Cardiopulmonary Bypass in a Patient with Factor XII Deficiency.

The performance of cardiopulmonary bypass (CPB) in the factor XII-deficient patient is challenging in that the normal method for monitoring anticoagulation is ineffective as a result of an impaired contact activation system. We report the case of a factor XII-deficient patient who underwent surgical revascularization on CPB. His factor XII level was replenished with fresh-frozen plasma immediately before surgery. This management strategy lowered the baseline activated clotting time (ACT) to near normal, providing a meaningful ACT value for CPB. Factor XII is also a key component in the fibrinolytic system and its deficiency is associated with increased thrombosis. Because the factor XII level quickly returns to baseline postoperatively, perioperative care must include strategies to avoid postoperative thromboembolic events.

Factor XII Deficiency and Cardiopulmonary Bypass.

Factor XII deficiency is a laboratory finding in patients who normally do not present with bleeding tendencies. This deficiency is important in the patient undergoing cardiopulmonary bypass because activated clotting times are not helpful in determining proper levels of heparin anticoagulation and its reversal. We present a case of a patient with factor XII deficiency that had coronary artery bypass grafting and cardiopulmonary bypass using heparin for anticoagulation. Cardiopulmonary bypass was successfully carried out by monitoring heparin concentration ensuring adequate heparinization during the procedure. Results from activated clotting time, heparin dose-response, and heparin protamine titration are given. Heparin anticoagulation in patients with factor XII deficiency can be safely carried out with heparin concentration monitoring.

Genetic analysis of a pedigree with combined factor XII and factor XI deficiency.

The objective of the present study was to identify the gene mutations of factor XI (FXI) and factor XII (FXII) in a Chinese pedigree with combined congenital FXI and FXII deficiencies. The proband was a 40-year-old woman with deficiency in both FXI (49%) and FXII (0%) activities. Blood samples from 10 other members of her family were collected and used for detection of FXI, FXII activities (FXI: C, FXII: C) and antigen levels. Genetic analysis to detect mutations in FXI, FXII genes was also performed. The proband's mother, three brothers, two sisters, her son and her daughter all have lowered FXII: C. Furthermore, her mother and one of her brothers also have lowered FXI: C. Gene sequencing for FXI in affected members revealed a heterozygous C23179T point mutation in exon 11 resulting in substitution of arginine 396 by cysteine. Gene sequencing for FXII revealed a C46T in the promoter region and a deletion mutation of two nucleotides CA at position 9160 and 9161 in exon 5. The deletion mutation can lead to frameshift mutation and premature termination of transcription in exon 6. We found a new heterozygous missense mutation in the FXI gene and a new nonsense mutation of two nucleotides deletion which caused frameshift mutation and premature termination of transcription in the FXII gene in a Chinese family with combined FXI and FXII deficiencies.

A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo.

Mice lacking factor XII (fXII) or factor XI (fXI) are resistant to experimentally-induced thrombosis, suggesting fXIIa activation of fXI contributes to thrombus formation in vivo. It is not clear whether this reaction has relevance for thrombosis in pri mates. In 2 carotid artery injury models (FeCl(3) and Rose Bengal/laser), fXII-deficient mice are more resistant to thrombosis than fXI- or factor IX (fIX)-deficient mice, raising the possibility that fXII and fXI function in distinct pathways. Antibody 14E11 binds fXI from a variety of mammals and interferes with fXI activation by fXIIa in vitro. In mice, 14E11 prevented arterial occlusion induced by FeCl(3) to a similar degree to total fXI deficiency. 14E11 also had a modest beneficial effect in a tissue factor-induced pulmonary embolism model, indicating fXI and fXII contribute to thrombus formation even when factor VIIa/tissue factor initiates thrombosis. In baboons, 14E11 reduced platelet-rich thrombus growth in collagen-coated grafts inserted into an arteriovenous shunt. These data support the hypothesis that fXIIa-mediated fXI activation contributes to thrombus formation in rodents and primates. Since fXII deficiency does not impair hemostasis, targeted inhibition of fXI activation by fXIIa may be a useful antithrombotic strategy associated with a low risk of bleeding complications.

Role of Factor XII in hemostasis and thrombosis: clinical implications.

The plasma coagulation system reacts quickly to limit blood loss from injury sites but also contributes to vascular thrombosis. In current models of hemostatic balance, normal coagulation and thrombosis represent two sides of the same coin, however, recent data from gene-deleted murine models have challenged this dogma. Deficiency of coagulation Factor XII (Hageman factor), a serine protease that initiates the intrinsic pathway of coagulation, severely impairs arterial thrombus formation but is not associated with excessive bleeding. These findings suggest that fibrin-generating mechanisms that operate during pathologic thrombus formation involve pathways distinct from those that are active during normal hemostasis. As Factor XII selectively contributes to thrombus formation in occlusive disease, but not to normal hemostasis, inhibition of this protease may offer a novel treatment strategy for prevention of arterial thrombosis with minimal or no risk of bleeding.

