Factor XII Deficiency in Mexico: High Prevalence in the General Population and Patients with Venous Thromboembolic Disease.

INTRODUCTION: Thrombosis is one of the leading causes of morbidity and mortality worldwide. Venous thromboembolic disease (VTD) is considered a new epidemic. FXII deficiency is supposed to be a cause of thrombosis. To search for unknown causes of thrombosis in our population, our aim was to determine if FXII deficiency can be considered a risk factor for VTD. METHODS: Young adult Mexican patients with at least one VTD episode and healthy controls were included in this prospective, observational, controlled study. Liver and renal function tests, blood cytometry, and blood coagulation assays were performed. Plasma FXII activity and its concentration were evaluated. RESULTS: Over a two-year period, 250 patients and 250 controls were included. FXII activity was significantly lower in the control group compared to patients with VTD (p = 0.005). However, percentage of patients and controls with FXII deficiency was 8.8 and 9.2%, respectively (p = 1.000). No significant association was found between FXII deficiency and VTD (p = 1.0). FXII plasma concentration was lower in controls vs. patients with VTD: 4.05 vs. 6.19 ng/mL (p <0.001). Percentage of patients with low FXII plasma concentration was 1.6% and 6.0% in patients and controls, respectively (p = 0.010). CONCLUSIONS: FXII deficiency is a frequent finding in patients with VTD and controls in Mexico. Some patients with FXII deficiency had normal APTT result, an effect not described above. FXII plasma concentration was lower in patients with low activity.

Homozygous missense variant F12 (Gly506Asp) associated with severe factor XII deficiency: a case report.

BACKGROUND: Factor XII deficiency can be related to either homozygous or compound heterozygous pathogenic variants in the F12 gene. The disease is commonly known as Hageman trait and is inherited in both autosomal recessive or dominant patterns. Clinically, factor XII deficiency is not associated with bleeding but conversely has been linked to thrombotic events, recurrent pregnancy loss, and hereditary angioedema. Molecular data of F12 deficiency are scarce and have revealed varying results between cases. However, most of the reported variants are missense mutations, gross deletions, or small insertion. Factor XII deficiency has been reported in the Saudi population in several studies, either as isolated case reports or included within the studies of rare bleeding factors deficiency. However, molecular data are lacking as no case report of genetic studies related to factor XII deficiency has been published in our local population, to the best of our knowledge. CASE REPORT: Herein we describe a homozygous missense variant involving exon 12 within F12 gene (5:176,830,269 G>A; p.Gly506Asp) in a 36-year-old Saudi multiparous female referred from the surgical clinic with significantly high activated partial thromboplastin time during preoperative assessment for sleeve gastrectomy. The patient had no history of bleeding episodes during the previous deliveries nor any tooth extractions. She had single event of spontaneous abortion during the 15th week of gestation without any bleeding complication. There was no history of thrombosis or skin manifestations, and she was not taking any medicines. There was no family history of bleeding or thrombosis. Family history revealed consanguinity as the parents are first-degree cousins. Physical examination was unremarkable. Upon investigation, the prolonged activated partial thromboplastin time was fully corrected by a 1:1 mixing study with normal pool plasma while lupus anticoagulant tests were negative. Factor assays and von Willebrand factor tests are all within normal ranges except for factor XII, which was severely deficient. A homozygous missense variant involving exon 12 within F12 gene (5:176,830,269 G>A; p.Gly506Asp) was identified. CONCLUSION: F12 (5:176,830,269 G>A; p.Gly506Asp) variant is likely to be a pathogenic variant among homozygous factor XII-deficient patients. Genetic counseling and management of the patients and families should be based on clinical evaluation.

Incidence of factor XII deficiency in critically ill patients with a prolonged activated partial thromboplastin time: a prospective observational study.

