Two Cases of Inherited Triple Deficiency in a Large Kindred with Thrombotic Diathesis and Deficiencies of Antithrombin III, Heparin Cofactor II, Protein C and Protein S

1991 ◽  
Vol 66 (03) ◽  
pp. 295-299 ◽  
Author(s):  
F Jobin ◽  
L Vu ◽  
M Lessard
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Large Family ◽  
Protein S ◽  
Type I ◽  
Heparin Cofactor Ii ◽  
First Case ◽  
Cofactor Activity ◽  
Deficiency Type

SummaryThirty-three subjects, belonging to a large family with functional antithrombin III (ATIII) deficiency (type IIa) and recurrent thromboembolism, were investigated for ATIII, heparin cofactor II (HCII), protein C (PC) and protein S (PS). We report the exceptional finding of two cases of triple deficiency: ATIII combined with HCII and PC in the first case aged 15 and ATIII combined with HCII and PS in the second case aged 27. Interestingly, both are asymptomatic thus far. Twenty-five other deficient members were found, among which seven are affected with a double deficiency. Totally, the results of our study show 38 deficiencies of four distinct antithrombotic protein: ATIII (n = 9), HCII (n = 9), PC (n = 7) or PS (n = 13). Two types of HCII deficiency were observed and type I PC deficiency was found. Functional PS deficiency was characterized by reduced levels of cofactor activity for activated PC. Our report demonstrates that combined deficiencies should be sought in a family already known to be deficient in one antithrombotic protein.

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.

PROTEIN C : ROUEN - A NEW HEREDITARY PROTEIN C ABNORMALITY WITH LOW ANTICOAGULANT BUT NORMAL AMIDOLYTIC ACTIVITIES

1987 ◽  
Author(s):  
J Y Borg ◽  
M Vasse ◽  
M Monconduit
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Protein S ◽  
Functional Assay ◽  
Type I ◽  
Functional Abnormality ◽  
Oral Anticoagulant Treatment ◽  
Crossed Immunoelectrophoresis ◽  
Deficiency Type ◽  
Hydrolysis Of

During the last three years, we could detect hereditary quantitative protein C (PC) deficiency in 43 patients belonging to 18 families. In those defects type I without oral anticoagulant treatment, the values of PC measured either by an ELISA method (PC:Ag) or by a chronometric functional assay were very closed and well correlated. (Results expressed in % of normal pooled plasmas PC:Ag m=44,l %, SD = 15,3 ; PC : activity m = 49,5, SD = 13,5 - correlation r = 0,82). In a 32 year#old man with a severe thrombo-embolic disease and in 11 related people, we could diagnose a hereditary qualitative PC deficiency type II, because of a discrepancy between normal PC:Ag levels (m = 105 %, SD = 20,3, range = 78-143) and low PC anticoagulant activities (m = 46 %, SD = 9,5, range = 30-60). FunctionalpC studies included assays, with or without preliminary adsorption on baryum citrate or aluminium hydroxide, with various PC activators (thrombin, PROTAC venom), in chronometric and amidolytic assays.(Normal protein S levelswere first tested).As shown by those results, PC activity is normal in amidolytic assays even after preliminary adsorption whatever the activation is. On the contrary, the PC anticoagulant activity is reduced in any technique. We can conclude that the activation is normal. Crossed immunoelectrophoresis (CIE) with or without calcium showed normal migration as compared to controls. Normal adsorption on insoluble salts and normal Ca-binding in CIE allow us to say that the abnormal PC is not completely acarboxylated. As amidolytic assays (normal in patients) do not assess the ability of activated PC to interact with protein S (PS) and phospholipids via calcium, 3 hypothesis can explain the functional abnormality:- abnormal binding to PS- abnormal binding to phospholipids due to partially carboxylated glutamic acids (which would be sufficient to promote adsorption)- defective inhibition of Va and Villa because a conformational change allowing only hydrolysis of little synthetic peptides.

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.

Haemostatic Studies in Carbohydrate-deficient Glycoprotein Syndrome Type I

1996 ◽  
Vol 76 (04) ◽  
pp. 502-504 ◽  
Author(s):  
A Fiumara ◽  
R Barone ◽  
P Buttitta ◽  
R Musso ◽  
L Pavone ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Protein C ◽  
Antithrombin Iii ◽  
Plasma Concentrations ◽  
Protein S ◽  
Coagulation Factors ◽  
Type I ◽  
Clotting Factors ◽  
Blood Coagulation Factors ◽  
D Dimer

SummaryCDG syndrome (CDGS) type I is the most frequent form of a group of metabolic disorders characterised by a defect of the carbohydrate moiety of glycoproteins. A large number of plasma glycoproteins, including clotting factors and inhibitors, are decreased and stroke-like episodes have been described in about half of the reported patients. We studied blood coagulation factors, inhibitors and D-dimer plasma levels in four subjects, aged 12-23 years, with CDGS type I. Factors VIII, XI, antithrombin III activity, antigen plasma levels of antithrombin III, free protein S and protein C were decreased whereas protein C as activity was normal. In addition two patients had reduction of factors II, V, VII, IX, X reflecting the phenotypic heterogeneity associated with CDGS type I. D-dimer plasma concentrations were elevated in all subjects. The hypercoagulable state as consequence of the combined deficiencies of coagulation inhibitors could contribute to the stroke-like phenomena in CDGS type I.

