Low Factor XIII Levels Research Articles

Low factor XIII levels and altered fibrinolysis in patients with multiple myeloma

BackgroundAcquired factor FXIII (FXIII) deficiency can be immune- or non-immune mediated and may cause severe bleeding symptoms. The incidence of acquired FXIII deficiency and its etiology in patients with multiple myeloma (MM) are poorly understood. ObjectivesTo assess FXIII levels and the balance of fibrinolysis in newly diagnosed, untreated MM and monoclonal gammopathy of undetermined significance (MGUS) patients. MethodsFXIII activity, mixing studies, FXIII-A2B2 antigen, total FXIII-B antigen were measured in platelet-poor plasma from 17 untreated MM patients, 33 untreated MGUS patients, and 30 age and sex-matched healthy controls. Besides routine laboratory measurements, the balance of coagulation and fibrinolysis was evaluated using quantitative fibrin monomer (FM) test, thrombin-antithrombin assay, α2-antiplasmin activity, plasmin-α2-antiplasmin (PAP) complex, D-dimer, plasmin generation assay, clot lysis assay, and ClotPro-TPA test. ResultsFXIII-A2B2 levels were significantly lower in MM patients compared to controls [median (IQR):14.6 (11.2–19.4) vs. 21.8 (17.1–26.4) mg/L, p = 0.0015], whereas total FXIII-B did not differ between groups. Decrease in FXIII activity was parallel to the decrease in FXIII-A2B2. An immune-mediated inhibitory mechanism was ruled out. Free/total FXIII-B was significantly higher in MM patients compared to MGUS and healthy controls, suggesting an etiology of FXIII-A consumption. In MM and MGUS patients, FM, D-dimer, and PAP complex were significantly elevated compared to controls, indicating hypercoagulability and ongoing fibrinolysis. ConclusionsLow FXIII levels due to consumption were observed in MM patients at diagnosis. Hypercoagulability and ongoing fibrinolysis were detected in MM and MGUS, indicating that a disturbed hemostasis balance is already present in the latter benign condition.

Coagulation Profile of Children on Extracorporeal Membrane Oxygenation (ECMO) - Is FXIII the Missing Link?

BackgroundPublished data about bleeding management on extracorporeal membrane oxygenation (ECMO) in children is sparse and to date no global transfusion algorithm has been established. Viscoelastic testing can be effective for determining the etiology and management of coagulopathic bleeding during cardiothoracic procedures, but data regarding its usefulness in ECMO patients are scarce. Recently, low factor XIII levels were determined to be a frequent finding in adult ECMO patients(Kalbhenn et al; Perfusion 2015;30:675-82).MethodsThis is a retrospective analysis of thromboelastometry (ROTEM®) and factor XIII data obtained in children (ages 0 to 18 years) undergoing ECMO since 2013 in a single center children’s hospital. Acute bleeding treatment was based on daily ROTEM testing, complete blood count and routine plasmatic coagulation testing. The transfusion algorithm targeted a hemoglobin level >13g dL-1, a Quick’s value >50%, a plasma fibrinogen level >1.5g L-1, and a platelet count of >100,000 µL-1. Red blood cells (RBC), solvent detergent (S/D) plasma and platelet apheresis concentrates were exclusively used to maintain hemostasis. Measurement of FXIII levels is not part of routine testing, but was assessed when unexplained bleeding was observed.ResultsLaboratory and transfusion data from sixteen patients, age 4 (1-15) months [median(IQR)] with a body weight of 6 (3-8) kg were included. Median time on ECMO was 7 (4-9) days. Large volumes of allogeneic blood were transfused to all children, meeting criteria for massive transfusion each individual day on ECMO (Tab.1). Overall, median daily ROTEM measurements were within reference ranges (Tab.2), while median levels of FXIII were decreased despite massive transfusion [FXIII levels 42% (28-51%)].ConclusionPediatric ECMO was almost always combined with daily massive transfusion, which led to correction of overall ROTEM values. Notably, despite transfusion of large amounts of plasma, decreased FXIII levels were noted. This finding is supported by results of a study in adult ECMO patients, where FXIII levels <50% were observed in 88% of all patients. Although inherited homozygous FXIII deficiency is usually defined by levels <5%, even mildly to moderately reduced FXIII levels have been reported to contribute to increased bleeding after cardiac surgery(Ternström et al; Thromb Res 2010;126:e128-33). Further studies should be performed to assess the impact of FXIII substitution in pediatric ECMO patients and to investigate whether substitution of FXIII may decrease bleeding without increasing thrombotic complications. [Display omitted] [Display omitted] DisclosuresHaas:CSL Behring: Speakers Bureau; TEM International: Speakers Bureau; Octapharma: Consultancy.

Clinically needed sensitivity for very low levels of Factor XIII: not yet proven for a new functional assay

Article Clinically needed sensitivity for very low levels of Factor XIII: not yet proven for a new functional assay was published on October 1, 2011 in the journal Clinical Chemistry and Laboratory Medicine (CCLM) (volume 49, issue 10).