Fibrinolytic defects and recurrent miscarriage: a systematic review and meta-analysis.

OBJECTIVE: To systematically review evidence of the association between fibrinolytic defects and recurrent miscarriage. DATA SOURCES: MEDLINE, EMBASE, and references of retrieved articles (last update September 2006) were used. METHODS OF STUDY SELECTION: Studies comparing the prevalence of fibrinolytic defects in patients with recurrent miscarriage and control women were reviewed. Of 111 potentially relevant studies, data from 14 were integrated with meta-analytic techniques and were presented as odds ratios (ORs). TABULATION, INTEGRATION, AND RESULTS: Plasminogen activator inhibitor-1 4G/5G polymorphism (OR 1.65, 95% confidence interval [CI] 0.92-2.95) and increased plasminogen activator inhibitor activity were not significantly associated with recurrent miscarriage, although the latter showed profound heterogeneity across studies. Although factor XII C46T polymorphism is not associated with recurrent miscarriage (OR 1.07, 95% CI 0.52-2.22), factor XII deficiency is significantly associated (five studies, 1,096 women; OR 18.11, 95% CI 5.52-59.39), with minimal heterogeneity across studies. Factor XIII Val34Leu and Tyr204Phe polymorphisms were not associated with recurrent miscarriage (OR 1.24, 95% CI 0.46-3.34 and OR 2.61, 95% CI 0.45-15.16, respectively). There were no eligible studies found for the rest of the factors searched (urokinase-type plasminogen activator, tissue-type plasminogen activator, kallicrein, a2-antiplasmin, a2-macroglobulin, thrombin-activated thrombolysis inhibitor, and factor XI). Only a small minority of studies ascertained miscarriage according to specific criteria, and none of the studies provided equal examination for confounders in cases and controls. CONCLUSION: Factor XII deficiency is associated with recurrent miscarriage. Data on the other factors either fail to show association or are quite limited.

Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.

PURPOSE: We tested the hypothesis that Sotos syndrome (SoS) due to the common deletion is a contiguous gene syndrome incorporating plasma coagulation factor twelve (FXII) deficiency. The relationship between FXII activity and the genotype at a functional polymorphism of the FXII gene was investigated. METHODS: A total of 21 patients including those with the common deletion, smaller deletions, and point mutations, and four control individuals were analyzed. We examined FXII activity in patients and controls, and analyzed their FXII 46C/T genotype using direct DNA sequencing. RESULTS: Among 10 common deletion patients, seven patients had lower FXII activity with the 46T allele of the FXII gene, whereas three patients had normal FXII activity with the 46C allele. Two patients with smaller deletions, whose FXII gene is not deleted had low FXII activity, but one patient with a smaller deletion had normal FXII. Four point mutation patients and controls all had FXII activities within the normal range. CONCLUSION: FXII activity in SoS patients with the common deletion is predominantly determined by the functional polymorphism of the remaining hemizygous FXII allele. Thus, Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.

Factor XII deficiency is strongly associated with primary recurrent abortions.

OBJECTIVE: To evaluate factor XII deficiency in women with primary and secondary recurrent abortion. DESIGN: Prospective case-control study. SETTING: University hospital. PATIENT(S): Sixty-seven women with primary and 33 women with secondary recurrent abortion of unexplained nature and 49 healthy controls with no history of thrombotic disease or adverse pregnancy outcomes. MAIL OUTCOME MEASURE(S): Plasma factor XII activity, activated protein C resistance, factor V Leiden mutation analysis, protein C, protein S, antithrombin III, karyotyping, and anticardiolipin antibodies. RESULT(S): Ten of 67 women with primary recurrent abortion (14.9%) and 4 of 33 women (12.1%) with secondary recurrent abortion had reduced factor XII activity (<60%). These results are highly significant in the former group and showed a tendency toward significance in the latter group. All controls had normal factor XII activity. CONCLUSION(S): Factor XII deficiency is strongly associated with primary recurrent abortion, and women with secondary recurrent abortion show a tendency toward factor XII deficiency.

The contact system.

