Administration Of Factor XIII Research Articles

P146 A phase II, randomised, double-blind, placebo-controlled trial exploring pharmacokinetics, safety and efficacy of intravenous factor XIII treatment in adults with systemic sclerosis

Abstract Background/Aims Systemic sclerosis (SSc) is a multi-system autoimmune disease with significant morbidity and mortality, and an unmet therapeutic need. The pathogenesis of SSc involves dysfunctional immune signalling, fibroblast behaviour and vascular development. Factor XIII (FXIII) is an enzyme involved in coagulation, and in wound healing where it promotes angiogenesis via inhibition of thrombospondin-1 (TSP-1). Therapeutic administration of FXIII in SSc is proposed to increase angiogenesis via suppression of TSP-1, which is known to be dysregulated in SSc. Previous preclinical and clinical studies suggest that therapeutic administration of factor XIII could improve vascular function in SSc. Methods Two interlinked clinical trials were conducted at a single centre. First, a single-dose open-label study was performed to assess the safety and pharmacokinetics of FXIII treatment in SSc. Eight adult patients with limited or diffuse SSc received a single dose of intravenous purified human FXIII, followed by a 6-week monitoring period. Second, a phase II, double-blind, randomised, placebo-controlled study was performed to investigate the safety and efficacy of factor XIII treatment in SSc. 18 adult patients with limited or diffuse SSc were randomised 2:1 to receive study intervention (intravenous purified human FXIII) or placebo (intravenous 0.9% sodium chloride solution). Safety endpoints were assessment of the safety and tolerability of FXIII treatment via review of adverse events, physical examination and monitoring of physiological function. Efficacy was explored as change in skin severity by modified Rodnan skin score (mRSS) at week 24 compared to baseline, and change in severity of Raynaud’s phenomenon, assessed by review of the Raynaud’s Condition Score (RCS) at week 24, compared to baseline. The study is registered with ClinicalTrials.gov (number NCT02551042). Results The main objective of the clinical trial was met by demonstrating that FXIII is safe and well tolerated in SSc. Pharmacokinetic analysis showed a predictable rise and fall in FXIII level following therapeutic administration, with the mean time taken for the FXIII level to return to within 10 IU/dL of the endogenous level being 16.6 days (SD 8.7). Adverse event and safety monitoring did not reveal any concerning pattern. Study intervention-related adverse events were self-resolving and tolerable. There was no statistically significant change in mRSS or RCS during the trial, but there was a trend towards improvement in RCS in the FXIII group (mean change in RCS of -1.2 (95% CI -2.26 to -0.14) in the FXIII group versus -0.83 (95% CI -3.44 to 1.77) in the placebo group). Conclusion Our results suggest that therapeutic strategies to modulate links between coagulation and tissue repair using FXIII are safe and feasible. Further studies with different patient populations and FXIII doses could investigate the role of FXIII in SSc further. Disclosure A. Leslie: Other; A.L. is an employee of GSK. S. Vigneswaran: None. K. Khan: None. V. Ong: None. C.P. Denton: Consultancies; C. D. has received consulting fees from Roche, Janssen, GlaxoSmithKline, Sanofi, Galapagos, Boehringer Ingelheim, and CSL Behring, and Acceleron. Grants/research support; C. D. has received research funding from CSL Behring, Horizon, Abbvie, and GlaxoSmithKline.

Relative effects of plasma, fibrinogen concentrate, and factor XIII on ROTEM coagulation profiles in an in vitro model of massive transfusion in trauma

