Reduction of FXIII during myelosuppression in acute leukemia after chemotherapy and adverse relation with bleeding events / 中华血液学杂志

Objective: To explore the relationship between plasma coagulation factor XIII (FXIII) and bleeding events. Methods: A total of 55 cases of acute leukemia (AL) at the myelosuppression phase after chemotherapy hospitalized in our hospital from August 2017 to March 2018 were enrolled, with 35 normal controls. The concentration of plasma coagulation factor XIII (FXIII) was detected by ELISA to determine the relationship between the plasma FXIII levels in AL patients at the myelosuppression phase after chemotherapy with bleeding events. Results: The level of FXIII in AL patients at the myelosuppression phase after chemotherapy was significantly lower than that in controls (P<0.001) . The level of FXIII was inversely related with the bleeding severity (the Spearman correlation coefficient -0.761) . Given the diagnosis cut-off point of FXIII concentration as 103.9 μg/L, the sensitivity of diagnosing bleeding in AL patients at the myelosuppression phase after chemotherapy was 0.939, and the specificity 0.909. Conclusion: AL patients at the myelosuppression phase after chemotherapy had low level of plasma FXIII, and patients with lower plasma FXIII associated with higher incidence and severity of bleeding. FXIII level was an independent influencing factor of bleeding in AL patients at the myelosuppression phase after chemotherapy.

Reduction of FXIII during myelosuppression in acute leukemia after chemotherapy and adverse relation with bleeding events / 中华血液学杂志

Objective@#To explore the relationship between plasma coagulation factor XIII (FXIII) and bleeding events.@*Methods@#A total of 55 cases of acute leukemia (AL) at the myelosuppression phase after chemotherapy hospitalized in our hospital from August 2017 to March 2018 were enrolled, with 35 normal controls. The concentration of plasma coagulation factor XIII (FXIII) was detected by ELISA to determine the relationship between the plasma FXIII levels in AL patients at the myelosuppression phase after chemotherapy with bleeding events.@*Results@#The level of FXIII in AL patients at the myelosuppression phase after chemotherapy was significantly lower than that in controls (P<0.001) . The level of FXIII was inversely related with the bleeding severity (the Spearman correlation coefficient -0.761) . Given the diagnosis cut-off point of FXIII concentration as 103.9 μg/L, the sensitivity of diagnosing bleeding in AL patients at the myelosuppression phase after chemotherapy was 0.939, and the specificity 0.909.@*Conclusion@#AL patients at the myelosuppression phase after chemotherapy had low level of plasma FXIII, and patients with lower plasma FXIII associated with higher incidence and severity of bleeding. FXIII level was an independent influencing factor of bleeding in AL patients at the myelosuppression phase after chemotherapy.

Factor XIII-guided treatment algorithm reduces blood transfusion in burn surgery / Algoritmo de tratamento guiado pelo fator XIII reduz a transfusão sanguínea na cirurgia de queimados

Abstract Background and objectives: Major burn surgery causes large hemorrhage and coagulation dysfunction. Treatment algorithms guided by ROTEM® and factor VIIa reduce the need for blood products, but there is no evidence regarding factor XIII. Factor XIII deficiency changes clot stability and decreases wound healing. This study evaluates the efficacy and safety of factor XIII correction and its repercussion on transfusion requirements in burn surgery. Methods: Randomized retrospective study with 40 patients undergoing surgery at the Burn Unit, allocated into Group A those with factor XIII assessment (n = 20), and Group B, those without assessment (n = 20). Erythrocyte transfusion was guided by a hemoglobin trigger of 10 g.dL-1 and the other blood products by routine coagulation and ROTEM® tests. Analysis of blood product consumption included units of erythrocytes, fresh frozen plasma, platelets, and fibrinogen. The coagulation biomarker analysis compared the pre- and post-operative values. Results and conclusions: Group A (with factor XIII study) and Group B had identical total body surface area burned. All patients in Group A had a preoperative factor XIII deficiency, whose correction significantly reduced units of erythrocyte concentrate transfusion (1.95 vs. 4.05, p = 0.001). Pre- and post-operative coagulation biomarkers were similar between groups, revealing that routine coagulation tests did not identify factor XIII deficiency. There were no recorded thromboembolic events. Correction of factor XIII deficiency in burn surgery proved to be safe and effective for reducing perioperative transfusion of erythrocyte units.

