Traumatic intracranial hemorrhage in pediatrics: Implications of factor XIII deficiency and consumptive coagulopathy in abusive head trauma evaluation.

For infants that present with intracranial hemorrhage in the setting of suspected abusive head trauma (AHT), the standard recommendation is to perform an evaluation for a bleeding disorder. Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder associated with intracranial hemorrhages in infancy, though testing for FXIII is not commonly included in the initial hemostatic evaluation. The current pediatric literature recognizes that trauma, especially traumatic brain injury, may induce coagulopathy in children, though FXIII is often overlooked as having a role in pediatric trauma-induced coagulopathy. We report an infant that presented with suspected AHT in whom laboratory workup revealed a decreased FXIII level, which was later determined to be caused by consumption in the setting of trauma induced coagulopathy, rather than a congenital disorder. Within the Child Abuse Pediatrics Research Network (CAPNET) database, 85 out of 569 (15 %) children had FXIII testing, 3 of those tested (3.5 %) had absent FXIII activity on qualitative testing, and 2 (2.4 %) children had activity levels below 30 % on quantitative testing. In this article we review the literature on the pathophysiology and treatment of low FXIII in the setting of trauma. This case and literature review demonstrate that FXIII consumption should be considered in the setting of pediatric AHT.

A multicenter, real-world experience with recombinant FXIII for the treatment of patients with FXIII deficiency: from pharmacokinetics to clinical practice. The Italian FXIII Study.

BACKGROUND: Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteen®) in a population of patients with FXIII deficiency. Other objectives were to compare the different pharmacokinetic (PK) profiles of each patient and to use them to create a tailored prophylaxis regimen. MATERIALS AND METHODS: We collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020. RESULTS: Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported. DISCUSSION: Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

Expression and methylation status of vascular endothelial growth factor and thrombospondin-1 genes in congenital factor XIII-deficient patients with intracranial hemorrhage.

Congenital factor XIII (FXIII) deficiency is one of the rarest bleeding disorders, with an incidence of one per 2 million persons. Intracranial hemorrhage (ICH), a major cause of mortality in FXIII deficiency, is reported to be associated with vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1). Therefore, we investigated the association of VEGF and TSP-1 expression and methylation patterns with ICH in congenital FXIII deficiency patients. This study was conducted on 40 participants with FXIII, 20 of whom experienced ICH (cases), and 20 who did not (controls). Methylation pattern, gene expression, and plasma protein level were assessed using bisulfite sequencing PCR, quantitative real-time PCR, and ELISA. We found a partially methylated pattern for both VEGF and TSP-1 (P > 0.05). VEGF mRNA levels of the case group were significantly higher than those of the control group (P < 0.05), whereas TSP-1 mRNA levels did not show significant upregulation (P > 0.05). Plasma VEGF and TSP-1 concentrations in the case group were higher, but not statistically significant (P > 0.05). Our findings showed no obvious correlation between VEGF or TSP-1 methylation patterns and expression, suggesting that their expression in FXIII deficiency may not solely be controlled by gene methylation.

Identification of novel pathogenic F13A1 mutation and novel NBEAL2 gene missense mutation in a pedigree with hereditary congenital factor XIII deficiency.

The genetic defects of a 12-year-old patient with factor XIII deficiency (FXIIID) and eight pedigree members suspected with FXIIID were studied. Clinical diagnosis, pedigree investigation, phenotypic study and genetic analysis were performed. DNA sequence analysis revealed that the proband had a novel deletion mutation of F13A1 gene (NM_000129: exon 12: c.1652delC: p.Thr551LysfsTer26) which he inherited from both the parents who were heterozygous for the same 1652delC deletion. This frameshift (p.Thr551LysfsTer26) led in homozygous form to severe FXIIID. Additionally, a homozygous missense mutation of NBEAL2 gene (NM_015175: exon 13: c.1367C > T: p.Ala456Val) was identified in the proband. Again, the mutation was inherited from both the parents who were heterozygous for the same c.1367C > T novel mutation. Other members of the pedigree were also revealed to be heterozygous for the same proband's F13A1 and NBEAL2 genes mutations. We first report a pedigree with pathogenic F13A1 gene mutation and a novel mutant NBEAL2 gene.

Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency.

Recombinant factor XIII-A2 (rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2 prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A2 (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A2 dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A2 efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A2; their median age was 26.0 years (range: 7.0-77.0). rFXIII-A2 was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A2 prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A2 dose, and four were performed 10 to 21 days after the last dose.