OBJECTIVES: To review the literature for conditions, diseases, and disorders that affect activity of the contact factors, and further to review the literature for evidence that less than normal activity of any of the contact factors may be associated with thrombophilia. DATA SOURCES: MEDLINE search for English-language articles published from 1988 to 2001 and pertinent references contained therein, as well as search of references in recent relevant articles and reviews. STUDY SELECTION: Relevant clinical and laboratory information was extracted from selected articles. Meta-analysis was not feasible because of heterogeneity of reports. DATA EXTRACTION AND SYNTHESIS: Evidence for association of altered levels of the contact factors and thrombophilia was sought. A wide variety of disorders is associated with decreased activity of the contact factors; chief among these disorders are liver disease, hepatic immaturity of newborns, the antiphospholipid syndrome, and, for factor XII, being of Asian descent. These disorders are more common than homozygous deficiency. The few series and case reports of thrombophilic events in patients homozygous for deficiency of contact factors are not persuasive enough to support causality. The apparent association between levels consistent with heterozygosity (40%-60% of normal) of any of the contact factors (but especially factor XII) in persons with antiphospholipid antibodies appears to be due to falsely decreased in vitro activity levels of these factors, which are normal on antigenic testing. The apparent association with thrombosis is better explained by the antiphospholipid syndrome than by the modest reduction of the levels of contact factors. CONCLUSIONS: Presently, it is not recommended to measure activity of contact factors during routine evaluation of patients who have suffered venous or arterial thromboembolism or acute coronary syndromes.

Combination of von Willebrand disease type 1 and partial factor XII deficiency in children: clinical evidence for a diminished bleeding tendency.

Factor XII deficiency can be associated with a thrombotic and VWF deficiency with a haemorrhagic clinical course. To study the potential influence of factor XII deficiency on bleeding tendency in patients suffering from VWD we retrospectively compared the clinical outcome of children with either an isolated factor XII deficiency, an isolated VWD, or a combination of both. Patients with the combined coagulation defect showed significantly fewer bleeding events when compared to patients with isolated VWD, although ristocetin cofactor activities were reduced to a comparable degree. As far as aPTT values are concerned, there were no significant differences among the three groups. Whether this combination of thrombophilic and haemorrhagic coagulation disorders is only coincidental or the result of an active modulation of one of the two counteracting coagulation factors is not known at present.

Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study.

The prevalence of haemostasis abnormalities was evaluated in 500 consecutive women with unexplained primary recurrent miscarriages. Two matched reference groups with no antecedent of miscarriage were studied: 100 healthy mothers and 50 childless women. In the prospective part of the study, we found 9.4% of the patients (95% C.I.: 6.8-12%) with an isolated factor XII deficiency, 7.4% of the patients (5.0-9.8%) with primary antiphopholipid antibodies, 47% of the patients (42.6-51.4%) with an insufficient response to the venous occlusion test and an isolated hypofibrinolysis was found in 42.6% (38.2-47%) of the patients (reference groups: respectively 0/150, 3/150, 2/150, p < 10(-3)). Willebrand disease, fibrinogen, deficiency, antithrombin, protein C or protein S deficiencies were not more frequent in recurrent aborters than in members of the reference groups. In the retrospective part of the study, cases of plasma resistance to activated protein C were not abnormally frequent. Patients had higher Willebrand factor antigen (vWF), tissue-type plasminogen activator antigen (t-PA), plasminogen activator inhibitor activity (PAI) and D-dimers (D-Di) than the reference women. Values of vWF, t-PA, PAI and D-Di were altogether correlated but were not related to C-reactive protein concentrations. Among patients, those with an antiphospholipid syndrome and those with an insufficient response to the venous occlusion test had higher vWF, t-PA, PAI and D-Di values than the patients with none of the haemostasis-related abnormalities. Thus, factor XII deficiency and hypofibrinolysis (mainly high PAI) are the most frequent haemostasis-related abnormalities found in unexplained primary recurrent aborters. In patients with antiphospholipid antibodies or hypofibrinolysis, there is a non-inflammatory ongoing chronic elevation of markers of endothelial stimulation associated with coagulation activation. This should allow to define subgroups of patients for future therapeutic trials.

Clinical implications of factor XII deficiency.

A patient with known factor XII deficiency underwent extraction of four impacted third molars. Significant preoperative laboratory values included a partial thromboplastin time (PTT) of greater than 100 seconds and a factor XII level of less than 1%. The third molars were removed without any significant intraoperative or postoperative bleeding. Factor XII not only has an important function in the initiation of the intrinsic pathway of the coagulation cascade, but it also plays a significant role in complement activation, kinin generation, and fibrinolysis. It would seem that a deficiency in this factor would have widespread clinical implications. In fact, the only clinical significance seems to be a predisposition to thromboembolism in factor XII deficient patients.

The contact activation system: biochemistry and interactions of these surface-mediated defense reactions.