Resumo Justificativa e objetivos: A cirurgia no grande queimado causa hemorragia de grande porte e disfunção da coagulação. Os algoritmos de tratamento guiados por ROTEM® e fator VIIa reduzem as necessidades de hemoderivados, mas falta evidência em relação ao fator XIII. A deficiência do fator XIII altera a estabilidade do coágulo e diminui a cicatrização. Este estudo avalia a eficácia e a segurança da correção do fator XIII e sua repercussão nas necessidades transfusionais na cirurgia do queimado. Métodos: Estudo retrospectivo randomizado de 40 doentes submetidos à cirurgia na Unidade de Queimados alocados em grupo A com estudo do fator XIII (n = 20) e grupo B sem estudo (n = 20). A transfusão eritrocitária foi guiada por gatilho de hemoglobina de 10 g.dL-1 e os outros hemoderivados por testes de coagulação de rotina e ROTEM®. A análise do consumo de hemoderivados incluiu unidades de eritrócitos, plasma fresco congelado, plaquetas e fibrinogênio. A análise dos biomarcadores da coagulação comparou os valores pré e pós-operatórios. Resultados e conclusões: O grupo A (com estudo de fator XIII) e o grupo B apresentaram área de superfície corporal total queimada idêntica. Todos os doentes do grupo A revelaram déficit pré-operatório de fator XIII, cuja correção reduziu significativamente a transfusão de unidades de concentrado eritrocitário (1,95 vs. 4,05, p = 0,001). Os biomarcadores de coagulação pré e pós-operatórios foram semelhantes entre os grupos, revelaram que os testes de coagulação de rotina não identificam o déficit de fator XIII. Sem eventos tromboembólicos registrados. A correção do fator XIII na cirurgia do queimado revelou-se segura e eficaz na redução da transfusão perioperatória de unidades de eritrócitos.

Impact of Rare Bleeding Disorders during Pregnancy on Maternal and Fetal Outcomes: Review of 29 Pregnancies at a Single Center / Impacto de distúrbios hemorrágicos raros durante a gestação na mãe e no feto: revisão de 29 gestações em um único centro

ABSTRACT Objective: This study aims to give information about the relationship between different types of factor deficiencies and maternal/obstetric outcomes. Methods We retrospectively reviewed the medical records of eight women with factor deficiency disorders. The demographic and clinical features of the patients after their last pregnancies were registered retrospectively. Results: There were 29 pregnancies among the 8 patients. The spontaneous abortion rate was relatively high in two patients with factor XIII deficiency (80% and 57.1%) compared with the other factor deficiency groups. There were 16 births, which included 1 set of twins, and 2 deaths (1 stillbirth and 1 postpartum exitus occurred in the same patient). Intrauterine growth restriction was noted in five cases; four of these occurred in factor X deficiency cases. The mean decrease in hemoglobin level of all patients after birth was 1.7 g/dL (range, 0.2-3.6 g/dL). Red blood cell transfusion was required only in one case of factor XIII deficiency. Conclusions: There is currently no consensus on the pregnancy management of women with factor deficiencies because of the limited knowledge due to the rarity of such disorders. Labor should be managed in a dedicated unit with a team consisting of an obstetrician, a hematologist, an anesthesiologist, a midwife, and a pediatrician to minimalize the complications.

RESUMO Objetivo: O presente estudo objetiva fornecer informações sobre a relação entre diferentes tipos de deficiências de fator e resultados obstétricos e maternais. Métodos Análise retrospectiva de registros médicos de oito mulheres com deficiências de fator. Dados demográficos e clínicos das pacientes após sua última gestação foram obtidos. Resultados: Vinte e nove gestações ocorreram entre as oito pacientes. As taxas de abortos espontâneos foram relativamente altas em duas pacientes com deficiência de fator XIII (80% e 57,1%) se comparadas aos demais grupos de deficiências de fator. Ocorreram dezesseis nascimentos, sendo que um deles foi o de um par de gêmeos, e dois óbitos (um natimorto e um pós-parto na mesma paciente). Restrição de crescimento intrauterino foi identificada em cinco casos, sendo quatro destes com deficiência de fator X. A principal baixa em nível de hemoglobina entre todas as pacientes após o parto foi de 1,7 g/dL (variação, 0,2-3,6 g/dL). Transfusão de hemácias foi necessária apenas em um caso com deficiência de fator XIII. Conclusão: Não há consenso atualmente para o manejo de gestantes com deficiências de fator em função do conhecimento limitado, dada a raridade de tais condições. O parto deve ocorrer em uma unidade específica com uma equipe composta de obstetra, hematologista, anestesista, parteira, e pediatra para minimizar as complicações

Clotting Factor XIII and desmopressin improve hemostasis in uncontrolled bleeding

