Plasma Factor XIII Activity Research Articles

The Involvement of Blood Coagulation Factor XIII in Fibrinolysis and Thrombosis

It has been known for a long time that blood coagulation factor XIII (FXIII) is essential for maintaining haemostasis, its deficiency leads to severe bleeding complication. Biochemical studies have revealed that FXIII is a key regulator of fibrinolysis and, in addition to its role in haemostasis, it has also been implicated in the pathology of arterial and venous thrombosis. Most recently, the polymorphisms in the FXIII subunit genes and their influence on the risk of thrombotic diseases have stirred a lot of interest. This review, besides including the basic biochemistry of FXIII, mainly concentrates on the biochemical and clinical aspects of the involvement of FXIII in fibrinolysis and thrombosis. Biochemical aspects: Basics on the structure and activation of plasma and cellular FXIII. The enzymological features of activated FXIII and its main substrates. The interaction of FXIIIa with fibrinogen/fibrin and with components of the fibrinolytic system. The impact of cross-linked fibrin clot formation on the fibrinolytic processes. The down-regulation of FXIIIa within the fibrin clot. FXIII polymorphisms and their biochemical consequences. Clinical Aspects: FXIII level and the risk of arterial thrombosis (coronary artery disease, peripheral artery disease, ischemic stroke). The effect of FXIII subunit polymorphisms on the risk of arterial thrombotic diseases. The interplay between FXIII polymorphisms and other factors influencing the risk of arterial thrombosis. FXIII and venous thromboembolism.

Cleavage of factor XIII by human neutrophil elastase results in a novel active truncated form of factor XIII A subunit

The first step in the activation of plasma factor XIII (FXIII) is the cleavage of R37-G38 bond in FXIII-A subunit (FXIII-A) by thrombin, which makes the subsequent formation of an active transglutaminase possible. No active truncated form of FXIII-A, other than G38-FXIII-A, has been identified. In contrast to thrombin, which has a preference toward arginine residues, human neutrophil elastase (HNE) cleaves peptide bonds at small side-chain aliphatic amino acids, preferably at valine. As there are several valine residues close to the thrombin cleavage-site, we tested if an active truncated FXIII-A was formed during fragmentation of FXIII by HNE. It was demonstrated by Western blotting and transglutaminase assay that HNE induced a limited cleavage of FXIII-A resulting in the activation of both plasma and cellular FXIII; the maximal transglutaminase activities were 52.5% and 67.4% of thrombin-activated FXIII, respectively. After the relatively rapid activation a much slower inactivation occurred. HNE-activated FXIII cross-linked fibrin gamma- and alpha-chains in the clot formed by batroxobin moojeni. MALDI-TOF analysis of the cleaved fragments and N-terminal Edman degradation of the truncated protein identified V39-N40 as the primary cleavage-site and N40-FXIII-A as the active form. No primary cleavage occurred at V34, V35, V47, V50 residues. FXIII-A V34L polymorphism, which increases the rate of FXIII-A cleavage by thrombin, was without effect on FXIII activation by HNE. Molecular modeling located the primary HNE cleavage-site in the middle of the flexible and accessible Q32-L45 loop and showed that other neighboring valine residues were in less favorable position.

Reply to J. I. Shin et al.

We thank Drs. Jae Il Shin and Jae Seung Lee for their interest in our article ”Henoch-Schönlein purpura (HSP) in an elderly patient with unusual manifestation” [1]. They, like other authors, suggest the utility of measurement of factor XIII activity in the diagnosis of atypical HSP without skin rash. We agree with them that the measurement of plasma factor XIII activity might be helpful in the diagnosis of atypical HSP. Nevertheless all the patients in the reports cited by Lee & Shin were children with severe abdominal pain [2] [3]. Abdominal pain is one of the major manifestations of HSP [4]; however, it was absent in our patient. Moreover, as Gunasekaran et al. reported, decrease of factor XIII activity is not specific for HSP [3].

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.

