patients with combined clinical factors had a higher risk of carrying some deficiency. Biological causes of venous thrombosis can be identified in 16.93% of unselected patients. Family history of thrombosis, juvenile, spontaneous and recurrent thrombosis are the main clinical factors which enhance the risk of a deficiency. Laboratory evaluation of thrombotic patients is advisable, especially if some of these clinical factors are present.

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.

Prothrombin Fragment F1+2 Is not Predictive for Recurrent Venous Thromboembolism

1997 ◽  
Vol 77 (05) ◽  
pp. 0829-0833 ◽  
Author(s):  
P A Kyrle ◽  
S Eichinger ◽  
I Pabinger ◽  
A Stümpflen ◽  
M Hirschl ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Protein C ◽  
Oral Anticoagulants ◽  
Factor V Leiden ◽  
Factor V ◽  
Recurrent Thrombosis ◽  
Prothrombin Fragment ◽  
Recurrent Venous Thromboembolism ◽  
History Of

SummaryIt would be important to estimate in advance the risk of recurrent thrombosis. Deficiencies of antithrombin, protein C or protein S, or resistance to activated protein C are associated with a biochemically detectable prethrombotic state. It is thus far unknown whether in patients with a history of thromboembolism but without a defined clotting abnormality a heightened coagulation activation is detectable.We investigated the value of prothrombin fragment Fl+2 (FI+2) as a predictor of recurrent venous thromboembolism. Furthermore, we compared the Fl+2 levels of thrombosis patients without a defined clotting defect to those of Factor V Leiden patients with a history of venous thrombosis and to those of healthy controls. 180 patients without a defined clotting abnormality and 73 patients with Factor V Leiden were prospectively followed after discontinuation of oral anticoagulants for venous thrombosis and Fl+2 was measured at regular intervals.Recurrent venous thromboembolism occurred in 23 (9%) of the 253 patients. Before or at several time points after oral anticoagulants, no significant difference in Fl+2 levels was found in patients with and without recurrent thrombosis. Fl+2 levels at 3 weeks and prior to recurrence were not significantly different in both patient groups. Over a one-year observation period, Fl+2 levels of both patients with and without Factor V Leiden were higher than those of the controls. No difference in Fl+2 was seen between patients with and without Factor V Leiden.We conclude that monitoring of Fl+2 is not suitable for identification of individuals at risk of recurrent venous thrombosis. Permanent hemostatic system activation is detectable both in patients with a defined abnormality of the clotting system and in patients in whom a particular defect has not (yet) been identified.

Familial Thrombophilia: A Review Analysis

1996 ◽  
Vol 2 (4) ◽  
pp. 227-236 ◽  
Author(s):  
Angelique G. M. van den Belt ◽  
Martin H. Prins ◽  
Menno V. Huisman ◽  
Jack Hirsh
Keyword(s):  
Risk Factor ◽  
Odds Ratio ◽  
Protein C ◽  
Antithrombin Iii ◽  
Family Members ◽  
Protein S ◽  
Biochemical Abnormality ◽  
Thrombotic Disease ◽  
History Of ◽  
Deficiency Type

The correct approach to the management of the asymptomatic carrier with a recognized inherited thrombophilic disorder is uncertain because reliable in formation of the risk of spontaneous (unprovoked) throm bosis in these disorders is not available. To determine the best available estimate of the annual incidence of spon taneous thrombosis in asymptomatic carriers of disorders that have been linked to familial thrombophilia, we per formed a literature review. Using Medline search from 1965 to 1992, supplemented by manual searches, we re trieved all articles that presented data on antithrombin III, protein C, protein S, dysfibrinogenemia, plasmino gen, histidine-rich glycoprotein, heparin cofactor II, and fibrinolysis in relation to thrombosis. Publications were included in the analysis if they (1) reported one or more probands with thrombotic disease and a heterozygous biochemical abnormality of the hemostatic system, (2) assessed the presence of this abnormality in family mem bers independent of the presence or absence of a history of thrombotic disease, and (3) assessed the presence of a history of thrombotic disease in all available family mem bers. The biochemical status and clinical details of all family members reported were extracted from each eligi ble article. For each abnormality the odds ratio for throm bosis was compared in family members with and without the biochemical abnormality. If applicable, thrombosis- free survival and age-specific incidences of thrombosis were calculated. The thrombotic episodes were classified as spontaneous or secondary to a recognized risk factor, and the proportion of spontaneous episodes was calcu lated. The influence of diagnostic suspicion bias in symp tomatic patients with a family history of thrombosis was reduced by recalculating the absolute incidence of throm bosis from the odds ratio after adjusting the incidence of venous thrombosis in nonaffected family members to that observed in the general population. Statistically signifi cant associations between the presence of a biochemical abnormality and a history of venous thrombosis were found for antithrombin III deficiency types 1 and 2a and 2b, protein C deficiency type 1, and protein S deficiency type I. Dysfibronogenemia was statistically significantly associated with venous as well as arterial thrombosis. Thirty-five to 67% of the events were classified as being provoked, as they occurred following exposure to a rec ognized risk factor for thrombosis. The recalculated an nual incidence of spontaneous thrombosis was 0.6 to 1.6%/year. It is concluded that this relatively low inci dence does not warrant life-long continuous use of anti coagulant prophylaxis since the reported risk of major and fatal bleeding associated with the use of oral antico agulants is 2-3 and 0.4%/year, respectively.

Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5314-5322 ◽  
Author(s):  
Willem M. Lijfering ◽  
Jan-Leendert P. Brouwer ◽  
Nic J. G. M. Veeger ◽  
Ivan Bank ◽  
Michiel Coppens ◽  
...  
Keyword(s):  
Family History ◽  
Venous Thrombosis ◽  
Protein C ◽  
Positive Family History ◽  
Protein S ◽  
Factor V ◽  
Recurrence Rates ◽  
Thrombotic Risk ◽  
History Of ◽  
Fv Leiden

Abstract Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C–, and protein S–deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. In relatives with factor V (FV) Leiden, prothrombin 20210G>A, or high FVIII levels, these were 0.49% (95% CI, 0.39-0.60), 0.34% (95% CI, 0.22-0.49), and 0.49% (95% CI, 0.41-0.51), respectively. High FIX, FXI, and TAFI, and hyperhomocysteinemia were not independent risk factors. Annual incidence of major bleeding in antithrombin-, protein C–, or protein S–deficient relatives on anticoagulants was 0.29% (95% CI, 0.03-1.04). Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.

The Frequency of Type I Heterozygous Protein S and Protein C Deficiency in 141 Unrelated Young Patients with Venous Thrombosis

1988 ◽  
Vol 59 (01) ◽  
pp. 018-022 ◽  
Author(s):  
C L Gladson ◽  
I Scharrer ◽  
V Hach ◽  
K H Beck ◽  
J H Griffin
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Antithrombin Iii ◽  
Young Patients ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Low Protein ◽  
S Deficiency

SummaryThe frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.

Hereditary Heparin Cofactor II Deficiency and the Risk of Development of Thrombosis

1987 ◽  
Vol 57 (02) ◽  
pp. 196-200 ◽  
Author(s):  
R M Bertina ◽  
I K van der Linden ◽  
L Engesser ◽  
H P Muller ◽  
E J P Brommer
Keyword(s):  
Liver Disease ◽  
Venous Thrombosis ◽  
Healthy Volunteers ◽  
Mean Value ◽  
Age Group ◽  
Normal Range ◽  
Heparin Cofactor Ii ◽  
History Of ◽  
Group 2 ◽  
Hereditary Nature

SummaryHeparin cofactor II (HC II) levels were measured by electroimmunoassay in healthy volunteers, and patients with liver disease, DIC, proteinuria or a history of venous thrombosis. Analysis of the data in 107 healthy volunteers revealed that plasma HC II increases with age (at least between 20 and 50 years). HC II was found to be decreased in most patients with liver disease (mean value: 43%) and only in some patients with DIC. Elevated levels were found in patients with proteinuria (mean value 145%). In 277 patients with a history of unexplained venous thrombosis three patients were identified with a HC II below the lower limit of the normal range (60%). Family studies demonstrated hereditary HC II deficiency in two cases. Among the 9 heterozygotes for HC II deficiency only one patient had a well documented history of unexplained thrombosis. Therefore the question was raised whether heterozygotes for HC II deficiency can also be found among healthy volunteers. When defining a group of individuals suspected of HC II deficiency as those who have a 90% probability that their plasma HC II is below the 95% tolerance limits of the normal distribution in the relevant age group, 2 suspected HC II deficiencies were identified among the healthy volunteers. In one case the hereditary nature of the defect could be established.It is concluded that hereditary HC II deficiency is as prevalent among healthy volunteers as in patients with thrombotic disease. Further it is unlikely that heterozygosity for HC II deficiency in itself is a risk factor for the development of venous thrombosis.

Decreased anticoagulant response to tissue factor pathway inhibitor in patients with venous thromboembolism and otherwise no evidence of hereditary or acquired thrombophilia

2004 ◽  
Vol 91 (01) ◽  
pp. 80-86 ◽  
Author(s):  
Brigitte Piccapietra ◽  
Johanna Boersma ◽  
Joerg Fehr ◽  
Thomas Bombeli
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Mean Value ◽  
Healthy Controls ◽  
Crude Odds Ratio ◽  
Sensitivity Ratio ◽  
Increased Risk ◽  
History Of ◽  
Anticoagulant Response ◽  
Acquired Thrombophilia

