Two Novel Mutations (G774A and A1685G) Causing Coagulation Factor XII Deficiency in a Patient with Acute Inferior Myocardial Infarction.

OBJECTIVE: To identify the gene mutation of the coagulation factor XII (FXII) in a patient with FXII deficiency and acute inferior myocardial infarction. METHODS: The proband was a 51-year-old Chinese man who was diagnosed with acute inferior myocardial infarction and had a history of FXII deficiency. The patient presented with a prolonged activated partial thromboplastin time (160 s) and decreased FXII activity (2.3%) and FXII antigen (1%). DNA sequence analysis of the FXII gene was performed by next generation sequencing. The mutant FXII cDNAs were constructed in an expression plasmid vector and transfected into 293T cells. The expression of FXII antigen was detected by western blot. RESULTS: Sequencing of the FXII gene revealed two novel heterozygous mutations, one at exon 8 (G774A; p: W258X) and the other at exon 14 (A1685G; p: D562G). Western blot showed that the FXII antigens were detected only in the supernatant and whole cell lysate of the wild-type and A1685G mutant type, but not in G774A or G774A plus the A1685G mutant type. In addition, the results showed that secretion but not synthesis of A1685G mutant protein was markedly reduced compared to the wild type. CONCLUSION: The present study indicated that the G774A mutation might impair the secretion and synthesis of FXII protein, while the A1685G mutation only influences the secretion of FXII protein. The definition of these new mutations could be useful tools for analyzing the intracellular protein transport and structure-function relationship of FXII protein transport in the future.

Acquired factor XII deficiency following transanal excision of rectal lesion by transanal minimally invasive surgery (TAMIS): a case report and literature review.

BACKGROUND: Local excision (LE) is currently one of the most effective methods used in cases of large benign polyps, not suitable for endoscopic treatment, or early-stage neoplasms. LE is also alternative to anterior rectal resection in selected patients suffering from major comorbidities and limits for major abdominal procedure. Furthermore, LE results in less pain, reduced impact on bowel function, shorter duration of hospital stay, and lower rates of morbidity, mortality and stoma creation. In particular, early data on transanal minimally invasive surgery (TAMIS) are promising, but they come from single centre case series related to small groups of patients and more data are needed to draw a final conclusion on the safety of this novel approach for transanal resection. CASE PRESENTATION: A 62-year-old woman, following a positive faecal occult blood test and with unremarkable medical history, was admitted to hospital for excision of a large flat neoplastic lesion. Endoscopic biopsy demonstrated a tubular adenoma with high-grade dysplasia and was decided to proceed with surgical excision by TAMIS. After surgery, short-term outcomes revealed prolonged activated partial thromboplastin time, undetectable factor XII activity, fever, and partial dehiscence of rectal wall defect suture. Cross-mixing studies of patient plasma show no correction in either the immediate or incubated activated partial thromboplastin time, indicating the presence of an acquired factor XII inhibitor. Activated partial thromboplastin time and factor XII improved in the following weeks without any specific therapy in addition to antibiotic therapy. CONCLUSION: This is the first report in which acquired inhibitor of coagulation factor XII is associated with a specific surgical procedure. This case has shown how trans-anal excision of rectal lesions, even when performed by minimally invasive means such as in case of TAMIS, is not free of complications. We consider the acute infection, resulting from early dehiscence of the suture, the trigger in an abnormal immune response, and inhibitor development.

Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome.

It was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8-14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of pre-eclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7-18.1) and body mass index (BMI) ≥ 25 kg/m² (4.3, 1.1-13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0-14.3) and BMI ≥ 25 kg/m² (4.0, 1.3-10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.

Adult cystic fibrosis patients with and without infective exacerbations and their factor XII levels.

We investigated haemostatic and inflammatory parameters in patients with cystic fibrosis in an attempt to understand a previous finding of low factor XII levels in this patient population. We selected two groups of patients, adults attending outpatient annual review clinic who were well, chronically inflammed and adult patients with an infective exacerbation requiring antibiotics or admission to hospital, acutely inflammed. We measured known positive acute phase haemostatic factors, fibrinogen and factor VIII. Antithrombin and factor XII were also measured as both these factors have been proposed to be negative acute phase proteins in in-vitro cell models. Interleukin-6 was also measured as the proposed modulator of these factors during inflammation. Activated factor XII was measured to exclude XII activation as a cause of the low XII activity levels. Cystic fibrosis patients admitted to hospital with infective exacerbations, showed significantly more evidence of inflammation than the annual review patients. Fibrinogen and factor VIII were higher and factor XII was lower in these patients. This work suggests that factor XII behaves as a negative acute phase protein with no signs of elevated activated XII levels in either group. This supports similar findings from in-vitro cell culture. This study also shows low antithrombin levels in both patient populations, although there was no statistical difference between groups, which is probably related to their liver disorder.