This review is intended to be a critical state-of-the-art overview of the activation and inhibition of the proteins (factor XII, prekallikrein, high molecular weight kininogen, and factor XI) of the contact phase of coagulation. Specifically, this review will reconsider the concept of the reciprocal activation of the proteases of the contact phase of coagulation, factor XII, and prekallikrein, in light of much recent evidence indicating that factor XII, itself, autoactivates when associated with negatively charged surfaces. In addition, the mechanisms for amplification of activation of the proteins of the contact phase of coagulation will be discussed from the pivotal role of high molecular weight kininogen, or one of its altered forms, serving as a cofactor to order the activation of the zymogens it is associated with. The role and relative importance of each of the naturally occurring plasma protease inhibitors (C1-inhibitor, alpha-2-macroglobulin, alpha-1-antitrypsin, antithrombin III, and alpha-1-antiplasmin) will be assessed as they relate to the dampening of contact phase activation. Finally, the contact phase of coagulation activation will be discussed not only as a plasma proteolytic mechanism, but also as it interacts with platelets.

The hypercoagulable states.

Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are associated with an increased risk of thrombosis (prethrombotic states) or if they have recurrent thrombosis without recognizable predisposing factors (thrombosis-prone). The number of specific primary hypercoagulable states that are recognized is growing. These disorders are generally inherited abnormalities of coagulation in which a physiologic anticoagulant mechanism is defective: for example, antithrombin III deficiency, protein C and protein S deficiency, abnormalities of the fibrinolytic system, and dysfibrinogenemias. Secondary hypercoagulable states are generally acquired disorders in patients with underlying systemic diseases or clinical conditions known to be associated with an increased risk of thrombosis: for example, malignancy, pregnancy, use of oral contraceptives, myeloproliferative disorders, hyperlipidemia, diabetes mellitus, and abnormalities of blood vessels and rheology. The complex pathophysiologic features of these secondary hypercoagulable states are discussed, and a framework is provided for the laboratory investigation and systematic clinical approach to the patient.

PIP: This review describes recent advances in understanding the pathophsiologic basis of the hypercoagulable states and presents a framework for a systematic clinical approach to patients. Hypercoagulability is broadly defined as encompassing 2 clinical situations: 1) the presence of laboratory abnormalities or clinical conditions considered to be associated with an increased risk of thromboembolic complications (prethrombotic states) and 2) recurrent thrombosis in patients with no recognizable predisposing factors (thrombosis-prone patients). Primary hypercoagulable states are generally inherited abnormalities in which a physiologic anticoagulant mechanism is defective (eg antithrombin III deficiency). Secondary hypercoagulable states are generally acquired disorders in patients with underlying systemic diseases or clinical conditions such as pregnancy or use of oral contraceptives that are known to be linked to an increased risk of thrombosis. Laboratory testing should be directed at the diagnosis of a specific primary or secondary hypercoagulable state. Among the factors that may indicate a primary hypercoagulable state are a family history of thrombosis, recurrent thrombosis without apparent precipitating factors, thrombosis at unusual anatomic sites, thrombosis at an early age, and resistance to conventional antithrombotic therapy. Testing should also be directed at identifying any underlying systemic disorder since treatment may improve the thrombotic tendendy.

The "contact system" in health and disease.

In the last 10 years, our understanding of the contact system, particularly its biochemistry, has greatly increased. The components of this system and their interactions have been elucidated from in vitro experiments. Although the activation of the contact system have been implicated in various types of human disease, in only a few instances is its role clearly defined. The physiologic role of the contact system is totally unknown at present. Obviously, more studies are needed to bridge a big gap between in vitro observations and in vivo phenomena.

[Factor XII (HAGEMAN FACTOR)]. / Der Faktor XIII (Hageman-Faktor).

The discovery of factor XII (Hageman factor), the attempts of characterizing it, the knowledge of its presence of absence in the various vertebrate classes are represented in a survey and recent opinions of molecular biology about its structure and composition are discussed. The effect of the activating substances for transferring the Hageman factor into its active form are represented with the role of the pre-kallikrein (Fletcher factor) and of the highly molecular kininogen (Fitzgerald factor) being referred to. Furthermore, the following systems influenced by factor XII are dealt with: 1. The endogenous and exogenous activating system of blood clotting and possible reasons for lower bleedings with factor XII deficiency. 2. Role of the Hageman factor in activating fibrinolysis. 3. Influence on the liberation of kinin. 4. Correlations towards the complement system. 5. Possible inhibitory effect of platelet aggregation. Finally the close connection of all these systems is referred to and the necessity of considering these complicated events in a complex way is stressed.