Massive traumatic haemorrhage is aggravated through the development of trauma-induced coagulopathy, which is managed by plasma transfusion and/or fibrinogen concentrate administration. It is yet unclear whether these treatments are equally potent in ensuring adequate haemostasis, and whether additional factor XIII (FXIII) administration provides further benefits. In this study, we compared ROTEM whole blood coagulation profiles after experimental massive transfusion with different transfusion regimens in an in vitro model of dilution- and transfusion-related coagulopathy. Healthy donor blood was mixed 1 + 1 with six different transfusion regimens. Each regimen contained RBC, platelet concentrate, and either fresh frozen plasma (FFP) or Ringer’s acetate (RA). The regimens were further augmented through addition of a low- or medium-dose fibrinogen concentrate and FXIII. Transfusion with FFP alone was insufficient to maintain tissue-factor activated clot strength, coincidental with a deficiency in fibrin-based clot strength. Fibrinogen concentrate conserved, but did not improve coagulation kinetics and overall clot strength. Only combination therapy with FFP and low-dose fibrinogen concentrate improved both coagulation kinetics and fibrin-based clot strength. Administration of FXIII did not result in an improvement of clot strength. In conclusion, combination therapy with both FFP and low-dose fibrinogen concentrate improved clotting time and produced firm clots, representing a possible preferred first-line regimen to manage trauma-induced coagulopathy when RBC and platelets are also transfused. Further research is required to identify optimal first-line transfusion fluids for massive traumatic haemorrhage.

術後髄液漏および低髄圧症候群に対する血液凝固第13因子の効果について

術後髄液漏および低髄圧症候群に対する血液凝固第13因子の効果について

Management of Aortic Replacement-Induced Chylothorax by Lipiodol Lymphography

Chylothorax is a rare but serious complication of thoracic aortic surgery, leading to malnutrition, respiratory insufficiency, and prolonged hospital stay. In this article, we describe the successful treatment of a case of intractable chylothorax by lipiodol lymphography. The patient was a 39-year-old man who underwent descending aortic replacement for a remaining dissected aneurysm after total arch replacement. Chylothorax developed postoperatively. After complete oral intake cessation, total parenteral nutrition, and plasmatic factor XIII administration, lipiodol lymphography detected the chyle leakage location and subsequently decreased pleural effusion. The patient recovered uneventfully and was discharged on postoperative day 30 without any complications.

79-jähriger Patient mit bedrohlicher Blutung nach Darmoperation bei normalen globalen Gerinnungsparametern

We report the case of a 79-year-old Caucasian male, who underwent anterior resection of the rectum for treatment of a colorectal carcinoma. Two days after the surgery, the patient had mild but persistent haemorrhage from all drains and around the wounds which eventually required blood transfusion (18units of erythrocyte concentrate and 8units of fresh-frozen plasma). Endoscopy revealed no surgical bleeding source, and standard coagulation tests were inconspicuous. Based on suspicion of factorXIII deficiency, the patient was treated with factorXIII concentrate (1250I.U. injections twice daily), starting on day4 of bleeding. The bleeding stopped after the second dose of factorXIII. Laboratory testing retrospectively revealed the lack of factorXIII (43 % at the first day of dosing). FactorXIII concentrate was administered for 10days. Withdrawal of factor XIII after 9days of treatment led to a bleeding recurrence. After resuming treatment for one more day, the therapy could be stopped without further bleeding. Thus, factorXIII deficiency should be considered in patients with unexplained postoperative bleeding and appropriate diagnostic measures be taken early. In cases of medical emergency, probative administration of factorXIII may be justified.

Thromboelastometric detection of clotting Factor XIII deficiency in cardiac surgery patients

In this article, we aimed to investigate plasma Factor XIII levels after extracorporeal circulation in cardiac surgery by thromboelastometric detection, as extracorporeal circulation causes various coagulation disorders due to the exposure of blood to artificial surfaces, inflammatory induction and mechanical destruction of platelets and coagulation factors, which may particularly affect factors with long half-lives, such as Factor XIII. Since transfusion algorithms are often empirical and laboratory analysis of Factor XIII plasma levels may not be available 24 h a day, bed-side testing using rotational thromboelastometry (ROTEM) could offer a splendid option to define the cause of excessive peri-operative bleeding disorders in general and Factor XIII levels in particular in a timely manner and thus facilitating exact substitution therapy. In this trial, we investigated 25 cardiac surgery patients with extracorporeal bypass times over 100 min. Standard laboratory and ROTEM analyses were performed post-operatively at the time of intensive care unit admission and 6 h later. We implemented EXTEM with additional Factor XIII (teenTEM) as additional test by adding 0·625 IU Factor XIII to standard EXTEM reagents. In this observational study, we could not demonstrate a correlation between Factor XIII and MCFEXTEM , CFTEXTEM or MLEXTEM . Neither Factor XIII plasma levels nor MCFEXTEM could predict blood loss. In accordance with previous findings, we were able to demonstrate increased maximum clot firmness (MCF), decreased clot formation time and decreased maximum lysis by adding Factor XIII in vitro (teenTEM vs EXTEM) indicating an improvement in the coagulation process. As shown before, we also found a strong correlation between MCF and platelet and fibrinogen plasma levels. In summary, 'teenTEM' test does not seem to detect Factor XIII deficient patients in cardiac surgery. Furthermore, post-operative blood loss could not be predicted neither by ROTEM nor by laboratory analysis of Factor XIII. In vitro administration of Factor XIII appears to improve laboratory measures of haemostasis.