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

Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery

We investigated the relationship between factor XIII, fibrinogen, blood coagulation screening tests and postoperative bleeding in 98 patients undergoing cardiopulmonary bypass (CPB) surgery. All patients received aprotinin. Blood samples were collected preoperatively (T1),after termination of CPB (T2),12 h (T3) and 24 h (T4) after surgery to determine FXIII activity, fibrinogen, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT) and D-dimers (DD). Laboratory results were correlated with the chest tube drainage 24 h after surgery and compared between patients with 24-hour chest tube drain volumes in the lower (Group 1) with those in the upper tertile (Group 3). Median FXIII and fibrinogen levels dropped by 33.9% and 34.2%, respectively, during CPB. No association between FXIII activity and the extent of postoperative bleeding was found. However, chest tube bleeding was significantly correlated with preoperative and postoperative fibrinogen. This was confirmed by comparing Groups 1 and 3. Group 3 patients had significantly lower fibrinogen levels than Group 1 at T1 - T4, although most fibrinogen values were within or above the reference range (medians, g/l: 3.5 vs. 4.0, p = 0.043 at T1; 2.3 vs. 2.7, p = 0.015 at T2; 2.9 vs. 3.3, p = 0.008 at T3; 4.2 vs. 5.2, p = 0.002 at T4). There was also a significant relationship of platelet count, PT and APTT, as measured after CPB (T2), with postoperative chest tube drainage. In conclusion, plasma FXIII activity does not influence postoperative bleeding in patients undergoing CPB surgery. There is however an inverse association between preoperative or postoperative plasma fibrinogen levels and postoperative bleeding. These findings indicate a modulation of postoperative bleeding by fibrinogen levels.

Effectiveness of Coagulation Factor XIII Concentrate for Reversing Loss of Tensile Strength of Rat Intestinal Anastomoses

Background: Blood coagulation factor XIII (F-XIII) promotes cross-linking of fibrin during blood coagulation. Impaired clot stabilization in patients with genetic deficiencies of F-XIII is associated with marked pathologies of wound healing. Methods: 60 rats given carbon tetrachloride underwent ileal anastomosis after which they received albumin (Alb animals) or F-XIII concentrate (F-XIII animals) immediately after surgery and daily thereafter until day 2 or 4 and were euthanized on day 3 or 5, respectively, or until day 5 and were euthanized on day 7, 10, or 21. We measured the plasma F-XIII activity and anastomotic tensile strength, followed by immunohistochemical localization of F-XIII subunit A within anastomoses. Results: On day 3, there were no significant differences between Alb and F-XIII animals for plasma F-XIII activity and tensile strength, and both groups of animals showed little immunostaining for F-XIII on anastomoses. Plasma F-XIII activities did not differ between Alb and F-XIII animals on day 5 (115.8 ± 16.8 vs. 137.3 ± 14.9%). Although the tensile strength in both groups was increased compared with that of day 3, that in F-XIII animals (129.8 ± 3.3 gf) was significantly higher than that in Alb animals (100.8 ± 5.3 gf, p = 0.014). F-XIII animals showed de novo collagen fibers and intense immunoreactivity of F-XIII in the extracellular matrix around the anastomoses. Similar differences occurred on day 7 but not days 10 and 21. Conclusions: F-XIII concentrate may accelerate the early healing process of intestinal anastomosis because of the protein’s accumulation in situ.

Attempted to Estimate for the Recovery of Liver Function after Partial Hepatectomy by the Determination of 67Ga Accumulation into the Liver and Plasma Factor XIII Activity

Gallium-67 accumulation into the liver of partially hepatectomized rats reached a maximum 2 days after partial hepatectomy. The activity of plasma FXIII from hepatectomized rats reached a minimum (70% of levels in normalrats) 2 days after partial hepatectomy. Time course of plasma FXIII activity is inversely related to 6 7 Ga accumulation pattern. The determination of plasma FXIII activity is a simple and rapid diagnosis procedure and may be used for the estimation to the recover of the liver function after partial hepatectomy. The determination of 6 7 Ga accumulation into the liver after partial hepatectomy indicates the liver regenerating process but may be not proper for the imaging of regenerating liver function in man because of low liver-to-blood ratio.