A large case series on surgical outcomes in congenital factor XIII deficiency patients in Iran.

Essentials Data on surgery in factor XIII (FXIII) deficiency patients are scarce and lack standardized guidelines. Variable dosage of 10-50 U kg-1 was given to FXIII deficiency patients undergoing surgery. Surgical outcomes showed excellent hemostasis with a minimal risk of post-operative complications. Surgery can be performed safely in FXIII deficiency patients following FXIII administration. SUMMARY: Background The lack of accepted standardized surgical guidelines leads to dependence on the treating physicians' and centers' experiences. Aim Our aim is to evaluate the surgical outcomes of a large group of congenital factor XIII deficiency (FXIIID) patients. Methods A case series study was conducted prior to surgery on congenital FXIIID patients in two major referral centers located in Iran from 2010 to 2016. All patients were on prophylaxis using plasma factor XIII concentrate (10 U kg-1 , every 28 days) except for three patients. Single doses of 10 U kg-1 or 30 U kg-1 plasma factor XIII concentrate were given before a minor procedure and circumcision, respectively. Two doses of plasma factor XIII concentrate, one 30 U kg-1 prior to the procedure and the second dose of 30 U kg-1 on postoperative day 3, were given for major surgery. The dose was 50 U kg-1 both before and after neurosurgical procedures. Results One hundred and sixty-two FXIIID patients underwent minor, major and obstetrical/gynecological surgeries. Median age of the patients was 14 years (ages ranged 15 days to 47 years). The male-to-female ratio was 89/73. Five postoperative complications, two bleeding and three thrombosis, were recorded. Conclusion Our study showed excellent hemostasis in FXIIID patients undergoing surgeries. During the period of these surgeries, we observed only 1.8% postoperative complications. Surgery can be performed safely in FXIIID patients, and our proposed treatment regimens lead to adequate hemostatic coverage with minimal risk, for both minor and major surgeries.

Long-term prophylaxis in patients with severe congenital factor XIII deficiency is not complicated by inhibitor formation.

: Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder accompanied by a variety of bleeding events. Severely deficient patients require regular replacement therapy. With development of FXIII concentrate, the risk of viral infections transmitted by fresh frozen plasma and cryoprecipitate is diminished, but the possibility of inhibitor development remains a challenging issue in the management of these patients. The aim of this study was to assess FXIII inhibitor development in Iranian patients with FXIII deficiency (FXIIID). This study enrolled 50 (30 women and 20 men) patients with severe congenital FXIIID from southeast Iran who underwent long-term (more than 4 years or more than 50 injections) prophylaxis with FXIII concentrate (Fibrogammin P, Dade Behring, Marburg, Germany). We evaluated plasma FXIII activity and FXIII inhibitor on day 28 after the last prophylaxis administration. The method for investigation of FXIII inhibitor was based on Bethesda assay. The mean age of the study population was 13.8 ±â€Š8.3 years. The minimum and maximum FXIII activity levels were less than 1-4.5% (mean ±â€ŠSD, 2.6 ±â€Š0.7%). Our investigations showed that all patients with severe form of FXIIID were treated without inciting inhibitor development. Despite long-term prophylaxis in the studied patients, none was found to have developed FXIII inhibitors.

Neoplasm-induced bleeding in inherited, heterozygous FXIII-A deficiency.

UNLABELLED: Inherited mild factor XIII deficiency belongs to one of the most underdiagnosed bleeding disorders so far. This is, because most patients do not develop bleeding complications in daily life. Patient, methods: A man (age: 64 years) without a history of bleeding presented with painful swelling of neck, weight loss, anemia and episodic bleeding from the right tonsil necessitating tonsillectomy. Histologic and immunohistochemical evaluation revealed cytokeratin-positive epitheloid angiosarcoma. Blood coagulation status showed significantly elevated D-dimer and decreased FXIII levels (FXIII-activity 35%, FXIIIA-Ag 16-26%). Plasma mixing studies excluded neutralizing antibodies against FXIII. RESULTS: A novel heterozygous F13A1 gene nonsense mutation (p.Glu103Ter, c.307G>T) was found confirming heterozygous FXIII-A deficiency. The same mutation was detected in two further asymptomatic relatives. For further clinical management the patient was transfused with FXIII-concentrate and showed an adequate increase of FXIII ruling out FXIII deficiency to be induced by increased turnover. Despite this haemostatic management and antifibrinolytic treatment the patient had to undergo several revisions due to delayed, Hb relevant bleeding after cervical lymph nodes extirpation and resection of tonsil. Two chemotherapy cycles with paclitaxel and palliative radiotherapy of the neck area were performed, but the patient died unfortunately two months after diagnosis. CONCLUSIONS: It is a unique case showing the combination of a highly aggressive angiosarcoma and presence of inherited FXIII deficiency. It is also a rare example demonstrating the benefit of FXIII genotyping besides the expected acquired FXIII deficiency possibly due to neoplasm induced increased consumption by elevated crosslinking of fibrin fibers.