Early Diagnosis and Successful Treatment of Idiopathic Autoimmune Factor XIII Deficiency Complicated by Intracerebral Hemorrhage

Abstract 4634 Summary:Autoimmune factor XIII (FXIII) deficiency is an extremely rare bleeding disorder that can be life-threatening without prompt diagnosis and treatment. Many clinicians, even experienced hematologists, are unaware of this critical disorder. The causes and mechanisms of autoimmune FXIII deficiency remain unclear, but patients should be given top priority in receiving FXIII concentrate and immunosuppressive drugs when this is suspected to avoid fatal hemorrhage. We report the first Japanese case of autoimmune FXIII deficiency presenting as acute intracerebral hemorrhage. The clinical manifestations allowed prompt diagnosis and effective treatment in the form of emergency open drainage and infusion of FXIII concentrates combined with prednisolone therapy, leading to success in saving the life of this patient. Case:A 68-year-old man was hospitalized in another department of our hospital with abdominal pain and diffuse purpura of the abdominal skin in the absence of any history of trauma. He did not have a family history of bleeding tendency. Since he had been receiving low-dose aspirin because of a previous stroke, he received a transfusion of red cell concentrate and was discharged after cessation of aspirin. Two weeks later, he was taken to an emergency room with left hemiplegia. Computed tomography (CT) revealed an intracerebral hemorrhage measuring 4 cm in diameter. Sixteen hours after hospitalization, emergency open drainage was performed because of decreased levels of consciousness due to an expanding intracerebral hemorrhage measuring 7 cm with midline shift. Bleeding was controlled during the operation and CT showed no evidence of further bleeding after surgery. However, on postoperative day 2, subcutaneous bleeding spontaneously developed on the patient's head. Platelet counts and coagulation tests were normal, and other tests showed no evidence of factor VIII, factor IX or von Willebrand factor deficiencies. Given the lack of evidence of other autoimmune disorders or family history of bleeding tendency, we suspected idiopathic autoimmune FXIII deficiency and immediately initiated administration of FXIII concentrate. After treatment with FXIII concentrate, subcutaneous bleeding on the head was arrested and level of consciousness had recovered at all. 3 days after it was confirmed that FXIII activity was as low as 11%, and was not corrected by normal plasma at 1:1 in the cross-mixing test, suggesting the presence of anti-FXIII inhibitor and corroborating our clinical diagnosis. Based on the detection of anti-FXIII A autoantibodies in dot blot assay, we immediately started immunosuppressive therapy using prednisolone at 1 mg/kg combined with FXIII concentrate. Three weeks later, inhibition of FXIII activity was partly improved. FXIII activity was 36%, and 1:1 cross-mixing test was corrected, indicating that immunosuppressive therapy with prednisolone was proving successful. Four weeks later, his surgical wound had healed and FXIII concentration injection was discontinued. Prednisolone tapering was started, and after 8 weeks, with prednisolone tapered to 35 mg, FXIII activity was elevated to 53%. This was not yet sufficient, but anti-FXIII A subunit autoantibodies had disappeared completely, first as free-form antibody and then as bound/complexed antibody. Successful results were achieved in response to short-term treatment. In fact, in some of the 28 cases reported from Japan, anti-FXIII inhibitors were continued despite immunosuppressive therapy for a few years. The next target was to stop prednisolone therapy, because the major causes of death in patients with autoimmune FXIII deficiency is bleeding or infection. Why and when the patient developed autoantibodies remains unclear, as he had no evidence of other autoimmune disorders. This report describes a remarkably successful case in which early diagnosis and treatment of autoimmune FXIII deficiency achieved good outcomes for a case complicated by intracerebral hemorrhage. All clinicians should consider the possibility of this rare disease when they encounter patients who present with life-threatening bleeding and normal coagulation tests are inconclusive. Prompt diagnosis and treatment are crucial in saving the life of the patient. Disclosures:No relevant conflicts of interest to declare.