Factor XII deficiency acquired by orthotopic liver transplantation: case report and review of the literature.

Transmission of congenital clotting factor deficiencies after orthotopic liver transplantation is rare. There are published reports of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia, protein S, factor VII and factor XI deficiencies. We report a case of transmission of factor XII deficiency with liver transplantation in a patient with Budd-Chiari syndrome. There was a persistent elevation of the activated partial thromboplastin time (aPTT), but no evidence of bleeding while the patient was maintained on warfarin. The presence of a persistently abnormal aPTT may raise suspicion for the presence of a clotting factor deficiency; however, deficiencies of other clotting factors may not be readily apparent on routine blood tests performed in a donor. Being aware of the possibilities of transmission of these inherited deficiencies of coagulation factors will aid in their early detection and management in the transplant donor and recipient.

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.

The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors.

Factor XII (FXII) deficiency has been reported to be a risk factor for the development of arterial and venous thromboembolism. However, no data are available on the prevalence of FXII deficiency within the normal population. Measuring APTT and FXII activity, seven FXII deficiencies could be detected among 300 healthy blood donors. This corresponds to an incidence of FXII deficiency of 2.3%. On the basis of these data the prevalence of severe and mild FXII deficiency in the normal population can be estimated to be 1.5-3.0%. Assessment of FXII antigen levels revealed, that all seven FXII deficient individuals had FXII antigen levels matching the activity. One presented a severe FXII deficiency (1/300, 0.3%) without detectable FXII activity and an APTT prolongation of more than 120 s. The remaining six FXII deficiencies (6/300, 2.0%) were moderate variations with FXII activities ranging from 20-45% and less prolonged APTTs. Among the 300 healthy donors 16 (5.3%) subjects with prolonged APTTs were identified. Causes for APTT-prolongation were FXII deficiency (7/16), lupus anticoagulant (6/16), mild FVIII deficiency (1/16) and hepatic disorder (1/16). In the remaining sample (1/16) the cause for the prolongation of the APTT remained unexplained. Although 8.7% (26/300) of the donors had a positive family-history of thromboembolism (TE-FHx), none of the FXII deficient subjects were among those with positive TE-FHx.

[Thrombosis of superior longitudinal sinus and pulmonary embolism in nephrotic syndrome]. / Thrombose du sinus longitudinal supérieur et embolie pulmonaire au cours d'une néphrose.

The authors report on the case of a child with the nephrotic syndrome complicated by thrombosis of superior longitudinal sinus, bilateral massive pulmonary embolism resulting in a sudden death. A dramatic deficiency in factor XII was demonstrated; the pathophysiology and management of such an abnormality are discussed.

Autologous bone marrow transplantation and factor XII, factor VII, and protein C deficiencies. Report of a new association and its possible relationship to endothelial cell injury.

Four patients who underwent treatment with high-dose chemotherapy (HDC) and autologous bone marrow transplantation (ABMT) and in whom posttreatment deficiencies of Factor XII and protein C subsequently developed are reported. Factor VII or Factor X deficiencies also developed in several of these patients. Three of these patients experienced chemotherapy-related cardiac, hepatic, or pulmonary toxicity. It is believed by many that endothelial cell injury may be the underlying lesion responsible for these various organ system toxicities seen in the setting of ABMT, although direct evidence of this is lacking. It is proposed that the factor deficiencies described in this report may be an additional consequence of endothelial cell injury or dysfunction. These coagulation factor deficiencies may therefore serve as both a marker to follow these organ system toxicities with and as a useful tool to better study and understand the mechanisms underlying these events. Additionally, deficiencies of either Factor VII or Factor X developed in several patients that were of a sufficient magnitude such that factor replacement therapy would be indicated before any invasive procedures or in the event of significant hemorrhage.