SummaryNo relevant deficiency of TFPI or genetic polymorphisms could thus far consistently be associated with venous thromboembolism. We hypothesized that the substrates of the TFPI protein, including FVII or FX (rather than the protein itself) could induce a hypercoagulable state. We created a novel TF-based clotting assay that evaluated the anticoagulant response to exogenously added recombinant TFPI. The response to TFPI was expressed as the ratio of the clotting time with and without TFPI. By using 118 healthy controls, we established a reference range between 1.31 and 1.93 (mean value ± 2 standard deviations (SD), 1.62 ± 0.31). We then evaluated samples from 120 patients with a history of venous thromboembolism but no evidence of hereditary and acquired thrombophilia. The range of the patients’ ratios was significantly (P < 0.001) lower, falling between 1.2 and 1.78 (mean value ± 2 SD, 1.49 ± 0.29). Of the 120 patients, 39 (32.5%) had a TFPI sensitivity ratio below the 10th percentile of the controls, compared with 11 (9.3%) of the healthy controls. The crude odds ratio for venous thrombosis for subjects with a TFPI sensitivity ratio below the 10th percentile was 13 (95% CI; range, 3.1 to 54.9) compared with those with a ratio above 1.8 (90th percentile). Patients with idiopathic thromboembolism did not have a decreased TFPI sensitivity ratio more often than patients with thrombosis with a circumstantial risk factor. Based on these results, a reduced response to TFPI may lead to an increased risk of venous thrombosis.

scholarly journals Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX)

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 42S-47S ◽  
Author(s):  
Antonio Girolami ◽  
Silvia Ferrari ◽  
Elisabetta Cosi ◽  
Claudia Santarossa ◽  
Maria Luigia Randi
Keyword(s):  
Venous Thrombosis ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Bleeding Tendency ◽  
Clotting Factors ◽  
Protein Z ◽  
Clinical Observations

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

The Risk of Deep Venous Thrombosis in Surgical Patients Using Multivariate Analysis

1975 ◽  
Author(s):  
A. N. Nicolaides ◽  
Doreen Irving
Keyword(s):  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Varicose Veins ◽  
Maximum Likelihood Estimates ◽  
Clinical Factors ◽  
Logistic Analysis ◽  
History Of ◽  
Fibrinogen Test ◽  
A Prospective Study ◽  
Significant Factors

The purpose of the present study was to develop a method of determining the patients who are at risk and require prophylaxis.In a prospective study of 535 patients various clinical factors believed to predispose to deep venous thrombosis have been studied using a linear logistic analysis. The patients had been screened with the 125I-fibrinogen test. A standard computer program was used to obtain the maximum likelihood estimates of the coefficients for the various factors studied. The most important factor was age; premedication with omnopon, presence of varicose veins, infection, history of previous DVT, severity and type of operation were also significant.For any patient the logit y can be estimated and expressed as a percentage risk of thrombosis using the equation y = −6.00 + (Age × 0.0617) + (History of previous DVT × 1.38) + (V. veins × 1.26) + (Premedication with omnopon × 0.97) + (Infection × 0.84) -(Urological operation × 1.94) - (Thoracic operation × 1.15) derived from the significant factors and their coefficients. (The values of factors other than age are either 0 = absent, or 1 = present.)

PROTEIN C, PROTEIN S AND THE FIBRINOLYTIC SYSTEM IN PATIENTS WITH A HISTORY OF THROMBOSIS

1987 ◽  
Author(s):  
J Malm ◽  
M Laurell ◽  
I M Nilsson ◽  
B Dahlbäck
Keyword(s):  
Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Protein C ◽  
Protein S ◽  
Protein S Deficiency ◽  
Functional Protein ◽  
Protein C Deficiency ◽  
S Deficiency ◽  
Tissue Plasminogen ◽  
History Of

Consecutive patients with a history of thrombo-embolic disease (n = 241, 109 males, 132 females, mean age 46 y), referred to the Coagulation Laboratory during an 18 month period, were analysed for defects in their coagulation and fibrinolytic systems. The diagnosis of thrombosis had been verified with phlebography and that of pulmonary embolus with scintigraphy or angiography. Retinal venous thrombosis was found in 15 of the patients. In 15 cases the thrombotic episodes occurred postoperatively, in 15 during pregnancy, in 12 during the postpartum period and in 20 during use of oral contraceptives. In the remaining cases no clinical riskfactors were identified.The concentration of protein C zymogen was measured with an immunoradiometric assay. Functional protein C was determined with a clotting inhibition assay. Protein C deficiency was found in 8 cases. Two of these had a functional protein C deficiency with normal zymogen levels. The concentration of total, as well as free (not in complex with C4b-binding protein), protein S was determined with a radioimmunoassay. Two cases of protein S deficiency were detected. Three patients with antithrombin III deficiency and two with plasminogen deficiency were found.The fibrinolytic activity after venous occlusion was analysed in 216 patients. Decreased levels were found in 32 %. The concentration of tissue plasminogen activator inhibitor (PAI) was measured in 110 patients and found to be increased in 65 % of the cases. In 99 patients both the fibrinolytic activity and the PAI concentration were measured. A combination of decreased fibrinolytic activity and increased levels of PAI was found in 44 cases. The concentration of tissue plasminogen activator antigen was decreased in 22 % of 105 cases analysed.Thus, in this material of patients with thrombo-embolic disease, abnormalities were found in 47 %. Defects in the fibrinolytic system were the most common findings. Protein C or protein S deficiency was diagnosed in less than 5 % of the cases.

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