PURPOSE: To investigate hemostatic effects of supplementary factor XIII and desmopressin (DDAVP) in resuscitation of uncontrolled bleeding. METHODS: Fifty-four rabbits were randomized in nine groups: G1: Sham; G2: FXIII and normotensive resuscitation (NBP); G3: FXIII and permissive hypotension (PH) (MAP 60% baseline); G4: FXIII/DDAVP/NBP; G5: FXIII/DDAVP/PH; G6: NBP only; G7: FXIII no hemorrhage; G8: FXIII/DDAVP no hemorrhage; G9: PH only. Thromboelastometry and intra-abdominal blood loss were assessed. Scanning electron microscopy (EM) of the clots was performed. RESULTS: Compared to Sham, only G8 (FXIII/DDAVP w/o hemorrhage) showed clotting time (CT) significantly lower (p<0.05). NBP alone (G6) resulted in significantly prolonged CT compared to G2, G3 and G5 (p<0.05). Similarly, median alpha angle was significantly larger in G3,4,5, and 9 compared to G6 (p<0.05). Area under the curve was significantly greater in G5 than G2. Intra-abdominal blood loss was lower in G5 and G9 compared to G2 and G6. FXIII/DDAVP and PH resulted in more robust fibrin mesh by EM. CONCLUSIONS: Normotensive resuscitation provokes more bleeding and worsens coagulation compared to pH, that is partially reversed by factor XIII and desmopressin. FXIII and DDAVP can synergistically improve coagulation. Permissive hypotension reduces bleeding regardless of those agents. .

Fibrin gel enhances osteogenic differentiation of rat mesenchymal stem cells / 中国组织工程研究

BACKGROUND: Fibrin is a kind of high polymer materials with biodegradation and good histocompatibility, and is a vector that can promote celland exogenous growth factor release. Fibrin stabilizing factor XIII has been verified to contribute to the migration of undifferentiated mesenchymal stem cels in gel scaffold with high crosslinking, and promote cellproliferation and differentiation. OBJECTIVE:To observe rat mesenchymal stem cellbehavior in a fibrin gel. METHODS:The rat fetal limbs cels was separated under the aseptic condition. The passage 3 cels were seeded in 0, 5, 10 and 20 g/L fibrin gel. cellmorphology was observed by inverted phase microscope and laser scanning confocal microscopy. Alkaline phosphatase activity and calcium deposition were measured respectively using a microplate reader and von Kossa staining. RESULTS AND CONCLUSION: 5 g/L fibrin gel contributed to cellmorphological changes, and 20 g/L fibrin gel contributed to osteogenic differentiation. Compared with the control group, alkaline phosphatase activity was higher in the formulations containing a 20 g/L fibrinogen concentration. Smal mineralization nodules were observed at 21 and 28 days in a formulation containing both 10 and 20 g/L fibrinogen concentration, but no mineralization was detected in the control group. These results indicate that morphology and osteogenic differentiation of rat mesenchymal stem cels depended on the fibrinogen concentration, suggesting that fibrin gel is conducive to osteogenic differentiation of mesenchymal stem cels.

Clinical analysis of gum bleeding caused by acquired factor XIII deficiency disease / 实用口腔医学杂志

Acquired factor XIII deficiency disease is rare.One case with gum bleeding as the first symptom caused by acquired factor XIII de-ficiency disease was encountered.The case was analyzed and relevant literatures were reviewed.

Percutaneous treatment of femoral pseudoaneurysms: comparison of fibrin sealant against thrombin / Tratamento percutaneo do pseudoaneurisma femoral: comparacao entre selante de fibrina e trombina

INTRODUCTION: Femoral pseudoaneurysms are a complication that occurs in connection with up to 8% of percutaneous procedures. Of the available treatments, ultrasound guided thrombin injection has a high success rate and is well-tolerated by patients. The combination of thrombin and fibrinogen known as fibrin sealant forms a stable clot and can be used to treat pseudoaneurysms, particularly those with complex anatomy and larger size. OBJECTIVE: To compare the results of treating femoral pseudoaneurysm in two ways: Group T was treated with thrombin alone and Group T+F was treated with fibrin sealant (thrombin+fibrinogen). METHODS: A retrospective analysis was conducted of femoral pseudoaneurysm cases treated between January 2005 and December 2012. RESULTS: Twenty-eight patients were treated, 21 with thrombin alone and seven with fibrin sealant. All patients in group T were treated successfully, but only four patients in group T+F were treated successfully (57.1% success rate in Group T+F, p<0.01). The three cases of failure in group T+F needed surgery and in one of these cases the complication was embolization to the femoral bifurcation. The pseudoaneurysms that were treated with fibrin sealant were larger (25 cm3 in Group T and 57.7 cm3 in Group T+F, p=0.02) and required larger volumes of thrombin (0.5 mL in Group T and 1.0 mL in Group T+F, p<0.01). There was one complication in Group T and two complications in Group T+F (p<0.01). CONCLUSIONS: Irrespective of the small number of cases reviewed, treatment with thrombin alone was superior to treating with fibrin sealant, since it caused few complications and was more effective at correcting pseudoaneurysms. .