Limited data is available on factor XII deficiency in critically ill patients with prolonged activated partial thromboplastin time (aPTT). The association of factor XII deficiency with an increased risk of thromboembolism is unclear. This prospective observational study assessed the incidence of factor XII deficiency among critically ill patients with prolonged aPTT (>40 s), whether factor XII deficiency manifesting as prolonged aPTT was associated with an increased risk of thromboembolism, and clotting time on a viscoelastic (ROTEM) test was useful to predict factor XII deficiency. Of the 40 included patients, 48% [95% confidence interval (CI) 33-63) had a factor XII deficiency (mean ±â€Šstandard deviation of factor XII level of all patients: 54% ±â€Š29%). Factor XII levels were not significantly correlated with the measured aPTT ( r  = -0.163, P  = 0.315). Factor XII deficiency was significantly more common in patients who were less critically ill ( P  = 0.027), but it was not significantly related to Disseminated Intravascular Coagulation scores ( P  = 0.567). The incidence of symptomatic venous thromboembolism ( P  = 0.246), allogeneic blood transfusion ( P  = 0.816), and hospital mortality ( P  = 0.201) were not significantly different between those with and without factor XII deficiency. The clotting time on the viscoelastic test was not predictive of factor XII deficiency (area under the receiver-operating characteristic = 0.605, P  = 0.264). Factor XII deficiency was common in critically ill patients with a prolonged aPTT. There was no association between factor XII deficiency and risk of thromboembolism. The clotting time on ROTEM was not predictive of the presence of factor XII deficiency.

A Novel Homozygous Missense Mutation (Ile583Asn) in a Consanguineous Marriage Family with Hereditary Factor XII Deficiency: A Case Report.

BACKGROUND: Hereditary coagulation factor XII (FXII) deficiency is an autosomal recessive disorder. At present, the contribution of severe FXII deficiency to the development of thromboembolism is still undetermined. There are limited reports on the relationship between the FXII defect and thromboembolism. CASE PRESENTATION: A 27-year-old woman came to our hospital for the treatment of shoulder trauma and cervical disc herniation caused by a car accident. The shoulder trauma was treated with five stitches. After physical examination, imaging examination, and routine coagulation examination, cervical disc herniation was treated conservatively. Combined with the examination results, the patient was diagnosed with FXII deficiency. Unfortunately, the patient was readmitted 10 days after the trauma with edema in the lower limbs and secondary varicose veins. The D-dimer increased to 6.22 mg/L. Thrombus in the inferior vena cava and right common iliac was shown by lower limb venography. According to the patient's medical history, the F12 gene was analyzed by direct sequencing. The patient was also screened for other thrombotic risk factors. Genetic analysis showed that the patient had a c.1748T > A (p.Ile583Asn) homozygous missense mutation in exon 14 of the F12 gene. No other hereditary thrombophilia risk factors screened were positive in the patient. CONCLUSION: The p.Ile583Asn missense mutation in exon 14 of the F12 gene might be responsible for the reduction of the FXII level in the patient.

An unanticipated prolonged baseline ACT during cardiac surgery due to factor XII deficiency.

Factor XII (FXII) deficiency is a congenital disorder inherited as an autosomal recessive condition. In his heterozygous form, it is relatively common in the general population. However, a total absence of FXII as seen in homozygous patients, is rare, with an incidence of approximately 1/1,000,000 individuals. Surprisingly, FXII deficiency is rather associated with thromboembolic complications. Patients do not experience a higher risk of surgical bleeding despite a markedly prolonged activated partial thromboplastin time. Given its low incidence in the general population, the finding of an unknown FXII deficiency is rare during cardiac surgery. This unique case describes a patient with an unanticipated prolonged baseline activated clotting time (ACT) during cardiac surgery in which his bleeding history and rotational thromboelastometry tracings lead us to the diagnosis of a FXII deficiency. The finding of a hypocoagulable INTEM tracing and a concurrent normal EXTEM tracing in a sample of a patient with prolonged ACT and adverse anamnestic bleeding history should prompt clinicians to consider a FXII deficiency. It may help clinicians in further perioperative management where there is not enough time to wait for the results of individual coagulation factor testing.

Cardiopulmonary bypass in a child with severe Factor XII deficiency.

Factor XII (FXII) deficiency presents as a prolonged activated partial thromboplastin time (aPTT) but is not associated with clinically significant bleeding. Activated clotting time (ACT) is used routinely to monitor anticoagulation with unfractionated heparin in patients undergoing cardiopulmonary bypass (CPB). The coagulation activator reagents in most ACT tests are dependent on adequate FXII concentrations to initiate contact factor coagulation pathways. We report the case of a 14.7 kg girl undergoing CPB with a pre-admission FXII concentration of <1% and aPTT >200 seconds. The child was transfused with fresh-frozen plasma to replenish FXII, allowing safe ACT monitoring of heparin anticoagulation throughout CPB.