Racial and genetic determinants of plasma factor XIII activity.

Factor XIII (F XIII), a plasma transglutaminase, is essential for normal hemostasis and fibrinolysis. Plasma F XIII consists of two catalytic A (F XIIIA) and two non-catalytic B (F XIIIB) subunits. Activated F XIII is involved in the formation of fibrin gel by covalently crosslinking fibrin monomers. As the characteristics of the fibrin gel structure have been shown to be associated with the risk of coronary heart disease (CHD), F XIII activity may play a seminal role in its etiology. In this investigation, we determined plasma F XIII activity in two racial groups, including Asian Indians (n = 258) and Chinese (n = 385). Adjusted plasma F XIII activity was significantly higher in Indian men (142 vs. 110%; P<0.0001) and women (158 vs. 111%; P<0.0001) than their Chinese counterparts. As compared to Indians where the distribution of F XIII activity was almost normal, in Chinese it was skewed towards low activity. In both racial groups, bivariate and multivariate analyses showed strong correlation of F XIII activity with plasma fibrinogen and plasminogen levels. Race explained about 25% of the variation in F XIII activity even after the adjustment of significant correlates. We also determined the contribution of common genetic polymorphisms in the F XIIIA and F XIIIB genes in affecting plasma F XIII activity. Both loci showed significant and independent effects on plasma F XIII activity in Indians (F XIIIA, P< 0.01; F XIIIB, P<0.05) and Chinese (F XIIIA, P<0.0001; F XIIIB, P<0.13) in a gene dosage fashion. This study shows that both racial and genetic components play a significant role in determining plasma F XIII activity, and consequently it may affect the quantitative risk of CHD.

Differential Behavior of Coagulation Factor XIII in Patients with Inflammatory Bowel Disease and in Patients with Giant Cell Arteritis

The aim of this prospective study was to examine the role of coagulation factor XIII (FXIII) in relation to disease activity in inflammatory bowel disease (IBD) and in giant cell arteritis. Plasma FXIII activity was studied during active and inactive disease in newly diagnosed patients with Crohn’s disease (CD; n = 20), ulcerative colitis (UC; n = 18) and giant cell arteritis (GCA; n = 19), in 3-month intervals (median follow-up 12 months). FXIII was also measured in two noninflammatory control groups, age and sex matched for IBD (n = 25) and GCA (n = 26). FXIII activity was significantly lower in active CD or UC than in active GCA or the noninflammatory controls. Both in CD and UC, FXIII activity correlated inversely with indices of clinical disease activity, the erythrocyte sedimentation rate, fibrinogen and C-reactive protein levels. Low FXIII activity is a characteristic feature of active IBD, and serial measurements may be useful to assess IBD activity.

Factor XIII deficiency.

Factor XIII deficiency.

Genotype/Phenotype Correlations for Coagulation Factor XIII: Specific Normal Polymorphisms Are Associated With High or Low Factor XIII Specific Activity

Factor XIII is a transglutaminase essential for normal hemostasis. We have studied the plasma FXIII levels and FXIII activity in 71 individuals and found these to be normally distributed. FXIII specific activity is also normally distributed. However, we show that FXIII activity is not directly dependent on FXIII levels, and individuals with low FXIII levels may have high FXIII activity and vice versa. We have determined the FXIIIA genotype in these individuals to assess whether the variation observed in FXIII specific activity is dependent on specific polymorphisms in the FXIIIA gene. Our data show that the Leu34 and Leu564 variants give rise to increased FXIII specific activity, while the Phe204 variant results in lower FXIII specific activity. We also report preliminary evidence that the Phe204 polymorphism may be associated with recurrent miscarriage. Overall, we have identified 23 unique FXIIIA genotypes. Certain specific FXIIIA genotypes consistently give rise to high, low, or median FXIII specific activity levels, while others appear to have little or no consistent influence on the FXIII phenotype. These genotype to phenotype relationships are discussed in light of the growing interest in the role of FXIII in clinical problems involving an increased thrombotic tendency.

