Definition of the Bleeding Tendency in Factor XI-Deficient Kindreds–A Clinical and Laboratory Study

1995 ◽  
Vol 73 (02) ◽  
pp. 194-202 ◽  
Author(s):  
P H B Bolton-Maggs ◽  
D A Patterson ◽  
R T Wensley ◽  
E G D Tuddenham
Keyword(s):  
Convincing Evidence ◽  
Factor Vii ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Excessive Bleeding ◽  
North West ◽  
Factor Xi Deficiency ◽  
History Analysis ◽  
Definition Of ◽  
Von Willebrand

SummaryIndividuals with severe factor XI deficiency are prone to excessive bleeding after injury or surgery, but the existence of a haemorrhagic tendency in partial factor XI deficiency is controversial. In this study, 172 members of 30 kindreds (20 non-Jewish) transmitting factor XI deficiency in North West England were interviewed and a bleeding history questionnaire completed. Blood was taken for coagulation assays. The questionnaires were categorised independently by two assessors to determine presence or absence of a bleeding tendency, in the absence of information about the factor XI level or family history. Analysis shows that 48% of heterozygotes have a bleeding tendency. Eighteen (60%) families came to attention because of bleeding problems in heterozygotes. Comparison of histories between partially deficient and non-deficient individuals demonstrated a higher incidence of menstrual problems, an increase in significant bruising, and an increased likelihood of excessive bleeding after tonsillectomy and dental extractions.The incidence of von Willebrand’s disease was not increased, but individuals with heterozygous factor XI deficiency who were bleeders tended to have lower levels of factor VIIIc and von Willebrand factor, and were more commonly of blood group 0. These features may contribute to the bleeding tendency. There was no evidence of alteration in factor VII activity (as defined by the ratio of activity to antigen) between the bleeders and non-bleeders.This is convincing evidence for abnormal bleeding in factor XI deficiency which is not confined to severely deficient patients.

Coagulation Abnormalities in Patients with Noonan Syndrome - a Single Centre Case Series.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1035-1035
Author(s):  
Jayson M. Stoffman ◽  
Bernard N. Chodirker ◽  
Sara J. Israels
Keyword(s):  
Platelet Aggregation ◽  
Noonan Syndrome ◽  
Case Series ◽  
Protein S ◽  
Bleeding Tendency ◽  
Thrombin Time ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Coagulation Abnormalities ◽  
Von Willebrand

Abstract Noonan syndrome (NS) is an autosomal dominant disorder that includes short stature, characteristic facies, congenital heart defect, webbed neck, and developmental delay. A mutation in the PTPN11 gene can be identified in 50% of patients. A bleeding tendency is included in the phenotypic spectrum, with factor XI deficiency and platelet abnormalities described most frequently. At Winnipeg’s Health Sciences Centre, 24 patients with features typical of NS have been studied by the Special Haemostasis Laboratory. Four patients in whom the diagnosis was suspected but not considered definite are also included in this analysis. Clinical complaints included easy bruising (9), epistaxis (2), menorrhagia (1), and a family history of bleeding problems (3). Sixteen patients were referred for investigation following the diagnosis of NS. All 28 patients had coagulation screening tests: 16 patients had an abnormal PT and 12 had an abnormal aPTT. Thrombin time was slightly prolonged in 6 of 23 patients. Reptilase time was normal in 8 patients, and fibrinogen concentration was normal in 20 patients. Factor XI levels were measured in 14 patients, with a mean value of 62% (range 32–99%). Only 2 patients had levels below the normal range. One of 13 patients evaluated for FXII levels was deficient (FXII 25%), and 2 of 19 patients evaluated for FIX levels had mild FIX deficiency (FIX 40 and 49%) without symptomatic bleeding. No other factor deficiencies were identified. Twenty-four patients had determinations of von Willebrand Factor antigen and activity; 2 had results consistent with mild Type 1 von Willebrand Disease. Platelet aggregation studies were done in 22 patients. A variety of abnormalities were noted, with the most frequent being abnormal aggregation with epinephrine (7/22). Dense granule number was decreased in 2 of 7 samples studied by electron microscopy. Lupus anticoagulants were detected in 3 of 13 patients screened. Thrombophilia investigations in 4 patients detected decreased protein S in one patient who had been diagnosed previously with protein S deficiency. This unselected case series, the largest reported to date in the literature, illustrates the heterogeneity of coagulation abnormalities that may occur in NS. Symptoms, when present, were mild, and often did not correlate with laboratory abnormalities. Non-specific platelet aggregation defects were the most commonly identified abnormalities. In contrast to the literature, factor XI deficiency was not prevalent. A specific etiology for the variable bleeding tendency has not yet been identified in NS.