The Standard Point-of-Care Hemochron Jr. ACT+ Test in Monitoring Heparin Administration for Cardiopulmonary Bypass in Severe Factor XII Deficiency.

Coagulation factor XII (FXII) is a plasma serine protease that belongs to the contact activation complex responsible for initiating the intrinsic coagulation pathway. FXII deficiency is a rare congenital disorder that is not associated with an increased tendency for bleeding. However, as contact activation is impaired in FXII deficiency, both the celite- and kaolin-initiated activated clotting time (ACT) measurements are prolonged markedly, which poses a challenge for anticoagulation monitoring in patients undergoing cardiac surgery. The authors successfully have used the standard Hemochron Jr. ACT+ test, which is activated by silica and phospholipid in addition to kaolin, to monitor anticoagulation for cardiopulmonary bypass in two patients with severe FXII deficiency. The ACT+ test showed low baseline values, increased adequately in response to heparin, and decreased to baseline after protamine. Importantly, there was no abnormal intra- or postoperative bleeding nor any thrombotic complications. Furthermore, in vitro dose-response ACT+ testing of FXII-deficient blood with increasing heparin concentrations supports the use of ACT+ in FXII deficiency.

Amelioration of Cognitive and Behavioral Deficits after Traumatic Brain Injury in Coagulation Factor XII Deficient Mice.

Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.

Factor XII (Hageman Factor) Deficiency: a rare harbinger of life threatening complications.

Hageman factor (factor XII) has a key role in activation of intrinsic coagulation system gauged by activated partial thromboplastin time (aPPT). Hageman factor deficiency is more often an autosomal recessive condition, but an autosomal dominant inheritance is also reported. This condition in its own is not known to cause bleeding complications rather is associated with paradoxical fatal thromboembolic complications. Exact prevalence of this condition is not known, as under normal conditions they are asymptomatic. In literature, a prevalence of 2.3% has been reported in one study on 300 patients presenting with complications. Homozygous patients has non-detectable levels of factor XII, while heterozygous individuals has variable levels ranging from 20-60%. Hageman factor is a pro-coagulation protein initiating intrinsic pathway. Intrinsic pathway is activated either by direct contact with a negative charged surface or by proteolytic activation on the endothelial cells via prekallikerin/kallikerin system. Factor XII as an integral part of this system leads to factor XI activation resulting in production of thrombin orchestrated by intrinsic system. In addition, there is concomitant activation of complement components C3 and C5 via C1-estrase activation. Patients with this condition are known to have spontaneous thromboembolic complications although less common but are prone to life threatening complications under provocating circumstances. The aim of this case report is to study the relation of factor XII deficiency and isolated raised activated partial thromboplastin time (aPPT) and how it can be prevented. We are presenting a Saudi female patient, 29 years of age who presented to accident and emergency room (A&E room) of our hospital with sudden severe breathlessness and chest pain.

Heterozygous FXII deficiency is not associated with an increased incidence of thrombotic events: Results of a long term study.

OBJECTIVE: To investigate the incidence of thrombotic events in patients heterozygous for FXII deficiency during a long observation period. PATIENTS AND METHODS: 103 heterozygotes for FXII deficiency, 49 female and 54 male were followed for 19.6 years (range 5-32 years). As controls 103 unaffected family members of same sex and similar age (±5 years) were enrolled. The thrombotic end points were: myocardial infarction, deep vein thrombosis and ischemic stroke. The mean Factor XII level in the heterozygotes was 48.5%: range (35-60%) that of control was 96.5% (range 70-155%). The heterozygotes showed one myocardial infarction, two deep vein thromboses and no ischemic stroke. The unaffected family members observed 2 myocardial infarctions, one deep vein thrombosis and one ischemic stroke. There were seven deliveries (five women) among the heterozygotes and six (five women) among the controls. Furthermore, four and five surgical procedures were carried out in the patient and in the control group, respectively. Immobilization times for surgical procedures or pregnancies were 50 days and 57 days for the heterozygotes and the unaffected family members, respectively. Heterozygotes for FXII deficiency did not show an increased incidence of thrombotic events as compared with unaffected family members during a long follow up.

Thrombotic events in severe FXII deficiency in comparison with unaffected family members during a long observation period.