Pharmacokinetics and safety of plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency.

UNLABELLED: Congenital factor XIII (FXIII) deficiency is a rare condition with substantial risk for life-threatening bleeding. Replacement of deficient FXIII with plasma-derived FXIII concentrate is a treatment option. The current 12-week study evaluated the steady-state pharmacokinetic (PK) and safety profile of prophylactic infusions of FXIII concentrate (human) in patients with congenital FXIII deficiency. Patients received FXIII concentrate (human) 40 IU kg(-1) on Days 0, 28, and 56. FXIII levels were assessed before and after each infusion; steady-state PK parameters were assessed up to 28 days after the infusion on Day 56. Treatment effectiveness in maintaining trough FXIII activity levels ≥ 5% over 28 days and safety parameters were also assessed. Fourteen patients received FXIII concentrate (human) and 13 completed the study. Post-infusion, FXIII activity levels increased to within the range found in patients without congenital FXIII deficiency without reaching supra-therapeutic levels. Non-baseline-adjusted trough FXIII activity levels were maintained at or above 10% at all post-baseline visits in all patients. Steady-state PK parameters were baseline-adjusted; maximum FXIII activity was 87.7% at 1.72 h post-infusion, subsequently declining to a minimum of 5.0%. The half-life was 6.6 days. FXIII concentrate (human) was generally well tolerated. Two patients had possibly treatment-related adverse events. There were no reports of thromboembolism, viral transmission, bleeding events or treatment-related hypersensitivity. These findings support use of FXIII concentrate (human) 40 IU kg(-1) every 28 days as an appropriate regimen for routine, long-term prophylaxis in children and adults with congenital FXIII deficiency. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov/ct2/show/NCT00883090.

Novel and recurrent mutations in the F13A1 gene in unrelated Korean patients with congenital factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive bleeding disorder mainly caused by mutations in the F13A1 gene on 6p25.1, which lead to defective A subunit of FXIII. We herein describe two unrelated Korean patients with congenital FXIII deficiency. Proband 1 (a 30-year-old man) and Proband 2 (a 10-year-old girl) presented with severe bleeding episodes (huge intramuscular hematoma and acute intracerebral hemorrhage). Coagulation screening tests for bleeding diathesis were normal, but the FXIII activity was undetectable on urea clot lysis assay. The molecular genetic analysis of F13A1 revealed two mutations in the patients: Proband 1 was homozygous for a previously reported mutation c.1984C>T (p.Arg662) and Proband 2 was compound heterozygous for c.1029T>A (p.His343Gln) and c.1984C>T (p.Arg662). His343Gln was a novel missense mutation occurring in the core domain of the FXIII A subunit. This is the first report of genetically confirmed FXIII deficiency in Korea, with novel and recurrent F13A1 mutations.

Efficacy and safety of prophylactic treatment with plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency.

UNLABELLED: Congenital factor XIII (FXIII) deficiency is an extremely rare, potentially life-threatening bleeding disorder. Routine prophylactic management is recommended for individuals with clinically relevant FXIII deficiency. This prospective, multicentre, open-label study evaluated the long-term efficacy and safety of prophylactic infusions of FXIII concentrate (human) 40 IU kg(-1) in patients with congenital FXIII deficiency. FXIII concentrate (human) was administered every 4 weeks for 12 months. Dosing was adjusted to maintain trough FXIII activity levels of 5-20%. Logistical and ethical constraints precluded use of a placebo control group. Annualized incidence of spontaneous bleeding was compared with historical rates; safety was assessed as a secondary objective. Forty-one patients were enrolled and completed the study. The annualized rate for spontaneous bleeding episodes requiring FXIII treatment was 0.000 episodes per patient-year (95% CI: 0.000; 0.097). The study met its primary endpoint: the upper limit of the 95% CI was substantially below the historical rate of 2.5 bleeding episodes per patient-year. Five spontaneous bleeding episodes (involving three patients; none requiring FXIII treatment) and eight trauma-related bleeding episodes (two requiring FXIII treatment) occurred. Five patients had surgery during the study, only one of whom required FXIII treatment for post-surgical bleeding. Most patients (≥ 85%) had trough FXIII activity levels ≥ 10%. No patient discontinued treatment due to an adverse event. No adverse events related to thromboembolism or viral transmission were reported. Prophylactic treatment with FXIII concentrate (human) was well tolerated and prevented spontaneous bleeding episodes that were serious enough to require treatment with FXIII-containing product. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov/ct2/show/NCT00885742.