The Effect of Combined Factor XI Deficiency with von Willebrand Factor Abnormalities on Haemorrhagic Diathesis

1990 ◽  
Vol 63 (01) ◽  
pp. 036-038 ◽  
Author(s):  
Shulamith Tavori ◽  
Benjamin Brenner ◽  
llana Tatarsky
Keyword(s):  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Haemorrhagic Diathesis ◽  
Von Willebrand’S Factor ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

SummaryTo account for the lack of correlation between the level of factor XI (FXI) in deficient patients and haemorrhagic manifestations, we correlated the prevalence of combined FXI and von Willebrand’s factor (vWF) deficiency in 212 FXI-deficient patients. Fifty-four patients had a combined FXI and vWF deficiency: 16 patients had severe and 38 patients had mild FXT deficiency. In a group of 28 patients with comparably mild FXI deficiency, 14 bleeders had significantly lower mean vWF, Ag, ristocetin cofactor and ristocetin induced platelet aggregation than 14 non-bleeders selected on the basis of comparable FXI levels. These findings suggest that the combination of FXI and vWF deficiency is common and may affect the bleeding tendency in mild FXI deficiency.

Production and Therapeutic Use of a Factor XI Concentrate from Plasma

1992 ◽  
Vol 67 (03) ◽  
pp. 314-319 ◽  
Author(s):  
P H B Bolton-Maggs ◽  
R T Wensley ◽  
P B A Kernoff ◽  
C K Kasper ◽  
L Winkelman ◽  
...  
Keyword(s):  
Parvovirus B19 ◽  
Virus Transmission ◽  
Liver Function Tests ◽  
Fresh Frozen Plasma ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Excessive Bleeding ◽  
Human Donor ◽  
Factor Xi Deficiency ◽  
The Mean

SummaryFactor XI deficiency is an uncommon bleeding disorder usually manifested by excessive bleeding after surgery or trauma. Until recently the only effective therapy has been fresh-frozen plasma (FFP) infusion. We describe the efficacy and safety of a new factor XI concentrate produced from human donor plasma by a modification of the method used for antithrombin III concentrate. The mean recovery of factor XI in the circulation measured on 62 occasions was approximately 91% of the injected dose, and the mean half-disappearance-time was 52 h. The concentrate was used for 31 invasive procedures in 30 patients, including 16 patients who had a definite bleeding tendency on previous occasions, with normal haemostasis being achieved in all but 1. Only 1 patient (previously experiencing allergy to FFP) experienced adverse effects during infusion. Monitoring of liver function tests and viral antibody status in suitable patients has shown no evidence of transmission of hepatitis viruses, HIV-1 or parvovirus B19.We conclude that this concentrate provides effective treatment for patients with factor XI deficiency. Preliminary results suggest safety from virus transmission, but this needs to be established in further studies of previously untreated patients.

scholarly journals The Thrombogram in Rare Inherited Coagulation Disorders: Its Relation to Clinical Bleeding

2002 ◽  
Vol 88 (10) ◽  
pp. 576-582 ◽  
Author(s):  
Raed Al Dieri ◽  
Flora Peyvandi ◽  
Elena Santagostino ◽  
Muriel Giansily ◽  
Pier Mannuccio Mannucci ◽  
...  
Keyword(s):  
Lag Time ◽  
Peak Height ◽  
Factor Vii ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Factor Xi ◽  
Factor Concentration