To investigate the occurrence of thrombotic events (myocardial infarction, deep vein thrombosis or ischemic stroke) in a group of 39 cases of severe FXII deficiency during a mean 22.5 years follow-up. All patients seen in Padua during the years 1968-2006 will the object of this investigation. FXII was less than or 1% of normal in all cases. Factor FXII activity in unaffected family members was 98% (range 90-140%). No patient or control had a thrombotic event in the past and none were on anticoagulant therapy. FV Leiden was present in one patient and in two controls whereas the G to A20210 prothrombin polymorphism was absent in both groups. There was one death among the patients (breast cancer) and one among the control (car accident). There were two thrombotic events (myocardial infarction and deep vein thrombosis) in the patient group and three (myocardial infarction and two deep vein thrombosis) in the control group. Heterozygous FV Leiden was present in the patient who had venous thrombosis, One of the two control subjects who developed venous thrombosis had heterozygous FV Leiden and was on oral contraception. The second control subject who developed venous thrombosis was on oral contraception and had varicose veins. No ischemic stroke was observed in the patients or controls. Periods of immobilization were 42 days and 38 days, respectively for FXII deficient patients and for the controls. Patients with severe FXII deficiency may present thrombotic events but these are similar to these presented by unaffected family members. As a consequence it may be stated that severe FXII deficiency does not appear to effect thrombotic events.

A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation.

Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and α-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII (FXII) or prekallikrein (PK), the zymogens of FXIIa and α-kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymes may have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and α-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis. Wild type mice developed carotid artery occlusion when the vessel was exposed to a 3.5% solution of ferric chloride (FeCl3). FXII-deficient mice were resistant to occlusion at 5% FeCl3 and partially resistant at 10% FeCl3. PK-deficient mice were resistant at 3.5% FeCl3 and partially resistant at 5% FeCl3. Mice lacking high molecular weight kininogen, a cofactor for PK activation and activity, were also partially resistant to thrombosis at 5% FeCl3. Induction of carotid artery thrombosis with Rose Bengal was delayed in FXII-deficient mice compared to wild type or PK-deficient animals. In human plasma supplemented with silica, DNA or collagen to induce contact activation, an antibody to the FXIIa active site was more effective at preventing thrombin generation than an antibody to the α-kallikrein active site. Similarly, the FXIIa antibody was more effective at reducing fibrin formation in human blood flowing through collagen coated-tubes. The findings suggest that inhibitors of FXIIa will have more potent anti-thrombotic effects than inhibitors of α-kallikrein.

Revisión de los pacientes estudiados por coagulopatía en una unidad de Oncohematología / Review of patients studied for coagulopathy in a Hematology/Oncology unit

INTRODUCCIÓN: Los síntomas/signos indicativos de una coagulopatía son un motivo de consulta frecuente en las unidades de Hematología Pediátrica. Tanto la clínica como los antecedentes familiares son fundamentales para el diagnóstico. PACIENTES Y MÉTODOS: Estudio retrospectivo y descriptivo de los pacientes derivados a una consulta de Hematología Pediátrica de un hospital de tercer nivel por posible coagulopatía durante el año 2012. RESULTADOS: Se estudiaron 47 niños. El 61,7% no había presentado previamente sangrado. El motivo de derivación más frecuente fue un tiempo de tromboplastina parcial activada alargado sin hemorragia (42,5%); de estos, un 25% fue diagnosticado de una coagulopatía con riesgo real de sangrado. En los pacientes derivados por tiempo de tromboplastina parcial activada alargado con clínica hemorrágica se detecta una coagulopatía con riesgo real de sangrado con mayor frecuencia (41,7%). En los niños con antecedentes familiares de sangrado se diagnostica con más frecuencia una coagulopatía con riesgo real de sangrado: 37,5 vs. 14,3% (niños sin antecedentes familiares). Los diagnósticos han sido: sano (48,9%), enfermedad de von Willebrand tipo1 (19,1%), déficit de factor XII (19,1%), déficit de factor XI(4,2%), déficit de precalicreína/cininógeno de alto peso molecular (2,1%), déficit adquirido de factor X (2,1%) y déficit de factor IX (2,1%). CONCLUSIONES: Los antecedentes personales y familiares de sangrado orientan el diagnóstico de una coagulopatía. El motivo de derivación debería basarse en mayor medida en la clínica hemorrágica y no solo en un tiempo de laboratorio alterado. Los diagnósticos más frecuentes han sido enfermedad de von Willebrand tipo 1 y déficit de factor XII

INTRODUCTION: Symptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. PATIENTS AND METHODS: Retrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. RESULTS: A total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor XII deficiency (19.1%), factor XI deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor X (2.1%), and factor IXdeficiency (2.1%). CONCLUSIONS: A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor XII deficiency

Factor XII (Hageman) levels in women with recurrent pregnancy loss.