Successful Delivery of Patients with FXIII Deficiency on Prophylaxis in Iran

Abstract 4363 IntroductionCoagulation factor XIII (FXIII) deficiency is a rare bleeding disorder with a general frequency of 1 in 2 million populations. Life-long bleeding tendencies, umbilical bleeding, defective wound healing and habitual abortions are the most important clinical problems in this patients.For prevention of abortion and pregnancy loss in severe FXIII-deficient women, replacement and prophylaxis with a source of FXIII throughout pregnancy is essential.The acceptance level of plasma FXIII level for successful delivery is above 10% as a result the administration of FXIII concentrate 250 IU weekly until 22 weeks gestation and 500 IU from 23 weeks is recommended to maintain this plasma level. The aim of this study was to evaluate the bleeding score and rate of successful delivery in Iranian FXIII deficient pregnant women on regular prophylaxis. Material and methodsA total of 17 FXIII deficient Iranian women with age range 18–35 years old (mean 24 years old) were enrolled in this study. The first record bleeding episodes were cord bleeding in 10 patients, echymosis in 4 patients, hemarthrosis in 1 patient, hematoma in 1 patient and CNS bleeding in 1 patient. All patients had history of abortion (one abortion in 12 patients, 2 abortions in 2 patients and 3 abortions in 2 patients) except one patient. All of patients were on regular prophylaxis (10 IU every 2 weeks) for 24–62 months, every 4 weeks before pregnancy and every 2 weeks during pregnancy. The patients were followed for any bleeding episodes and also evaluated for bleeding score before and after prophylaxis according on standard form. ResultsThe monochloroacetic acid test was normal in all patients during prophylaxis.The bleeding score was significantly decreased from 11–16 (mean 12) to 1–2 (mean1.5) starting prophylaxis. Two bleeding episodes were recorded in 2 patients, one subject in 11 patients and 3 patients didn't experience any bleeding episodes. All of patients had successful delivery at 36 weeks gestation without any significant coagulation complications. DiscussionPregnancy loss is a main complication in women with FXIII deficiency and prophylaxis is critical for pregnancy maintenance in these patients. In this study we experienced a successful pregnancy maintenance and delivery in Iranian women with FXIII deficiency. It is recommended to precise detection and diagnosis of FXIII in women with coagulation disorders for appropriate prophylaxis and prevention of pregnancy loss. Disclosures:No relevant conflicts of interest to declare.

Spinal anaesthesia and caesarean section in a patient with hypofibrinogenaemia and factor XIII deficiency*

We report the peri-operative management of a 32-year-old patient suffering from symptomatic hypofibrinogenaemia and factor XIII deficiency scheduled for caesarean section. Starting with an impaired fibrinogen (1.04 g x l(-1)) and factor XIII level (48%), fibrinogen and factor XIII administration was guided by point-of-care rotational thrombelastometry (ROTEM) to achieve normal whole blood coagulation, which allowed uncomplicated spinal anaesthesia and an uneventful surgical procedure. We conclude that rotational thrombelastometry may be suitable to guide administration of coagulation factors in patients with hereditary bleeding disorders and allow otherwise contraindicated neuraxial anaesthesia and surgery to proceed without increased risk of blood loss.

Congenital Factor XIII Deficiency as Cause for Intracraneal Hemorrhage.