INTRODUÇÃO: O pseudoaneurisma femoral é complicação descrita em até 8% dos procedimentos percutâneos. Dentre os tratamentos, a injeção de trombina guiada por ultrassom tem alta taxa de sucesso e boa tolerância pelos pacientes. O uso da trombina associada ao fibrinogênio, chamado selante de fibrina, forma um coágulo estável que pode ser usado para o tratamento do pseudoaneurisma, principalmente aqueles de anatomia complexa e maiores. OBJETIVO: Comparar os resultados do tratamento do pseudoaneurisma femoral em dois grupos: Grupo T, tratado com trombina isoladamente, e Grupo T+F, tratado com selante de fibrina (trombina+fibrinogênio). MÉTODO: Análise retrospectiva dos casos de pseudoaneurisma femoral tratados entre janeiro/2005 e dezembro/2012. RESULTADOS: Foram tratados 28 pacientes, 21 com trombina isolada e sete com selante de fibrina. Houve sucesso no tratamento de todos os pacientes do grupo T e somente em quatro casos do grupo T+F (57,1% no Grupo T+F, p<0,01). Os três casos de insucesso no grupo T+F necessitaram cirurgia, sendo que, em um deles, a causa foi embolização para a bifurcação femoral. Os pseudoaneurismas tratados com selante de fibrina apresentaram maior tamanho (25 cm3 no Grupo T e 57,7 cm3 no Grupo T+F, p=0,02) e houve necessidade de maior volume de trombina (0,5 mL no Grupo T e 1,0 mL no Grupo T+F, p<0,01). Houve uma complicação no Grupo T e duas no Grupo T+F (p<0,01). CONCLUSÃO: Apesar do número reduzido de casos, o tratamento com trombina isolada foi superior ao selante de fibrina, levando a poucas complicações e à maior eficácia para resolução do pseudoaneurisma. .

Correlation of FXIII Val34Leu Polymorphism with Decreased Risk of Myocardial Infarction in Egypt.

Aim: Factor XIII is a transglutaminase that crosslinks fibrin in the last steps of the coagulation process. A few polymorphic sites have been identified in this gene, one of them being a point mutation (FXIII Val34Leu), leading to an amino acid change of valine to leucine. Several studies were published on the association between FXIII 34Leu allele and a decreased incidence of myocardial infarction (MI) with high controversy results dependent on the population. The aim of our study was to further investigate the possible protective role of the FXIII 34Leu allele polymorphism against acute MI in Egyptian patients. Study Design: Clinical examination by cardiologist specialists, blood test for biochemical markers and DNA genotyping using specific molecular sensing probes in Real Time PCR. Place and Duration of Study: Patients were recruited from consecutive admission to the coronary care unit, Suez Canal University Hospital, Ismailia, Egypt. Material and Methods: Total 107 subjects were recruited and subdivided into two main groups; patients (82) and control group (25). On admission, the following data were fulfilled: age, smoking, history of Diabetes Mellitus (DM) and Hypertension (HTN), family history of MI. Clinical examination: Blood pressure and Body Mass Index calculation were done and for patients a short outcome prognosis was done using left ventricular Ejection Fraction (EF). Routine laboratory investigations for recruited groups including fasting and postprandial glucose level, Triglycerides, total Cholesterol, HDL-C and LDLC were carried out. Factor XIII Val34Leu was genotyped for all the recruited subjects using site specific molecular probes in real time PCR. Results: Obtained data were analyzed using OD and CI values, Pearson correlation coefficient Inter-correlations and Regression analysis model that showed insignificant association between FXIII Val34Leu polymorphism and MI patients. Conclusion: FXIII 34Leu variant has no association with reduced incidence of myocardial infarction in Egyptian patients.

Relationships of Coagulation Factor XIII Activity with Cell-Type and Stage of Non-Small Cell Lung Cancer

PURPOSE: Factor XIII (FXIII), a thrombin-activated plasma transglutaminase zymogen, is involved in cancer development and progression through a triggered coagulation pathway. The aim of this study was to examine whether FXIII activity levels differed in non-small cell lung cancer (NSCLC) patients according to histological types and TNM stage when compared with healthy subjects. MATERIALS AND METHODS: Twenty-eight NSCLC patients and 28 normal controls who had been individually age-, gender-, body mass index-, smoking status-, and smoking amount-matched were enrolled: 13 adenocarcinomas, 11 squamous cell carcinomas, and four undifferentiated NSCLCs; four stage I, two stage II, 12 stage III, and 10 stage IV NSCLCs. FXIII activity was measured using fluorescence-based protein arrays. RESULTS: The median FXIII activity level of the NSCLC group [24.2 Loewy U/mL, interquartile range (IQR) 14.9-40.4 Loewy U/mL] was significantly higher than that of the healthy group (17.5 Loewy U/mL, IQR 12.6-26.4 Loewy U/mL) (p=0.01). There were no differences in FXIII activity between adenocarcinoma (median 18.6 Loewy U/mL) and squamous cell carcinoma (median 28.7 Loewy U/mL). NSCLC stage significantly influenced FXIII activity (p=0.02). The FXIII activity of patients with stage III NSCLC (median 27.3 Loewy U/mL, IQR 19.3-40.5 Loewy U/mL) was significantly higher than those of patients with stage I or II (median 14.0 Loewy U/mL, IQR 13.1-23.1 Loewy U/mL, p=0.04). FXIII activity was negatively correlated with aPTT in NSCLC patients (r=-0.38, p=0.04). CONCLUSION: Patients with advanced-stage NSCLC exhibited higher coagulation FXIII activity than healthy controls and early-stage NSCLC patients.