OBJECTIVE: To evaluate factor XII levels in women with recurrent pregnancy loss (RPL) in a tertiary referral hospital. METHODS: Women who were referred to our hospital for two consecutive abortions or three abortions in between 2007 and 2013 were included in this retrospective observational study. Women were further grouped according to factor XII levels, as <60% and ≥ 60%. RESULTS: Mean factor XII level was 109.1 ± 35.7% (range: 9-200). Ninety-three (7.4%) women had factor XII levels < 60%. Mean factor XII level was 44.8 ± 13.1, and levels ranged between 9 and 60 in this group. Only one woman had factor XII level < 10 %. Remaining 1164 (92.6%) women had factor XII levels ≥ 60%. Mean factor XII level was 114.3 ± 31.7, and levels ranged between 60.3 and 200 in this group, while 1015 (72.4%) women had factor XII levels within the normal range (60%-150% [100% = 30 µg/mL]). CONCLUSION: Decreased activity of F-XII was diagnosed in 7.4% of women with RPL. We concluded factor XII deficiency that might be a rare but significant factor for RPL, and should be evaluated in women who are investigated for recurrent pregnancy loss.

Trombosis venosa retiniana en paciente joven con déficit de factor XII de la coagulación / Retinal venous thrombosis in a young patient with coagulation factor XII deficiency

CASO CLÍNICO: Mujer de 35 años enviada a la consulta por disminución de la visión en ojo izquierdo. En la oftalmoscopia se apreció una trombosis venosa de rama en ese mismo ojo. La paciente fue derivada a la unidad de hematología para estudio de trombofilia, siendo diagnosticada de déficit de factor XII de la coagulación o factor de Hageman. DISCUSIÓN: El desarrollo de fenómenos trombóticos oculares en pacientes sanos menores de 50 años debe hacer sospechar la presencia de trombofilia o estados de hipercoagulabilidad. El déficit de factor XII es poco frecuente y su presencia contribuye al desarrollo de procesos trombóticos

CASE REPORT: A 35-year-old woman, with no relevant medical history, was referred for sudden vision loss in the left eye. Ophthalmological examination showed best corrected visual acuity of 1.0 in the right eye and 0.3 in left eye, with normal anterior pole and intraocular pressure. Fundus examination of the left eye revealed a venous thrombosis in the superior temporal branch, with dilated and tortuous retinal veins. The patient was referred to the hematology unit for thrombophilia study, and was diagnosed with a coagulation XII or Hageman factor deficiency. DISCUSSION: THE development of retinal vessel occlusions, in patients under 50 years of age, is frequently associated with thrombophilia or hypercoagulability disorders. Factor XII deficiency is a rare condition, and its presence could contribute to a higher risk of thromboembolic events

Role of coagulation factor XII in unexplained recurrent abortions in the Greek population.

OBJECTIVE: To investigate the prevalence and clinical significance of congenital factor XII (FXII) deficiency in the South-European Caucasian (Greek) population in a cohort of women with recurrent spontaneous abortions (RSAs). STUDY DESIGN: One hundred women with a history of > or =2 RSAs of unexplained nature were compared to 100 age-matched, healthy controls with no history of thrombotic disease or adverse pregnancy outcomes, regarding FXII activity. Women were included in the RSA group if they had normal coagulation parameters and no congenital or acquired thrombophilia. RESULTS: Fifteen of 100 women with RSA had reduced FXII activity, whereas all controls had normal FXII activity. FXII activity was significantly lower in the RSA than in the control group (median 100.5, range 10-150 vs. median 104.2, range 58.3-143.2, p < 0.016 by Mann-Whitney test). FXII activity was positively correlated with age in both the RSA and the control groups (r = +0.1, p = 0.04 and r = +0.04, p = 0.2, respectively), but this correlation reached statistical significance in the RSA group only. A negative correlation between FXII activity and the number of abortions in the RSA group was found (r = -0.2, p = 0.03). CONCLUSION: Congenital FXII deficiency is strongly associated with RSA in the Greek population.