Abstract 4208Severe congenital factor XIII (FXIII) deficiency is an autosomal recessive disease of with a low prevalence in the general population (3-5 cases per million), associated with generally severe hemorrhagic diathesis, where the presence of intracraneal hemorrhage (ICH) is much higher than in other coagulopathologies such as hemophilia A or B. However, the basic coagulation tests are normal, which could delay the diagnosis.We present three cases of severe congenital FXIII deficiency (not diagnosed when referred to our center) with severe hemorrhagic pathology. These patients had normal basic coagulation tests and did not have a family bleeding history. The table show the results.TablePatient 1Patient 2Patient 3Date of birth195919782006SexFemaleFemaleFemaleAge at diagnosis15 years old12 years old18 months oldCause of patient remissionAnkle hemarthrosisSeizures Subdural hematomaSubdural hematomaPrior hemorrhagic history-umbilical cord bleeding-frontal hematoma requiring surgical management at 12 months-bleeding with dentition-umbilical cord bleeding-hematoma in buttock requiring RBC transfusion for anemia.-hemarthrosis in both knees-umbilical cord bleeding-growing cephalohematoma until 3rd week of life-hematoma by venipuncture lasting 2-3 weeks at 6 months.-delayed healing-Subdural hematoma after minor trauma 3 days prior.basic coagulation tests (PT, APTT, TT, fibrinogen)NormalNormalNormalLevel of functional FXIII<1%< 5 %< 5 %Initial treatmentPlasmaPlasmaFXIII concentrateProphylaxis-Plasma: 2 Units every 6 weeks -FXIII concentrate every 4 weeks (since 1994)FXIII concentrate every 4 weeksFXIII concentrate every 3 weeksEvolutionMajor ICH at 30 years old. (had suspended prophylactic treatment in1989)Favorable evolution without consequences.Favorable evolution without consequences. COMMENTSCongenital Factor XIII deficiency, although infrequent, should be included in the differential diagnosis of hemorrhagic processes with normal coagulation tests, especially if triggered spontaneously or in a disproportionate manner (in quantity and/or duration). Bleeding of the umbilical cord in the first days or weeks after birth is characteristic of this deficiency (present in 80% of cases). The prophylactic administration of Factor XIII is fundamental due to the frequency of intracranial hemorrhaging. Disclosures:No relevant conflicts of interest to declare.

Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice

Factor XIII (FXIII) is a proenzyme of plasma transglutaminase consisting of enzymatic A (FXIII-A) and noncatalytic B subunits (FXIII-B), and acts in hemostasis and wound healing. We freshly generated mice lacking either FXIII-A or FXIII-B to investigate the physiological functions of FXIII in vivo. Mice carrying the disrupted allele were born at the expected Mendelian ratios, and the homozygous mice were viable and fertile under specific pathogen-free conditions. Although all homozygous and heterozygous mice showed no marked difference from the wild-type animals in general appearance, homozygous mice of either FXIII-A- or FXIII-B-deficiency did have prolonged bleeding times. It was confirmed that thrombin-dependent amine incorporation and fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice; however, the gene expression of each subunit was regulated independently. Recombinant human FXIII-B (rFXIII-B) was expressed in a baculovirus expression system. When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma, indicating that FXIII-B assisted the maintenance of FXIII-A levels in the circulation. These mouse strains will be useful in exploring the possible pathophysiological roles of each subunit in vivo.

Therapy for Children with Henoch-Schonlein Purpura Nephritis: A Systematic Review

Although severe kidney involvement in children with Henoch-Shonlein purpura (HSP) is rarer than that in adults, morbidity should not be underevaluated and follow-up is mandatory. Some drugs are introduced as well-defined treatment options, others can be promising therapeutic alternatives.Therapy of HSP nephritis in children can range from simply steroids to combined immunosuppressant treatments. The prophylactic treatment for renal complication of patients with HSP has been sometimes suggested, but with conflicting results and ultimately not clearly proven. The treatment of overt HSP nephritis includes steroids and other immunosuppressant drugs. Methylprednisolone pulse therapy and prednisone per os are tested drugs. These steroids could be used in combination with other immunosuppressant drugs, such as cyclosporin A and cyclophosphamide. Unfortunately, of these two drugs, only cyclophosphamide is demonstrated as effective in a recent randomized controlled trial. However, since there are insufficient data and unstructured study designs, ACE-I, azathioprine, mycophenolate mofetil, and urokinase need to be more tested in childhood HSP nephritis. In addition to drugs, other techniques are used to treat the severe form of nephritis. Of these, in a multicenter study, plasmapheresis demonstrated efficacy in delaying the progression of kidney disease. However, no convincing studies have been made to date concerning either intravenous immunoglobulin, factor XIII administration, antioxidant vitamin E, and fish oil to treat HSP nephritis.