Presencia de marcadores de las vías de activación de los macrófagos en periodontitis crónica / Presence of markers of activation pathways of macrophages in chronic periodontitis

La periodontitis crónica es una patología infecciosa, causada por un complejo de especies bacterianas, que afecta principalmente los tejidos de inserción de los dientes. La respuesta inmune-inflamatoria producida se caracteriza por la presencia de un infiltrado inflamatorio, en el cual los macrófagos representan entre 5 al 30 por ciento. Es sabido que los macrófagos se activan mediante dos vías: Clásica y Alterna, caracterizadas por la presencia de marcadores indirectos: IFN-y e IL-6 para la vía clásica e IL-4 para la vía alterna, ampliamente abordados. Recientemente, se ha descrito a la subunidad A del factor XIII de la coagulación (FXIII-A) como un buen marcador de la vía alterna. El objetivo de este estudio consiste en determinar la presencia de IFN-y, IL-6, FXIII-A e IL-4 como marcadores de las vías de activación de los macrófagos, en pacientes con periodontitis crónica. Para tal efecto, se realizó inmunohistoquímica y Western-Blot para los cuatro marcadores junto a CD-68, marcador de macrófagos, en 18 biopsias de tejido periodontal sano y 18 con periodontitis crónica. Se detectó la presencia de IFN-y, IL-6, IL-4 y FXIII-A junto a CD68+, en todas las muestras de pacientes sanos y con periodontitis. Los resultados obtenidos sugieren que al estar presente IFN-y, IL-6, IL-4 y FXIII-A, los macrófagos se activarían a través de ambas vías, lo cual, produciría una respuesta tanto proinflamatoria (Th1) como antinflamatoria (Th2). Son necesarios más estudios para determinar si existe una vía preferencial de activación.

Periodontitis is a chronic infectious disease caused by a bacterial species complex, which affects mainly the insertion tissues of the teeth. The immune-inflammatory response produced is characterized by an inflammatory infiltrate in which macrophages represent between 5 to 30 percent. It is known and has been widely discussed that macrophages are activated in two ways: Classical and Alterna, characterized by the presence of indirect markers: IFN-y and IL-6 for the classical pathway and IL-4 for the alternative pathway. Recently the subunit A of the clotting factor XIII (FXIII-A) has been described as a good marker of the alternative pathway. The objective of this study is to determine the presence of IFN-y, IL-6, IL-4 and FXIII-A as markers of the macrophage activation pathways in patients with chronic periodontitis. To this end, we performed immunohistochemistry and Western blot for the four markers with CD68 macrophage marker, in 18 healthy periodontal tissue biopsies and 18 with chronic periodontitis. We detected the presence of IFN-y, IL-6, IL-4 and FXIII-A with CD68 +, in all samples of healthy patients and periodontitis. The results suggest that when present, IFN-y, IL-6, IL-4 and FXIII-A, activate macrophages through both routes, which would produce a proinflammatory response (Th1) as antiinflammatory (Th2). Further studies are necessary to determine whether there is a preferential pathway activation.

Riesgo de sangrado y complicaciones ginecoobstétricas en una paciente con déficit de factor XIII. Presentación de un caso y revisión de la literatura / Risk of bleeding and gyneconstetric complications in a patient with factor XIII deficiency. Case report and literature review

La deficiencia de factor XIII de la coagulación es un trastorno raro de la coagulación, entre los que están la afibrinogenemis y los de factor II, V, V+VIII, VII, X y XI. Estos son son anormalidades de la hemostasia con herencia autosómica recesiva; su prevalencia es de 1 en 500,000 a 2 millones de personas. Por su rareza, tipo y severidad de las hemorragias y lo poco claro que es el defecto molecular y su manejo son un reto diagnóstico y terapéutico. Para algunas de estas deficiencias no existen concentrados del factor de coagulación implicado disponibles, por lo que es necesario utilizar derivados sanguíneos o medicamentos hemostáticos alternativos, lo que puede generar complicaciones, en ocasiones fatales; estas complicaciones pueden ser minimizadas evaluando en cada caso el riesgo de sangrado o de trombosis seleccionando como tratamiento alternativas diferentes a los derivados de la sangre, o incluso no administrando tratamiento en los episodios hemorrágicos leves. En este artículo se describe el caso de una paciente con diagnóstico de déficit de factor XIII que debutó con hematuria y complicaciones ginecoobstétricas; hay historia familiar de consanguinidad y de déficit de factor XIII; recibió manejo con crioprecipitados y antifibrinolíticos y profilaxis con crioprecipitados durante el transcurso de su segundo embarazo, lográndose un producto a término con un parto por cesárea sin complicaciones hemorrágicas o trombóticas.