Quantification of coagulation factor XIII activity by a thio-NADH based assay using factor XIII immuno-depleted plasma as a diluent for calibration

Accurate determination of factor XIII (FXIII) activity is crucial for replacement therapy. FXIII activity is typically determined using a coupled enzymatic reaction that measures nicotinamide adenine dinucleotide hydride (NADH) consumption at 340 nm. Here, we describe the development of a prototype for a novel FXIII activity assay for detection at 405 nm by replacing NADH with thio-NADH, and the application of FXIII immuno-depleted plasma as a diluent for calibration. Performance data show up to two-fold lower susceptibility of the prototype assay to interferences from hemolyzed, icteric, and lipemic samples when compared to a NADH assay format. In addition, the use of FXIII immuno-depleted plasma as diluent for calibration improved recovery almost two-fold in the lower measurement range. The novel prototype assay correlates well with a conventional assay (r=0.98, y=0.99·x+2.17% FXIII, n=173). The described prototype assay has the potential to (a) increase trueness of measurement of low levels of FXIII, (b) improve robustness due to reduction from interferences, and (c) can be used on a broad range of coagulation instruments due to its detection at 405 nm.

Factor XIII deficiency as a potential cause of supratentorial haemorrhage after posterior fossa surgery

Postoperative intracranial haemorrhage can be a dramatic event, carrying significant morbidity and mortality. Bleeding at sites remote from the operation area represents a small percentage of haemorrhages whose aetiology remains unclear (Harders et al. Acta Neurochir (Wien) 74(1-2):57-60, 1985). We present the case of a 60-year-old patient who underwent posterior fossa craniotomy for the removal of a space-occupying lesion and suffered supratentorial haemorrhage soon after the operation. A thorough postoperative investigation revealed low levels of factor XIII (FXIII), the factor mainly responsible for fibrin clot stabilisation. We suggest that reduced FXIII activity may be an important but preventable predisposing factor to remote postoperative haemorrhage in neurosurgical patients.

Low levels of fibrin-stabilizing factor (factor XIII) in human Plasmodium falciparum malaria: correlation with clinical severity.

Plasmodium falciparum malaria is associated with procoagulant activity but not with thromboembolism. We measured coagulation factor XIII, i.e., fibrin-stabilizing factor, in 45 patients with falciparum malaria over time. Of these, 22 had organ complications. The factor XIII antigen (subunits A and B) and plasma activity levels were abnormally low in those with falciparum malaria. They increased during antiparasitic therapy. In 14 of 22 patients with complications, but in no patient with mild disease (P < 0.001), subunit A and activity was < 50%. The factor X.III levels were inversely correlated with clinical severity, parasitemia, and human neutrophil elastase (HNE), but not with thrombin-antithrombin III levels. Thus, low factor XIII levels may reflect proteolysis by HNE, rather than procoagulant activity. One could speculate that factor XIII degradation in severe malaria prevents thromboembolism. On the other hand, factor XIII deficiency might reduce protection of the vascular endothelium against HNE and reactive oxygen species, which would promote organ damage.

ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group.

A questionnaire was sent out in 1993 to more than 350 European institutions caring for patients with hemorrhagic disorders with the request to provide data of patients with congenital factor XIII deficiency, to pursue the following aims: (1) establish a registry of congenital factor XIII deficiency patients, (2) promote exchange between clinicians and basic researchers, (3) improve diagnostic and therapeutic approaches, and (4) stimulate research on gene defects and their impact on factor XIII function. So far, 72 patient questionnaires from 60 families have been collected. Their bleeding pattern is typical, with frequent involvement of the umbilical cord and the central nervous system. Forty-nine patients receive regular factor XIII replacement, but obviously some patients with mild symptoms do not require prophylactic substitution, despite low factor XIII levels. On the other hand, 18 patients had factor XIII activities of > or = 5% of normal, but only 3 of those patients were reported to have no bleeding symptoms. Furthermore, 17 symptomatic, apparently heterozygous relatives in eight families were observed. Seven out of 30 females aged over 18 years had experienced spontaneous abortions; wound healing problems were seen in 26 patients. Currently, a second questionnaire is being distributed to obtain more detailed information on bleeding and other symptoms, diagnostic approaches, and exclusion of concurrent other bleeding diatheses. Future activities will be validation and standardization of assays, and study of gene defects and their impact on the structure of factor XIII and symptoms of patients. We intend to expand the survey to countries outside Europe.

Hemostasis in Crohn's disease: low factor XIII levels in active disease.