Congenital deficiency of factor XIII caused by two missense mutations in a Dutch family

We present the clinical, biochemical and genomic findings of a family with congenital factor XIII (FXIII) deficiency. Congenital FXIII deficiency is a very rare autosomal recessive bleeding disorder, characterized by umbilical cord bleeding at birth and spontaneous intracranial haemorrhage. Routine clotting tests are normal, which may delay the diagnosis, leading to an increased chance of severe sequelae. The propositus and her brother, known with haemorrhagic diathesis, were found to be compound heterozygous with a known missense mutation (1050 G --> T transversion in exon 7, Val316Phe substitution) and a novel mutation 889 G --> A in exon 6, which predicts a Gly262Glu substitution. As these mutations were known in the family, DNA obtained from cord blood of the youngest sister was analysed for mutations in exons 6 and 7 only. We postulate that the diagnosis was facilitated by determining the two different mutations in the genotype of this family. The analysis showed that she was heterozygous for the exon 7 mutation. Hence, she was not at risk of experiencing haemorrhagic diathesis. This diagnosis avoided the administration of FXIII concentrate to the newborn.

Adult Henoch-Schönlein Purpura with Severe Abdominal Pain Treated with Dapsone and Factor XIII Concentrate

We describe an adult patient with Henoch-Schönlein purpura who had arthralgia, severe abdominal pain, and low plasma factor XIII activity. Corticosteroids were not used because of his history of multidrug-resistant pulmonary tuberculosis. Dapsone had no immediate effect on his abdominal pain, but appeared to have some effect on the purpura and arthralgia. Marked improvement of the abdominal pain was observed immediately after the administration of factor XIII concentrate. Factor XIII concentrate may be useful for alleviating abdominal pain in Henoch-Schönlein purpura patients when corticosteroids are contraindicated

Morphologic changes in neo-intimal proliferation in an experimental aneurysm after coil embolization : effect of factor XIII administration

Morphologic changes in neo-intimal proliferation in an experimental aneurysm after coil embolization : effect of factor XIII administration

Morphologic changes in neo-intimal proliferation in an experimental aneurysm after coil embolization: effect of factor XIII administration

We investigated histological changes in aneurysmal orifices after embolization with Guglielmi detachable coils (GDCs) and determined the effects of the wound-healing factor, factor XIII, on promoting intimal proliferation by scanning electron microscopy (SEM). GDC embolization was performed in an experimental model of aneurysm in swine. In the control group (17 aneurysms), the aneurysms were resected immediately after surgery, at 1 and 3 weeks after the procedure. In the factor XIII-administered group (13 aneurysms), the swine received factor XIII postoperatively, and the aneurysms were excised at 1 and 3 weeks. The endothelial cell proliferation changes in the aneurysm orifices in both groups were evaluated by SEM. The histological changes at the orifices began immediately after the procedure, and endothelialization was observed at 1 week. One week after the procedure, the rate of endothelial cell proliferation was significantly higher in the factor XIII group (P<0.05). But no difference was observed at 3 weeks, when endothelialization of the orifices was essentially completed. The process of intimal proliferation after coil embolization was similar to the wound-healing process after vascular intimal injury. Administration of the wound-healing factor, factor XIII, would contribute rapid intimal proliferation and may be effective to facilitate complete obliteration of aneurysms after coil embolization.

A case of giant expanding cephalhematoma: does the administration of blood coagulation factor XIII reverse symptoms?