The factor XIII deficiency is a rare clotting disorder, among which are afibrinogenemia and factor II, V, V+VIII, VII, X and XI ones. These are hemostasis anomalies with autosomal recessive herency; its prevalence is 1 in 500,000 to 2 million people. For its rarity, type and bleeding severity, and its unclear molecular defect, this is a challenge diagnostic and therapeutic effort. The are not clotting factor concentrates available, reason what it is necessary to use blood derivatives or alternative hemostatic agents, which can generate complications, sometimes fatal; these complications can be minimized assessing in each case its bleeding or thrombosis riks to select alternatives to blood or not to do treatment in mild bleeding episodes. This paper describes a case of a women diagnosed with XIII deficiency that began with hematuria and gynocobstetric complications; she received plasma concentrates and antifibrinolytic agents, plus prophylaxis with these products in her second pregnancy, achieving a at term product by caesarean section without any complications.

Evaluation of a Blood Coagulation Factor XIII Assay Kit

BACKGROUND: Plasma coagulation factor XIII (FXIII) catalyzes the formation of covalent bounds between fibrin monomers, thus stabilizing the fibrin clot and increasing its resistance to fibrinolysis. Alteration of FXIII may contribute to bleeding, wound dehiscence and recurrent abortion. However, standard clotting tests cannot detect the FXIII deficiency. In this study, we evaluated a newly developed FXIII test kit (CoalinkTM, PeopleBio Inc., Seoul, Korea) in patients with various clinical conditions. METHODS: We evaluated the linearity and precision of the new FXIII test kit and compared the results of the new kit and the Pefakit FXIII assay. The FXIII was tested in idiopathic thrombocytopenic purpura (ITP) (n=40) patients, chronic renal failure (CRF) (n=20) patients, liver cirrhosis (LC) (n=40) patients, EDTA-induced pseudothrombocytopenia (EDTAIP) (n=10) patients, and in normal healthy persons (n=50). In the normal healthy persons, we determined a complete blood count (CBC), Ed-highlight-the second (n=50) is redundant. prothrombin time (PT) measurement and activated partial prothrombin time (aPTT) measurement and evaluated the results using the two assays. RESULTS: Serial dilution experiments with five samples provided good linearity (r2=0.9717). The intra- and inter assay precisions (CV) were 2.3~8.6% and 3.9~14.9%, respectively (n=20). There was a significant correlation between the use of the new kit and the Pefakit FXIII assay (r=0.8798, n=50). The FXIII activities of the normal healthy persons, ITP, CRF, LC and EDTAIP patients were 103.3+/-23.3%, 79.7+/-41.0%, 117.9+/-82.3%, 56.9+/-23.7% and 130.0+/-29.0%, respectively and they were significantly decreased in the ITP and LC patients (P<0.05). The rates below 80% of the FXIII level were 67.5% in the ITP patients, 90.0% in the LC patients, 35.0% in the CRF patients and 0.0% in the EDTAIP patients. FXIII activities were closely related to platelet count (r=0.832, P<0.05) and negatively correlated with PT (r=-0.389, P<0.05) and aPTT (r=-0.326, P<0.05). CONCLUSION: The new kit was determined to have good linearity and precision. Moreover, it was simple and rapid to perform. This method may prove useful for the evaluation of FXIII.

Plasma Factor XIII Activity in Patients with Disseminated Intravascular Coagulation

The objective of this study was to investigate the correlation between factor XIII (FXIII) activity and disseminated intravascular coagulation (DIC) parameters and also to evaluate the clinical usefulness of DIC diagnosis. Citrated plasma from eighty patients with potential DIC was analyzed for FXIII activity. The primary patient conditions (48 male and 32 female, mean age, 51 years) were malignancy (n = 29), infection (n = 25), inflammation (n = 6), heart disease (n= 3), thrombosis (n = 2), injury (n = 2), and other miscellaneous conditions (n = 13). FXIII testing was performed using the CoaLinkTM FXIII Incorporation Assay Kit (PeopleBio Inc.). Among 80 patients who were suspected to have DIC based on clinical analysis, 46 (57.5%) fulfilled the overt DIC criteria (DIC score > = 5) according to the International Society of Thrombosis and Haemostasis. FXIII levels in the plasma were significantly decreased in overt DIC compared to non-overt DIC patients (mean 75.1% and 199.7% respectively, p < 0.0001). Interestingly, we found a significant inverse correlation between DIC scores and FXIII activity. In addition, FXIII activity significantly correlated with other hemostatic markers that included platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer. FXIII levels were significantly lower in patients with liver or renal dysfunction. In conclusion, FXIII cross-linking activity measurements may have differential diagnostic value as well as predictive value in patients who are suspected to have DIC.