Circulating anticoagulant against factor XII in smoldering leukemia.

A circulating anticoagulant against factor XII was detected in a patient with smoldering leukemia. Despite severe associated thrombocytopenia the patient suffered two thromboembolic episodes, besides mucosal bleeding. The circulating anticoagulant was demonstrated not only in the plasma but also in the serum. Its activity was not affected by heating at 56 degrees C for 30 min and it was not adsorbed by SO4Ba or A1(OH)3. The circulating anticoagulant was not dializable and demonstrated to be an IgG. This is apparently the first reported association of smoldering leukemia and a circulating anticoagulant against factor XII.

Deficiency and urinary losses of factor XII in adult nephrotic syndrome.

Factor XII was measured in the plasma and urine of 16 adult patients with nephrotic syndrome and 10 normal volunteers using a monospecific antibody to human factor XII. In addition plasma factor XII procoagulant activity was determined in both groups. Plasma immunoreactive factor XII level was significantly lower in the nephrotic group than the control group. This was associated with a significant reduction of plasma factor XII procoagulant activity. To examine the effect of albumin concentration on factor XII procoagulant activity purified human serum albumin was added in the in vitro system. Manipulation of albumin concentration failed to alter plasma factor XII activity. Considerable amounts of factor XII were recovered in the urine of all but one of the tested nephrotic patients while none were found in the urine of the control group. Plasma factor XII concentration was within normal limits in the single patient whose urine contained no detectable factor XII. Moreover, there was a significant negative correlation between plasma and urinary factor XII concentrations (r = -0.79; p less than 0.01). In addition, plasma factor XII concentration showed a significant correlation with serum albumin concentration (r = 0.63; p less than 0.05). It thus appears that renal losses of this plasma protein contribute to its low plasma concentration in our patients.

Role of splenic red pulp in endotoxin-induced disseminated intravascular coagulation.

As an extension of our studies on vascular responses to endotoxemia, we evaluated sequential ultrastructural lesions of splenic red pulp and correlated these lesions with coagulation changes observed in rhesus monkeys following infusion with endotoxin either as a single bolus (10 mg. per kg.) or at a continuous rate of 10 mg. per kg. per hour for periods up to 16 hours. Controls included monkeys infused with Ringer's lactate solution. Progressive reactions of the splenic cords included increased phagocytic activity of macrophages in association with aggregation and degranulation of platelets and prominent fibrinous deposits characteristically abutting basement membranes of endothelial and reticular cells. The sinuses demonstrated endothelial damage, platelet-fibrin microthrombi obstructing interendothelial slits, and severe engorgement with entrapment of erythrocytes by tactoids of fibrin. The thrombotic lesions of the red pulp developed earlier than similar lesions in hepatic sinusoids, and they were accompanied by progressive thrombocytopenia and disseminated intravascular coagulation. The findings suggest that the unique microcirculation of the spleen is an early target and trigger of endotoxin-induced microthrombosis. It is proposed that phagocytosis of endotoxin by splenic phagocytic cells and associated inflammatory events result in disruption of reticular cells and endothelium leading to massive microthrombosis with breakdown of the splenic filter. In addition, rapid activation of coagulation mechanisms in the red pulp as well as liver sinusoids may promote the development of thrombocytopenia and disseminated intravascular coagulation in endotoxic shock.

Acquired factor XII Deficiency in a patient with nephrotic syndrome.

A patient with nephrotic syndrome and an acquired factor XII deficiency associated with a factor XII-like procoagulant activity in the urine was investigated. The urinary protein with procoagulant activity was isolated and comparative investigations revealed similar properties to plasma factor XII. It is suggested that the acquired coagulation defect may result from an insufficient biosynthetic capacity to compensate for the loss of factor XII in the urine.

Deficiency of coagulation factors VII and XII in a patient with Hodgkin's disease.

A patient with Hodgkin's disease is described in whom deficiencies of coagulation factors VII and XII were discovered. Depressed levels of these factors appear to reflect increased Hodgkin's disease activity and returned to normal when chemotherapy was instituted. There was no evidence of accelerated fibrinolysis, intravascular coagulation, or circulating anticoagulants in the patient. Possible mechanisms for the abnormality include impaired production and/or increased consumption of coagulation factors. This observation suggests that all patients with lymphoreticular neoplasms should be screened carefully for clotting disturbances prior to treatment.