Background The mechanism of continuous massive hemorrhage into the subperiosteal space in children without coagulation defects is unknown. We report a case of giant expanding cephalhematoma reversed by the administration of blood coagulation factor XIII concentrate. Method The patient was an 8-year-old boy with a history of minor head trauma who developed a giant expanding cephalhematoma with intraorbital extension. The laboratory data showed severe anemia, but a routine blood coagulation test showed no abnormalities except for a low factor XIII level. Result The administration of factor XIII concentrate completely reversed the symptoms in 2 weeks. Conclusion We speculate that one of the possible mechanisms of cephalhematoma expansion without blood coagulation defects might be acquired factor XIII deficiency from severe hemorrhage in a hematoma.

Histological Investigation of Endothelial Cell Proliferation on the Coil Surface after Endovascular Treatment Using FactorXIII. Preliminary Results in Swine Model.

Recently, endovascular treatment of coil embolisation has been widely used for obliterating cerebral aneurysms. However, the process of endothelial cell growth within aneurysms to prevent aneurysmal rupture associated with endovascular coil embolisation remains unclear. Fourteen aneurysms were produced in seven matured swine and embolised with Guglielmi Detachable coils (GDCs). The aneurysms were resected either immediately or three weeks after coil embolisation, and subjected to histological and scanning electron microscopic examinations. Blood coagulation factor XIII was administered in four animals on the day of embolisation and on the following four days. These aneurysms were also resected three weeks after the embolisation and investigated histologically. Marked fibroblast proliferation and growth of endothelial cells on the intraluminal surface of the coil were observed more often in the group administered factor XIII than in those not given factor XIII. These results suggest that administration of factor XIII may contribute to more effective aneurysm obliteration during coil embolisation.

Factor XIII Improves Gastric Stress Lesions in Rats

Background/Aims: Tissue transglutaminase has been reported to be involved in the healing of experimental gastric ulcer; nevertheless, other type(s) of transglutaminase could be involved. The present experiments aimed at examining whether plasma transglutaminase (factor XIIIa) contributes to such healing and at evaluating whether factor XIII supplementation improves gastric mucosal lesions. Methods: The healing effect of 200 U/kg of factor XIII administered intravenously was examined using a water immersion restraint rat model of stress gastric damage. The rats were sacrified 0, 2, 4, and 12 h after stress. The gastric mucosa was examined macroscopically and microscopically, and the transglutaminase activities were assayed in serum and gastric mucosa. Factor XIIIa and tissue transglutaminase protein levels in the gastric mucosa were analyzed by immunoblot. Immunohistochemistry was used to identify the location of tissue transglutaminase, factor XIIIa, and fibronectin in the gastric mucosa. Results: The transglutaminase activity, reduced by stress in the gastric mucosa, increased up to 12 h after stress, peaking at 4 h, when the ulcer index significantly decreased. The serum transglutaminase level was low at all time points. Exogenous administration of factor XIII allowed a faster reduction of the ulcer index that was coincident with an increased transglutaminase activity in the mucosa. Both tissue transglutaminase and factor XIIIa protein levels were reduced by 6 h of stress and increased after factor XIII administration. Immunohistochemistry showed a colocalization of both factor XIIIa and tissue transglutaminase with fibronectin in the extracellular matrix of the damaged area. Conclusions: Two forms of transglutaminase are involved in the healing of stress-induced gastric erosions, and factor XIII administration allows faster gastric mucosa healing.

Evaluation of spontaneous intracranial hypotension: assessment on ICP monitoring and radiological imaging

We describe two recent cases of spontaneous intracranial hypotension. A 38-year-old woman developed a severe postural headache. Magnetic resonance imaging (MRI) showed marked dural enhancement. Histopathological findings of dural biopsy showed numerous dilated vessels in the dura, rather than hypertrophic change. Lumber CSF pressure was 5 cmH 2 O and RI cisternography suggested CSF leakage. A 58-year-old woman with postural headache and vertigo had bilateral subdural haematoma associated with diffuse dural enhancement on MRI. Lumber CSF monitoring confirmed persistent low pressure ranging from 0‘5 cm H 2 O. MRI myelography revealed multiple CSF pouches along the whole spinal axis. CSF leakage was demonstrated on Radioisotope (RI) cisternography. Both cases described in this report were diagnosed as spontaneous intracranial hypotension caused by CSF leakage from spinal meningeal diverticula and were successfully treated by intravenous Factor XIII administration.