SummaryWe investigated the relation between clotting factor concentration, the parameters of the thrombin generation curve (the thrombogram) and the severity of clinically observed bleeding in patients with congenital deficiency of prothrombin (n = 21), factor V (n = 22), factor VII (n = 22), factor X (n = 10), factor XI (n = 7) and factor XII (n = 6). The parameters used were: area under the curve (endogenous thrombin potential, ETP), peak concentration of thrombin attained and lag time before manifest formation.Peak height and ETP varied linearly with the concentration of prothrombin. For the other factors these parameters hyperbolically approached to the 100% limit with increasing clotting factor concentration. Half normal ETP was seen at about the following concentrations: prothrombin (50%), factor V (1%), factor VII (2%), factor X (5%) and factor XI (1%). As a rule, the peak height was somewhat more sensitive to clotting factor decrease than the ETP was.In all the patients with severe bleeding symptoms the ETP was less than 20% of normal. Bleeding tendency was absent or mild in patients with an ETP of 30% or higher. This value (except for prothrombin) is already obtained at concentrations of clotting factor of 1%-2%, which corroborates the clinical observation that a severe bleeding tendency is only seen in severe clotting factor deficiencies (less than 1%). The one exception was a patient with factor VII deficiency and severe bleeding, who showed a normal ETP value, albeit with a decreased peak height and a prolonged lag-time.

The Use of Factor XI Concentrates (Hemoleven, LFB) in Patients with Congenital Factor XI Deficiency and a Known Bleeding Tendency.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1796-1796
Author(s):  
Vickie McDonald ◽  
Savidge F. Geoffrey ◽  
Savita Rangarajan ◽  
Mike Mitchell
Keyword(s):  
Fresh Frozen Plasma ◽  
Incidence Rates ◽  
Treatment Modalities ◽  
Bleeding Tendency ◽  
Normal Range ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Unit Dose ◽  
The Mean ◽  
Congenital Factor

Abstract Traditional treatment modalities for FXI deficiency (UK prevalence 400 cases) include antifibrinolytics, desmopressin, fresh frozen plasma (FFP) and FXI concentrates but there has been reluctance to use FXI concentrates because of reported incidence rates of thrombosis up to 10%. Concerns over the safety and efficacy of FFP, with additional viral inactivation steps possibly leading to reduced FXI recoveries, have led us to increase our use of FXI concentrates. We aimed to assess the indications, dosage, recovery, efficacy and safety of Hemoleven, a plasma derived, purified and virally inactivated FXI concentrate, which also contains heparin and antithrombin, in patients with congenital factor XI deficiency. A retrospective study was performed using hospital notes and laboratory records of all patients who had received Hemoleven over a 2-year period. Eleven patients (6 male, 5 female) had been treated with a median age of 38 years (range 7–74) and mean baseline FXI:C levels of 25.4U/dl (3–50). All patients received Hemoleven as prophylaxis for surgery or dental work and had all previously had excess bleeding when surgically challenged. One patient died of a condition unrelated to FXI treatment. Pre- and post-FXI:C levels were available for a total of 60 treatment episodes of which 25 were 1000-unit doses and 35 were 2000-unit doses. The mean increase in FXI:C per 1000-unit dose was 25.4 U/dl (12.4–43.9) while the mean increase in FXI:C per 2000-unit dose was 50.5 U/dl (11.8–106.5). This is consistent with the manufacturer’s data. Ten minute post infusion FXI:C levels were above the normal range (73–133 U/kg) in 8% of patients given 1000 units and 11% of patients given 2000 units but below the normal range in 24% of patients who received 1000 units and 20% of patients who received 2000 units. 90% of treatment episodes led to FXI:C levels above the usual treatment target of 65 U/dl. Genetic analysis of 9/11 patients showed that 2 were homozygous (one type II and one type III), 6 were heterozygous for other recognised mutations and one had no mutation identified but apparent absence of RNA from one allele demonstrated in a relative by qRT-PCR. No excess bleeding or inhibitor development was recorded even in one patient who had had a poor haemostatic response with FFP. There were no episodes of arterial or venous thrombotic complications within this group and no clinical or laboratory evidence of DIC following treatment. In summary, treatment with factor XI concentrates gave consistent increments in FXI:C at the doses given and achieved good haemostasis with no episodes of thrombosis in this study, even in patients over the age of 60y. While the risk of prion transmission is still unknown, use of FXI concentrates is not associated with the risks of fluid overload and TRALI that are seen with FFP. We acknowledge that the study includes small numbers of patients however the cohort of patients with a bleeding diathesis in this condition is small. We conclude that Hemoleven appears to be an effective and reliable treatment for patients with FXI:C deficiency but should be given in the context of FXI:C level monitoring in order to detect those patients who may develop high levels and possible thrombosis.