Genotype/Phenotype Correlations for Coagulation Factor XIII: Specific Normal Polymorphisms Are Associated With High or Low Factor XIII Specific Activity

AbstractFactor XIII is a transglutaminase essential for normal hemostasis. We have studied the plasma FXIII levels and FXIII activity in 71 individuals and found these to be normally distributed. FXIII specific activity is also normally distributed. However, we show that FXIII activity is not directly dependent on FXIII levels, and individuals with low FXIII levels may have high FXIII activity and vice versa. We have determined the FXIIIA genotype in these individuals to assess whether the variation observed in FXIII specific activity is dependent on specific polymorphisms in the FXIIIA gene. Our data show that the Leu34 and Leu564 variants give rise to increased FXIII specific activity, while the Phe204 variant results in lower FXIII specific activity. We also report preliminary evidence that the Phe204 polymorphism may be associated with recurrent miscarriage. Overall, we have identified 23 unique FXIIIA genotypes. Certain specific FXIIIA genotypes consistently give rise to high, low, or median FXIII specific activity levels, while others appear to have little or no consistent influence on the FXIII phenotype. These genotype to phenotype relationships are discussed in light of the growing interest in the role of FXIII in clinical problems involving an increased thrombotic tendency.

The role of factor XIIIVal34Leu in cardiovascular disease.

Blood coagulation factor XIII (also called fibrin-stabilizing factor1) plays an important role in clot stabilization by crosslinking fibrin chains.2 Factor XIII (FXIII) was discovered over 70 years ago by Barkan et al. , who observed the insolubility of fibrin clots in the presence of calcium.3 Most studies on FXIII have been carried out in patients with FXIII deficiency which results in a serious bleeding diathesis, defective wound healing and a high risk of miscarriage in the deficient female.4,5 Most of these subjects show no plasma FXIII activity because of a complete absence of the A-subunit in plasma, platelets and monocytes.6 Little is known about the role of FXIII in vascular diseases. Although Kloczko et al. showed increased levels of FXIII A-subunit antigen in patients with obliterative atherosclerosis of the lower limbs and in patients with diabetic angiopathy, small patient numbers make the interpretation of these data difficult.7,8 However, increased plasma concentration of cross-linked fibrin polymers in acute myocardial infarction has been described, assuming the presence of increased plasma FXIII plasma activity in patients with coronary artery disease.9 Results from our laboratory add further support in the involvement of FXIII in cardiovascular diseases.10,11 Here we discuss some new insights regarding the role of FXIII in vascular disease, with emphasis on a common polymorphism in the A-subunit gene of FXIII (FXIIIVal34Leu) and its association with myocardial infarction, stroke and venous thromboembolism. Blood coagulation FXIII is a transglutaminase composed of two A- and two B-subunits circulating in plasma as a tetramer (A2B2).12 All A-subunit molecules in plasma are in complex with the B-subunit (carrier protein) at a concentration of approximately 21 μg/ml, whereas the B-subunit is present in both free and complexed form.13 …

Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function.

Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated by the concerted action of thrombin and Ca2+ in the final stage of the clotting cascade. In addition to plasma, FXIII also occurs in platelets, monocytes, and monocyte-derived macrophages. While the plasma factor is a heterotetramer consisting of paired A and B subunits (A2B2), its cellular counterpart lacks the B subunits and is a homodimer of potentially active A subunits (A2). The gene coding for the A and B subunits has been localized to chromosomes 6p24-25 and 1q31-32.1, respectively. The genomic as well as the primary protein structure of both subunits has been established, and most recently the three-dimensional structure of recombinant cellular FXIII has also been revealed. Monocytes/macrophages synthesize their own FXIII, and very likely FXIII in platelets is synthesized by the megakaryocytes. Cells of bone marrow origin seem to be the primary site for the synthesis of subunit A in plasma FXIII, but hepatocytes might also contribute. The B subunit of plasma FXIII is synthesized in the liver. Plasma FXIII circulates in association with its substrate precursor, fibrinogen. Fibrin(ogen) has an important regulatory role in the activation of plasma FXIII. The most important steps of the activation of plasma FXIII are the proteolytic removal of activation peptide by thrombin, the dissociation of subunits A and B, and the exposure of the originally buried active site on the free A subunits. The end result of this process is the formation of an active transglutaminase, which cross-links peptide chains through epsilon(gamma-glutamyl)lysyl isopeptide bonds. Cellular FXIII in platelets becomes activated through a nonproteolytic process. When intracytoplasmic Ca2+ is raised during platelet activation, the zymogen--in the absence of subunit B--assumes an active configuration. The protein substrates of activated FXIII include components of the clotting-fibrinolytic system, adhesive and contractile proteins. The main physiological function of plasma FXIII is to cross-link fibrin and protect it from the fibrinolytic plasmin. The latter effect is achieved mainly by covalently linking alpha 2 antiplasmin, the most potent physiological inhibitor of plasmin, to fibrin. Plasma FXIII seems to be involved in wound healing and tissue repair, and it is essential to maintaining pregnancy. Cellular FXIII, if exposed to the surface of the cells, might support or perhaps take over the hemostatic functions of plasma FXIII; however, its intracellular role has remained mostly unexplored.

Involvement of blood coagulation factor XIII in burn healing in the carbon tetrachloride-induced hepatic injury model in rats.

An involvement of blood coagulation factor XIII (FXIII) in healing of burns was examined in rats with the carbon tetrachloride (CCl4)-induced hepatic injury. The oral administration of 2 and 4 ml/kg CCl4 to rats every 4 days delayed healing of the burns induced on the back skin and decreased FXIII activity. These animals showed some hepatotoxic signs (increased glutamic-oxaloacetic and glutamic-pyruvic transaminases) and accelerated blood coagulation system (increased fibrino-peptide A and fibrin degradation product). The delay in the burn healing was shortened by repeated intravenous injections with normal human placenta-derived FXIII concentrate (Fibrogammin P; 120 U/body) every 4 days. There was a negative correlation between plasma FXIII activity at the end of experiment and the time required for wound healing. These findings suggest that reduction in FXIII activity may be one of the factors inducing delayed wound healing in the CCl4-induced hepatic injury rats.

Pharmacokinetics and Tolerability of Factor XIII Concentrates Prepared from Human Placenta or Plasma: a Crossover Randomised Study

The pharmacokinetics and tolerability of factor XIII (FXIII) from plasma were compared with those of FXIII from placenta in a randomised, double-blind, crossover study involving 13 patients with congenital FXIII deficiency. Both FXIII activity and FXIII antigen were monitored. No difference was seen in the mean half-lives of the two preparations (9.3 days and 9.1 days for plasma and placenta FXIII activity, respectively). Response was similar for both preparations, but was slightly greater for FXIII from plasma (1.6 ormula: see text] vs 1.5 [formula: see text]). Similar results were found for recovery (65% vs 60%). The area under the data completed by extrapolation was significantly higher for FXIII from plasma. No differences between preparations in terms of efficacy or tolerability were observed. It can be concluded that treatment with FXIII concentrate from plasma is as efficient as with FXIII concentrate from placenta in terms of recovery and half-life. Both preparations were equivalent in terms of safety during the observation period. With the administration of monthly injections of approximately 30 U/kg serious bleeding events were prevented and no other serious adverse events occurred.