Massive gastrointestinal hemorrhage sometimes occurs in Crohn's disease. To examine the possible role of acquired disorders of hemostasis contributing to such events, several laboratory indicators of hemostasis (APT time, Normotest, platelet count, bleeding time, fibrinogen, factor VIII activity, vWF:Ag, factor X, factor XIII, antithrombin III, fibrinopeptide A, and B beta(15-42] were studied in 10 patients with active Crohn's disease (Crohn's disease activity index (CDAI) greater than 150) and 10 patients with quiescent disease (CDAI less than 150). Marked thrombocytosis was seen in three patients with active disease. Factor VIII activity and fibrinogen levels were significantly elevated in patients with Crohn's disease (p less than 0.001), and the factor VIII activity levels were significantly higher (p less than 0.05) in the patients with active disease than in those with quiescent disease. Factor XIII levels were significantly lower (p less than 0.02) in patients with active disease. Three of the patients with active disease had factor XIII levels below the lower reference limit. The two patients with the lowest levels had hemorrhagic diarrhea and spontaneous bleeding from the rectal mucosa. Fibrinopeptide A and B beta(15-42) levels were significantly elevated in both groups. The other coagulation analyses were essentially normal in both patient groups. The results suggest that factor XIII deficiency acquired through gastrointestinal leakage may contribute to gastrointestinal hemorrhage in some patients with active Crohn's disease.

A possible contributory role of the platelet in the formation of plasma factor XIII.

Factor XIII is a proenzyme found in plasma and platelets which, when activated, catalyses the formation of ε‐(γ‐glutamyl)lysyl bonds in fibrin. Plasma factor XIII is composed of two different polypeptides, a and b, whereas platelet factor XIII has only a subunit. Factor XIIIa, the active enzyme, from both plasma and platelets is enzymatically the same. Platelet factor XIII is synthesized in megakaryocytes and accounts for 50% of the total factor XIII activity in blood. In this study the role of platelet factor XIII in the formation of plasma factor XIII was investigated. The chemotherapeutic agents—quinidine, vincristine, methotrexate and cyclophosphamide—were used to induce thrombocytopenia in rats. Platelet count, plasma factor XIII activity, and fibrinogen concentration were determined along with other haematological parameters. With all four drugs there were concomitant decreases in plasma factor XIII activity along with decreases in the platelet count. Throughout the experiment, fibrinogen concentrations remained within pretreatment levels. In the saline‐treated control animals, the platelet count and plasma factor XIII activity did not significantly differ from the pre‐treatment levels. These observations suggest that the low levels of factor XIII achieved in the treated groups resulted from the effects of the chemotherapeutic agents on thrombocytopoiesis. Statistical analyses of the data indicated a high correlation between platelet count and plasma factor XIII activity. From this study, it is apparent that platelet factor XIII could be a source of a subunit for plasma factor XIII.

Generalized proteolysis in a young woman with Weber-Christian disease (nodular nonsuppurative panniculitis).

A patient with Weber-Christian disease (syn. nodular nonsuppurative panniculitis) is reported. The generalized cellular destruction in this patient resulted in liberation of proteolytic enzymes into the circulation, which led to multiple haemostatic disturbances with haemorrhagic diathesis. The most prominent haemostatic defects were thrombocytopenia with a normal life span of isologous platelets, high levels of AHF-related antigen, hypofibronigenaemia with short fibrinogen survival, low levels of Factor XIII (fibrin stabilizing factor = FSF) and increased amounts of fibrin/fibrinogen degradation products (FDP). Proteolytic enzymes, other than thrombin and plasmin which especially degrade Factor XIII and fibrongen, derived from destroyed cells (probably leukocytes) seem to have been involved in the pathogenesis of the bleeding disorder in this patient.

Fibrinogen-fibrin degradation products and factor XIII.

The effect of fibrinogen/fibrin degradation products (FDP) on the stabilisation of fibrin was tested <i>in vitro </i>by the clot solubility assay and by the transamidase assay of ¹⁴C-glycine-ethyl-ester incorporation into casein. No significant interference with the action of factor XIII by FDP was demonstrated. FDP, prepared <i>in vitro, </i>could act as substrate for factor XIII although compared with casein FDP are a poor substrate. Patients with high titres of FDP in their sera form normal insoluble clot. Defective fibrin stabilisation does not appear to be important in the bleeding diathesis seen in disseminated intravascular coagulation, even though both high titres of FDP and low levels of factor XIII are found.

Clinical Studies Concerning Factor XIII; with Special Reference to Hyperlipemia

SummaryFactor XIII, estimated according to the method of Heene, was found to be diminished in patients with cirrhosis of the liver, in acute renal failure and, to a lesser extent, postoperatively, owing probably to both a decreased synthesis and an accelerated utilization. When compared to values obtained in healthy, normal weight, normolipemic control subjects, the level of factor XIII was higher in hyperlipemic and especially in hypertriglyceridemic patients, whether clinical atherosclerosis was present or not. Low levels of factor XIII were usually accompanied by a decrease in serum pseudocholinesterase, while high values of this enzyme produced by the liver were noted in hypertriglyceridemic patients. The hypothesis of an enhanced synthesis of factor XIII by the liver, in subjects with endogenous hypertriglyceridemia is considered. It is also suggested that accelerated stabilization of fibrin might contribute to the fibrinolytic insufficiency of hyperlipemic patients and enhance certain atherogenic mechanisms.