Identification of Plasma Coagulation Factor XIII, Transglutaminase 3 and N epsilon-(gamma-glutamyl) lysine cross-Link in the Silicotic Nodule by Immunohistochemistry / 대한산업의학회지

OBJECTIVES: This study was performed to examine the immunohistochemical distribution of TGase 1, 2, 3, coagulation factor XIII and N epsilon-(gamma-glutamyl) lysine cross-link in the silicotic nodules formed after an intratracheal instillation of the silica. METHODS: The immunohistochemical examinations used antibodies against TGase 1, 2, 3, coagulation factor XIII and N epsilon-(gamma-glutamyl) lysine isopeptide in the silicotic nodules induced after an intratracheal instillation of 50 mg of size fractionated, crystalline silica. RESULTS: A high level of TGase 3 was related to the severity of fibrosis in silicotic nodules and extracellular coagulation factor XIII was detected around the nodules. Expressions of both membrane-bound TGase 1 and TGase 2 were barely detected in the nodules although high expressions were detected in the intact lung. Formation of N epsilon-(gamma-glutamyl) lysine cross-links was increased in severe fibrotic nodules. CONCLUSIONS: TGase 3 might contribute to the eventual stone-like fibrosis via formation of N epsilon-(gamma-glutamyl) lysine cross-links. Futhermore, coagulation factor XIII plays a role in the formation of a provisional matrix which results in fibrogenesis during silicotic nodule formation.

Efeito do fator XIII da coagulação na cicatrização da pele de ratos em uso de corticosteróide / Effect of factor XIII on the healing of rat skin in use of corticosteroid

OBJETIVOS: Observar o efeito do fator XIII da coagulação (Fibrogamin®) na cicatrização de feridas incisas da pele de ratos tratados com corticosteróide. Foi feita a avaliação quanto ao aspecto histopatológico dos tecidos em cicatrização e sua resistência à tensão. MÉTODO: Foram utilizados 40 ratos Wistar, divididos em quatro grupos. No grupo A (n=10), foi administrado corticosteróide. No grupo B (n=10) foi usado corticosteróide e fator XIII. No grupo C (n=10) foi injetado fator XIII e no grupo D (n=10) foi administrado placebo (controle). A resistência à tensão foi medida através de tensiômetro computadorizado e as alterações histopatológicas quantificadas por análise digital. RESULTADOS: Ocorreu uma significativa diminuição da resistência da ferida de pele no grupo A (523,6gf), quando comparado com o controle (1480,4gf). No grupo B (868,8gf) notou-se significativa diferença em relação ao grupo A (p<0,0001). O grupo C não mostrou diferença (p=0,067) em relação ao grupo controle (D), entretanto foram observadas diferenças significativas quando comparados os grupos A e C; A e D (p<0,0001). A análise da densidade do colágeno e de células inflamatórias revelou as mesmas diferenças observadas na resistência à tensão. CONCLUSÕES: Foi observado que a ação do corticosteróide dificultou a cicatrização da pele de ratos e diminuiu a resistência à tensão, ação revertida pelo uso do fator XIII . A utilização do fator XIII sem uso de corticosteróide não demonstrou ação de melhora nos resultados da cicatrização em relação ao controle.

OBJETIVE: There is increasing evidence that coagulation factor XIII is protective in models of wound healing . Our purpose is to observe the effects of coagulation factor XIII on the healing of skin wound of rats treated with corticosteroid. METHOD: Fourty Wistar rats, weighing 245±15g, were randomly divided into four groups. In group A (n=10) the rats received corticosteroid IM. In group B (n=10) corticosteroid and factor XIII were used IM. In group C ( n=10) the rats received only factor XIII and in group D (n=10) saline solution was used (control). The tensil strenght of the wound was measured by a computed tensiometer and the hystopatologic evolution of healing was quantitated by a digital system. RESULTS: The results indicated a significant difference (p<0.0001) of tensil strenght between group A ((523.6gf) and the control (D) group (1480.4gf). In group B the tensil strenght (868.8gf) was significantly greater than in group A (p<0.0001). The factor XIII didn't increase the tensil strenght in group C, when compared with control (p=0,067). The hystopatologic analysis indicated a similar tendency observed in tensil strenght. CONCLUSIONS: There was a strong correlation between factor XIII, tensil strenght and healing of sutured skin wounds of rats treated with corticosteroid. The fator XIII didn't change the wound healing in rats with no corticosteroid.