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.

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.

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.

Molekularbiologische Grundlagen und Diagnostik der hereditären Defekte von Antithrombin III, Protein C und Protein S

2002 ◽  
Vol 22 (02) ◽  
pp. 57-66
Author(s):  
I. Witt
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Protein S ◽  
Klinische Relevanz ◽  
At Iii

ZusammenfassungDie enormen Fortschritte in der Molekularbiologie in den letzten Jahren ermöglichten sowohl die Aufklärung der Nukleotidsequenzen der Gene für Antithrombin III (AT III), Protein C (PROC) und Protein S (PROS) als auch die Identifizierung zahlreicher Mutationen bei hereditären Defekten dieser wichtigen Inhibitoren des plasmatischen Gerinnungssystems. Da die Gene für AT III (13,8 kb) und PROC (11,2 kb) nicht groß und relativ leicht zu analysieren sind, gibt es bereits umfangreiche »databases« der Mutationen (50, 73). Für AT III sind 79 und für PROC 160 unterschiedliche Mutationen beschrieben.Sowohl beim AT-III-Mangel als auch beim Protein-C-Mangel hat die Mutationsaufklärung neue Erkenntnisse über die Struktur-Funktions-Beziehung der Proteine gebracht. Beim Protein-C-Mangel steht die klinische Relevanz der DNA-Analyse im Vordergrund, da die Diagnostik des Protein-C-Mangels auf der Proteinebene nicht immer zuverlässig möglich ist.Das Protein-S-Gen ist für die Analytik schwer zugänglich, da es groß ist (80 kb) und außerdem ein Pseudogen existiert. Es sind schon zahlreiche Mutationen bei Patienten mit Protein-S-Mangel identifiziert worden. Eine Database ist bisher nicht publiziert. Die klinische Notwendigkeit zur Mutationsaufklärung besteht ebenso wie beim Protein-C-Mangel. Es ist zu erwarten, dass zukünftig die Identifizierung von Mutationen auch beim Protein-S-Mangel beschleunigt vorangeht.

A Mutation in the Protein S Pseudogene Is Linked to Protein S Deficiency in a Thrombophilic Family

1989 ◽  
Vol 62 (03) ◽  
pp. 897-901 ◽  
Author(s):  
Hans K Ploos van Amstel ◽  
Pieter H Reitsma ◽  
Karly Hamulyák ◽  
Christine E M de Die-Smulders ◽  
Pier M Mannucci ◽  
...  
Keyword(s):  
Total Protein ◽  
Protein S ◽  
Southern Analysis ◽  
Type I ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
The Family ◽  
Dna Pattern ◽  
Deficiency Type ◽  
S Genes

SummaryProbands from 15 unrelated families with hereditary protein S deficiency type I, that is having a plasma total protein S concentration fifty percent of normal, were screened for abnormalities in their protein S genes by Southern analysis. Two probands were found to have a deviating DNA pattern with the restriction enzyme Mspl. In the two patients the alteration concerned the disappearance of a Mspl restriction site, CCGG, giving rise to an additional hybridizing Mspl fragment.Analysis of relatives of both probands showed that in one family the mutation does not co-segregate with the phenotype of reduced plasma protein S. In the family of the other proband, however, complete linkage between the mutated gene pattern and the reduced total protein S concentration was found: 12 heterozygous relatives showed the additional Mspl fragment but none of the investigated 26 normal members of the family. The mutation is shown to reside in the PSβ gene, the inactive protein S gene. The cause of type I protein S deficiency, a defect PSα gene has escaped detection by Southern analysis. No recombination has occurred between the PSα gene and the PSβ gene in 23 informative meioses. This suggests that the two protein S genes, located near the centromere of chromosome 3, are within 4 centiMorgan of each other.

Protein S mRNA in Patients with Protein S Deficiency

1995 ◽  
Vol 73 (05) ◽  
pp. 746-749 ◽  
Author(s):  
E Sacchi ◽  
M Pinotti ◽  
G Marchetti ◽  
G Merati ◽  
L Tagliabue ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Total Protein ◽  
Restriction Analysis ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Phenotypic Analysis ◽  
S Deficiency ◽  
Deficiency Type ◽  
S Genes

SummaryA protein S gene polymorphism, detectable by restriction analysis (BstXI) of amplified exonic sequences (exon 15), was studied in seven Italian families with protein S deficiency. In the 17 individuals heterozygous for the polymorphism the study was extended to platelet mRNA through reverse transcription, amplification and densitometric analysis. mRNA produced by the putative defective protein S genes was absent in three families and reduced to a different extent (as expressed by altered allelic ratios) in four families. The allelic ratios helped to distinguish total protein S deficiency (type I) from free protein S deficiency (type IIa) in families with equivocal phenotypes. This study indicates that the study of platelet mRNA, in association with phenotypic analysis based upon protein S assays in plasma, helps to classify patients with protein S deficiency.

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