A G>A Transition in the Non-Coding Exon 1 of the Factor XI Gene as the Cause of Factor XI Deficiency in Three Afro-Caribbean Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1788-1788
Author(s):  
Michael J. Mitchell ◽  
Letian Dai ◽  
Anwar Alhaq ◽  
Geoffrey F. Savidge
Keyword(s):  
Base Change ◽  
Clinical Severity ◽  
Molecular Defect ◽  
Polymorphism Analysis ◽  
Bleeding Tendency ◽  
Translation Efficiency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Plasma Factor ◽  
Exon 1

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of 9%, associated with two common founder mutations E117X (Type II) and F283L (Type III). However, factor XI deficiency is found in all ethnic groups, with causative mutations being highly heterogeneous - mutations having been described in all exons with the exception of the non-coding exon 1. In a study of >120 ethnically diverse factor XI deficient patients, three patients of Afro-Caribbean origin were found to be heterozygous for a G>A transition at nucleotide −53 within exon 1 of the factor XI gene. All three patients showed a low FXI:C on at least 3 different occasions (SM[female] 44.3–57.1, AB[female] 42.3–51.2 and GA[male] 70.3–72.9, Range 76–136u/dl). The 2 female patients were both reported to have a lupus anticoagulant which may explain the lower levels seen, although a lupus screen was negative. No variation within the coding sequence of the factor XI gene was detected. Two of the patients were heterozygous for the −403 G>T promoter polymorphism, whilst the remaining patient was homozygous for the −403 T allele and heterozygous for the −273 C>G polymorphism. Analysis of >50 factor XI alleles in patients of Afro-Caribbean origin failed to detect this base change in individuals with normal factor XI levels. Purine-rich sequences, such as that in exon 1 affected by the −53 G>A substitution, are known to form extremely stable minihairpin loops. These sequences /structures have been shown to be important as splicing enhancers and in mRNA stability, particularly in making them more resistant to nucleases. Within the 5′ untranslated region (5′-UTR) of genes they have been demonstrated to be important in modulating translation efficiency. The -53 G>A substitution is located just 10 bases prior to the start of the factor XI mRNA and any of these mechanism could potentially explain the causative nature of this change. The -53 G>A substitution is predicted to cause ‘slippage’ within the postulated minihairpin loop, potentially making it unstable. Further work is on-going to try and prove and explain the causality of this mutation. We speculate that the -53 G>A base change affects the normal processing of factor XI mRNA and, possibly in combination with the promoter polymorphisms, results in a mildly reduced plasma factor XI level.

Correlation of a Condensed Bleeding Score with New Diagnosis of a Congenital Bleeding Disorder in Patients Referred to a Tertiary Centre

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1226-1226
Author(s):  
Deepa Ranjani Jayakody Arachchillage ◽  
Tina Biss ◽  
John Hanley ◽  
Kate Talks
Keyword(s):  
Laboratory Tests ◽  
Conflicts Of Interest ◽  
Bleeding Disorder ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Number Of Patients ◽  
Abnormal Bleeding ◽  
Bleeding Score