Platelet Factor XIII Becomes Active without the Release of Activation Peptide during Platelet Activation

The potentially active A subunit of factor XIII of blood coagulation has also been detected in platelets and monocytes/macrophages through the exact function of this cellular protransglutaminase has not yet been elucidated. In physiological conditions the first step in the activation of plasma factor XIII is the removal of an activation peptide from the N-terminal end of subunit A by thrombin. The A subunit then, in the presence of Ca2+, dissociates from the inhibitory B subunit and assumes an active conformation. Cellular factor XIII, which lacks B subunit, can be proteolytically activated in vitro by thrombin and the intracellular Ca2+ sensitive protease, calpain, in the same way as plasma factor XIII subunit A, and calpain has been suggested as the intracellular protease involved in the activation of cellular factor XIII in platelets. In the present experiments it was shown by SDS PAGE that during long-term stimulation of platelets with thrombin nondisulfide-crosslinked high M(r) protein polymers not penetrating the concentrating gel were formed. The lack of these polymers in thrombin-stimulated factor XIII deficient platelets clearly indicated that their formation in normal platelets was due to factor XIII that became active during platelet activation. However, no release of the activation peptide could be detected by Western blotting during this process. Similarly, no proteolytic cleavage of factor XIII was detectable when platelets were stimulated by Ca2+ ionophore through this stimulus activated calpain as it was clearly demonstrated by the breakdown of major intracellular calpain substrates.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions of factor XIII with fibrin as substrate and cofactor

Factor XIIIa (a2') is a homodimeric transglutaminase that is formed via limited alpha-thrombin-catalyzed proteolysis of the platelet (a2) or plasma (a2b2) factor XIII zymogen in a reaction that results in proteolytic removal of a 37-aminoacyl residue peptide from the N-terminus of the a chains and exposure of the active-site thiol group in the resulting a' chains of factor XIIIa. In this study, we characterized interactions of factor XIII and factor XIIIa with fibrin, a natural substrate for factor XIIIa and a cofactor for the alpha-thrombin-catalyzed activation of plasma factor XIII. The carbamylmethyl derivatives of the active-site thiol group of platelet factor XIII (CMa2) and factor XIIIa (CMa2') were prepared, and their interactions with fibrin were measured. The enzyme-like derivative (CMa2') which contained nicked a' chains bound more tightly to fibrin (Kd = 2.1 microM) than did CMa2 (Kd = 14 microM), the platelet zymogen-like derivative with intact a chains, but the binding of each was weaker than the binding of plasma factor XIII zymogen (a2b2) to fibrin (Kd = 0.20 microM) under the same conditions. Saturation of fibrin with plasma factor XIII zymogen (a2b2) did not affect the binding of CMa2' to fibrin, suggesting that the plasma factor XIII zymogen (a2b2) and the active-site-modified form of factor XIIIa (CMa2') bind to separate, noninteracting sites of fibrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of calcium ion in the generation of factor XIII activity

The involvement of calcium ion in the activation of both plasma factor XIII (alpha 2 beta 2) and platelet factor XIII (alpha 2) was investigated. The second-order dependence of the rate constant for exposure of the active-site thiol group of alpha-thrombin-cleaved plasma factor XIII (alpha 2'beta 2) on the concentration of calcium ion suggested that the binding of two calcium ions is required for transformation of the alpha 2'beta 2 tetramer to enzymatically active factor XIIIa. Fibrinogen, previously reported to lower the calcium ion concentration required for efficient activation of alpha 2'beta 2 [Credo, R. B., Curtis, C. G., & Lorand, L. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 4234-4237], was found in the present study to increase the rate of exposure of the active-site thiol group. Whereas calcium ion is required for exposure of the active-site thiol group in cleaved plasma factor XIII (alpha 2'beta 2), exposure of an active-site thiol group in cleaved platelet factor XIII (alpha 2') occurs in the absence of calcium ion. The rate constant (2.2 x 10(5) M-1 s-1) for alpha-thrombin-catalyed exposure of the active-site thiol group of platelet factor XIII zymogen (alpha 2) in the presence of calcium ion was greater than the rate constant (0.7 x 10(5) M-1 s-1) determined in the absence of calcium ion.(ABSTRACT TRUNCATED AT 250 WORDS)