A Case of Congenital Factor XIII Deficiency Diagnosed by Semiquantitative Method / 대한혈액학회지

Factor XIII (fibrin stabilizing factor) has roles of stabilizing clot and cross-linking fibrin polymer, so the congenital factor XIII deficient patient has clot unstability and delayed bleeding episodes. We experienced a case of 11 years old girl who had experienced delayed umbilical healing, several episodes of intraabdominal and intracranial hemorrhage. But her coagulation screening studies with prothrombin time, aPTT (activated partial thromboplastin time), bleeding time showed normal value at each episode. These findings suggested typical features of congenital factor XIII deficiency. We used semiquantitative method to diagnose Factor XIII deficiency and quantify Factor XIII. We has treated her successfully with prophylactic fresh frozen plasma through plasmapheresis from two donors.

No Association of Factor XIII Val34Leu Polymorphism with Primary Intracerebral Hemorrhage and Healthy Controls in Korean Population

The polymorphism in the factor XIII A-subunit gene (FXIII Val34Leu) has been recognized as a risk factor for primary intracerebral hemorrhage (PICH). In addition, FXIII Val34Leu has a significant ethnic heterogeneity. FXIII Val34Leu was detected in 41.7-54.8% of the Westerners, but in 2.5% of the Asians. We aimed to evaluate the prevalence of FXIII Val34Leu in patients with PICH and in healthy controls among Koreans. We recruited 58 in-patients with PICH, defined by brain computed tomography or magnetic resonance imaging, and 48 controls matched for age, sex, and risk factors for cerebrovascular diseases. Genomic DNA was extracted from blood. A 183-bp fragment of exon 2/intron B of the factor XIII Asubunit gene was amplified by polymerase chain reaction (PCR). The factor XIII genotype was determined through a single-stranded conformational polymorphism. Fifty-eight patients and 48 controls showed the same band patterns on SSCP. In addition, we directly sequenced six random-selected DNA segments using DNA auto-sequencer. In conclusion, the results of this study suggest that FXIII Val34Leu be absent or rare both in patients with PICH and in healthy controls among Koreans.

Effects of Val34Leu and Val35Leu polymorphism on the enzyme activity of the coagulation factor XIII-A

Change in fibrin stabilizing activity of factor XIII A subunit (FXIII-A) caused by a specific mutation, Val34Leu, is recently implicated to incidences of pathophysiology of thrombosis. In an effort to understand the effect of Val34Leu on enhanced catalytic role of FXIII-A, wild type human factor XIII A (HFXIII-A) and mutant HFXIII-A: HFXIII-A (V34L), HFXIII-A (V35L) and HFXIII-A (V34L/V35L) cDNA were expressed in E.coli system where the purified recombinant FXIII-A (rFXIII-A) showed a similar specific transglutaminase activity comparable to the human native FXIII-A from platelet. Using these rFXIII-A mutants, the activation kinetics by thrombin and the enzymatic properties of the activated rFXIII-A were characterized. rFXIII-A (V34L) and rFXIII-A (V34L/V35L) mutants were activated by thrombin much faster than those of wild type rFXIII-A and V35L variant. However, the activated rFXIII-A and mutants showed the identical catalytic efficiency as measured by in vitro assay. These results suggest that ready activation caused by a specific mutation of neighboring thrombin cleavage site(s) in the activation peptide of FXIII-A like V34L resulted in the real-time amount of the activated factor XIII-A that could influence the outcome of fibrin stabilization in vivo such as alpha2- plasmin inhibitor crosslinking to fibrin, a reaction known to be dependent on the initial concentration of active factor-XIII-A.

Effect of Plasma Coagulation Factor XIII Deficiency on the Healing Following Trabeculectomy in Rabbits

Conjunctival fibroblastic proliferation with contracting scar formation has been implicated as a possible cause of glaucoma filtering surgery failure. The inhibitory effect of plasma coagulation factor XIII deficiency on the healing following trabeculectomy of the eyes in rabbits was studied. The plasma coagulation factor XIII deficiency was induced by two successive intravenous injections of anti-rabbit plasma coagulation factor XIII-goat immunoglobulin. Grossly, artificially prepared filtering bleb was well preserved on plasma coagulation factor XIII ddicient groups compared with control groups. Histologically. wound healing following trabeculectomy was delayed and the size of the scar was reduced on plasma coagulation factor XIII deficient groups compared with control groups. The above findings suggest that plasma coagulation factor XIII deficiency inhibit the healing precess following traheculectomy.