Abstract Abstract 1226 The performance and utility of a condensed bleeding score (Bowman et al, J Thromb Haemost., 2008;6:2062) in relation to the diagnosis of a congenital bleeding disorder in new referrals to a regional haemostasis clinic over an 8 month period is presented. Between November 2010 and June 2011, 50 patients over the age of 16 (median age, 31 years; range, 16–79), including 32 females, were referred for investigation of a possible congenital bleeding disorder following detection of abnormal coagulation results and/or presentation with a bleeding history. A bleeding score was performed as part of their initial assessment. 12(24%) patients were from local referral and 38(76%) patients were referred from other hospitals in the region for further investigation of a suspected bleeding disorder. Basic coagulation tests (activated partial thromboplastin time (APTT), prothrombin time Clauss fibrinogen and platelet count) were normal in the referred patients from other centres. 50% (6/12) of the local referrals were for investigation of a prolonged APTT detected on routine coagulation screening prior to major surgery. The median bleeding score was 6 with a range of −1 to 14 (Table 1). The presence of a congenital bleeding disorder was confirmed in 31 of the 50 patients (62%), including 19/31 (61%) of the female patients and 12/31(39%) of the males. Correlation of an abnormal bleeding score (score ≥ 4) with diagnosis of a congenital bleeding disorder was only seen for diagnosis of type 1 Von Willebrand Disease (VWD) (Table 2). Analysis of the cases with low scores and abnormal results identified two groups of patients; firstly, those who had not yet had a significant haemostatic challenge, and secondly, those in whom the abnormal coagulation results were explained by a non-haemostatically significant reduction in a coagulation factor level (e.g. FVII, 15%; dysfibrinogenaemia; F XII deficiency). These clinically insignificant laboratory abnormalities explain the discrepancy between the number of patients with abnormal laboratory tests (35) and the number of patients diagnosed with a congenital bleeding disorder (31).Table 1Bleeding score (range)Number of patients with normal lab resultsNumber of patients with abnormal lab results−1 to +1382–44105–74128–102311–1422Total1535Table 2DiagnosisNumber of patientsMedian bleeding scoreAge rangeType 1 VWD116 (4–10)17–51Type 2 VWD48 (5–13)17–36Factor XI123 (1–8)17–76Platelet function defect46 (2–9)17–57 Compared to previous reports the range of scores found with this assessment tool was narrow and could not exclude patients from further laboratory assessment. However the condensed bleeding score has only been validated prospectively for the diagnosis of type 1 VWD and all patients in this cohort who were diagnosed with type 1 VWD had an abnormal bleeding score (≥ 4). This observation supports the role of this scoring system in the assessment of patients for type 1 VWD. The use of the condensed bleeding score in assessing patients with suspected factor XI deficiency is difficult due to the lack of a phenotypic relationship between residual factor XI activity and a bleeding tendency. Furthermore, although factor XI deficiency is a rare congenital bleeding disorder in our cohort of patients 12/31(39%) were diagnosed with factor XI deficiency. This may explain the overall lack of correlation between bleeding score and diagnosis of a congenital bleeding disorder. Patients who have an abnormal bleeding score but normal laboratory tests need consideration of further investigations before concluding they are normal. The possibility of an acquired bleeding disorder should be considered. A thorough drug history is also important as one of the patients with a bleeding score of 14 was taking a non-steroidal anti-inflammatory drug. The use of the condensed bleeding score in the detection of congenital bleeding disorders other than type 1 VWD requires further validation in a larger number of patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1314-1319
Author(s):  
PM Mannucci ◽  
KA Bauer ◽  
E Santagostino ◽  
E Faioni ◽  
S Barzegar ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Activated Factor Vii ◽  
Before And After ◽  
Post Infusion ◽  
Secondary Hyperfibrinolysis

Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.

Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1314-1319 ◽  
Author(s):  
PM Mannucci ◽  
KA Bauer ◽  
E Santagostino ◽  
E Faioni ◽  
S Barzegar ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Activated Factor Vii ◽  
Before And After ◽  
Post Infusion ◽  
Secondary Hyperfibrinolysis

Abstract Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.

scholarly journals Factor IX is activated in vivo by the tissue factor mechanism

Blood ◽  
1990 ◽  
Vol 76 (4) ◽  
pp. 731-736 ◽  
Author(s):  
KA Bauer ◽  
BL Kass ◽  
H ten Cate ◽  
JJ Hawiger ◽  
RD Rosenberg
Keyword(s):  
Tissue Factor ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor Xii ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Factor Ixa ◽  
Coagulant Activity ◽  
The Mean

Abstract Despite significant progress in elucidating the biochemistry of the hemostatic mechanism, the process of blood coagulation in vivo remains poorly understood. Factor IX is a vitamin K-dependent glycoprotein that can be activated by factor XIa or the factor VII-tissue factor complex in vitro. To investigate the role of these two pathways in factor IX activation in humans, we have developed a sensitive procedure for quantifying the peptide that is liberated with the generation of factor IXa. The antibody population used for the immunoassay was raised in rabbits and chromatographed on a factor IX-agarose immunoadsorbent to obtain antibody populations with minimal intrinsic reactivity toward factor IX. We determined that the mean level of the factor IX activation peptide (FIXP) in normal individuals under the age of 40 years was 203 pmol/L and that levels increased significantly with advancing age. The mean concentration of FIXP was markedly reduced to 22.7 pmol/L in nine patients with hereditary factor VII deficiency (factor VII coagulant activity less than 7%) but was not significantly different from normal controls in nine subjects with factor XI deficiency (factor XI coagulant activity less than 8%). These data indicate that factor IXa generation in vivo results mainly from the activity of the tissue factor mechanism rather than the contact system (factor XII, prekallikrein, high molecular-weight kininogen, factor XI). Our results may also help to explain the absence of a bleeding diathesis in many patients with deficiencies of the contact factors of coagulation.

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