Recurrent episodes of severe bleeding caused by congenital factor XIII deficiency in a dog.

CASE DESCRIPTION: A 5-year-old castrated male Toy Poodle cross was evaluated because of lethargy, inappetence, and suspected abdominal hemorrhage. The dog had been evaluated on 4 other occasions for episodes of excessive bleeding associated with trauma or surgical procedures. CLINICAL FINDINGS: At previous evaluations, results of repeated measurements of prothrombin time, partial thromboplastin time, and buccal mucosal bleeding time were unremarkable; activated clotting time, plasma von Willebrand factor concentration, results of platelet function testing, and plasma factor VII, VIII, IX, X, XI, and XII concentrations were considered normal. At this evaluation, clinicopathologic analyses revealed mild regenerative anemia that progressed over a 4-day period to moderate regenerative anemia and acute inflammation with panhypoproteinemia. Abdominal ultrasonography revealed a large mass (suspected to be a hematoma) near the urinary bladder. Rotational thromboelastometry revealed that clotting times were within reference limits, with abnormal clot formation times and clot firmness. The result of a factor XIII (FXIII) clot solubility assay confirmed FXIII deficiency. TREATMENT AND OUTCOME: The dog's bleeding diathesis resolved with inpatient care and IV fluid therapy, although plasma transfusions had been required at previous evaluations. Seven months after discharge from the hospital, the dog continued to do well clinically, although it had several additional episodes of excessive bleeding. CLINICAL RELEVANCE: To the authors' knowledge, this is the first reported case of congenital FXIII deficiency in a dog. In addition to more common inherited coagulopathies, FXIII deficiency should be a differential diagnosis for dogs with episodes of excessive bleeding and apparently normal results of standard coagulation tests.

Factor XIII: congenital deficiency factor XIII, acquired deficiency, factor XIII A-subunit, and factor XIII B-subunit.

Factor XIII (FXIII) is a transglutaminase consisting of 2 catalytic A subunits and 2 noncatalytic B subunits in plasma. The noncatalytic B subunits protect the catalytic A subunits from clearance. Congenital FXIII deficiency may manifest as a lifelong bleeding tendency, abnormal wound healing, and recurrent miscarriage. Acquired FXIII deficiency, with significant reductions in FXIII levels, has been reported in several medical conditions. The routine screening tests for coagulopathies-prothrombin time, activated partial thromboplastin time, and thrombin time-do not show abnormalities in cases of FXIII deficiency. A quantitative, functional, FXIII activity assay that detects all forms of FXIII deficiency should be used as a first-line screening test. Treatment consists of recombinant FXIII or FXIII concentrate. If these are unavailable, then fresh-frozen plasma and cryoprecipitates may be used. Factor XIII has a long half-life; therefore, the patients can lead near-normal lives with regular replacements. Patients with acquired FXIII deficiency with inhibitors need immunosuppressive therapy in addition to factor replacements.

Recurrent spontaneous splenic rupture in a patient with congenital factor XIII deficiency.

We describe an unusual presentation of factor XIII (FXIII) deficiency in a 17-year-old boy who was diagnosed with this congenital deficiency at the age of 18 months. He had a history of spontaneous splenic rupture 8 years ago, which was managed conservatively. He now presented with sudden severe abdominal and left shoulder pain for 1 day, with no history of antecedent trauma. He was in shock, and examination revealed diffuse peritonitis. A computed tomography scan showed a grade IV splenic laceration. He was taken as an emergency to the operating room where he was found to have a shattered spleen, and a splenectomy was performed. He received cryoprecipitate transfusions perioperatively. After an uneventful recovery, the patient was discharged. To the best of our knowledge, this is the first described case of a recurrent splenic rupture in a patient with FXIII deficiency.

Congenital factor XIII deficiency in women: a systematic review of literature.

Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder. There is a paucity of data in the literature about obstetrics and gynaecological problems in women affected by FXIII deficiency. The aim of this study was to examine gynaecological problems and obstetric complications and outcome in women with congenital FXIII deficiency. An electronic search was performed to identify the published literature on PUBMED, MEDLINE, EMBASE, Journals @OVID and CINAHL Plus databases using the following keywords: 'congenital factor XIII deficiency' AND 'women OR Pregnancy'. A total of 39 relevant articles were found and included in this systematic review; 27 case reports and 12 case series dating from 1964 to 2012. A total of 121 women were identified. Menorrhagia (26%) was the second most common bleeding reported after umbilical bleeding. Ovulation bleeding reported in 8% of women. Among 63 women, 192 pregnancies were reported; of these, 127 (66%) resulted in a miscarriage and 65 (34%) reached viability stage. In 136 pregnancies without prophylactic therapy, 124 (91%) resulted in a miscarriage and 12(9%) progressed to viability stage. Antepartum haemorrhage occurred in 5/65 (8%) pregnancies reaching viability stage while postpartum haemorrhage (PPH) seen in 16 (25%) cases. Women with congenital FXIII deficiency suffer significant bleeding complications. Menorrhagia and ovulation bleeding are common gynaecological problems and more prevalent than reported. Pregnancies in women with FXIII deficiency have a significant risk of miscarriage, placental abruption and PPH if not on prophylaxis treatment.

Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency.

Factor XIII (FXIII) is a fibrin-stabilising factor consisting of catalytic A subunits (FXIII-A) and carrier B subunits (FXIII-B). FXIII-B prevents the fast clearance of FXIII-A from the circulation. Congenital FXIII-A deficiency is a rare bleeding disorder, and congenital FXIII-B deficiency is even rarer. Through our recent nationwide survey on "acquired haemophilia-like disease due to anti-FXIII autoantibodies," we newly diagnosed severe congenital FXIII-B deficiency in a Japanese man. He developed thrombocytopenia and gingival bleedings at the age of 73, and his FXIII activity was as low as 10% of the normal. When he suddenly developed spontaneous intramuscular haematoma, the bleeding was arrested by infusing FXIII concentrates. However, his FXIII activity remained around 10% of the normal. At the age of 74, ELISA and western blotting assay unexpectedly revealed complete absence of FXIII-B in the patient's plasma. A dot blot assay detected anti-FXIII-B alloantibodies for the first time in this disease, which could be attributed to the infusion of exogenous FXIII. He was found to be homozygous for a Japanese founder-effect mutation of F13B. Repeated infusions of exogenous FXIII for hemostasis increased anti-FXIII-B alloantibodies that resisted FXIII substitution. To the best knowledge of the authors, none of the remaining 10 reported cases of congenital FXIII-B deficiency developed alloantibodies to exogenous FXIII-B of plasma FXIII. An originally mild bleeding phenotype of severe congenital FXIII-B deficiency can be exaggerated by additional acquired conditions. Physicians should consider congenital FXIII-B deficiency when they encounter cases of unexplained bleeding disorders.

Molecular modeling predicts structural changes in the A subunit of factor XIII caused by two novel mutations identified in a neonate with severe congenital factor XIII deficiency.

INTRODUCTION: Coagulation factor XIII (FXIII) is a fibrin-stabilizing factor, which contributes to hemostasis, wound healing, and maintenance of pregnancy. Accordingly, patients with congenital FXIII deficiency manifest a life-long bleeding tendency, abnormal wound healing and recurrent miscarriage. In order to understand the molecular mechanisms of congenital FXIII deficiency, genetic analysis and molecular modeling were carried out in a Japanese male neonate with severe FXIII deficiency. METHODS AND RESULTS: Two novel mutations, Y204Stop (or Y204X, TAT to TAA) and S708R (AGC to AGG), were heterozygously identified by nucleotide sequencing analysis in exons V and XV of the gene for the A subunit of FXIII (FXIII-A). Y204X and S708R would lead to nonsense mediated mRNA decay and misfolding of the FXIII-A molecule, respectively. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, the presence of these mutations was confirmed both together in the proband and one each separately in either the maternal or paternal sides of his family. In addition, moderately decreased FXIII activity was associated with the presence of either mutation. Molecular modeling predicted that the mutant molecule of S708R would be structurally compromised by the substitution of the Ser with the larger extended bulky and positively charged Arg side-chain. CONCLUSION: It is probable that the impaired tertiary structure of the mutant S708R molecule leads to its instability, which is at least in part responsible for the FXIII deficiency of this patient. This is consistent with the fact that the mutations and the reduced FXIII activities co-segregate among the patient's family members.