Bleeding from the umbilical cord in newborns is considered to be one of the principal symptoms of FXIII deficiency [9], while development of hematomas, soft-tissue bruising, and prolonged wound bleeding are common complaints as well [2] [7]. CNS hemorrhage, both intracranially and extracranially, has been documented in temporal, occipital and subdural regions in severe forms of the disease [6]. Due to the vital role FXIII plays in maintaining pregnancy, recurrent miscarriages in the absence of other potential causes may be reported by women [2].

• Pain

  The most common adverse reactions reported in the clinical trials (> or = 1 percent) were headache, pain in the extremities, injection site pain, and D dimer increase. [prnewswire.com]

  Other possible side effects may include pain in your arms or legs, headache, and pain at the injection site. These are not all the possible side effects of Tretten ®. [tretten-us.com]

  Adverse Reactions: Headache, pain in the extremities, injection site pain, increase in fibrin D-dimer levels; hypersensitivity reactions. [empr.com]

  Some of the side effects reported in this study were headache, pain in the extremities and pain at injection site. No individual in the trial developed abnormal clots. [globalgenes.org]

  The most common adverse reactions reported in clinical trials (≥1%) were headache, pain in the extremities, pain at injection site, and increase in fibrin D dimer levels. [trettenpro.com]

• Falling

  […] inherited FXIII deficiency - FXIII inhibitors - rare but may be seen in association with Isoniazid - Henoch-Schoenlein purpura (HSP) - In patients on and following cardiopulmonary bypass - Chronic inflammatory bowel disease - Severe GvHD of the gut - Levels fall [practical-haemostasis.com]

  Still, much of the networking and education about this deficiency fall to those most affected by it. [hemaware.org]

  When she started to walk a fall from her altitude generated an extensive gluteal hematoma. [mjhid.org]

• Ecchymosis

  Percent of people who have these symptoms is not available through HPO Autosomal recessive inheritance 0000007 Bruising susceptibility Bruise easily Easy bruisability Easy bruising [ more ] 0000978 Congenital onset Symptoms present at birth 0003577 Ecchymosis [rarediseases.info.nih.gov]

• Epilepsy

  Birnbaum, MD Quality Leadership Award Named as one of the 100 Best Hospitals in America by Becker's Hospital Review Level 4 (highest) c omprehensive epilepsy center National Cancer Institute-designated cancer center More successful high-risk liver transplants [nebraskamed.com]

• Prolonged Bleeding

  Persistent bleeding after trauma Excessive bleeding after minor trauma Frequent bleeding with trauma Prolonged bleeding after minor trauma [ more ] 0001934 Poor wound healing 0001058 Post-partum hemorrhage Bleeding post-delivery 0011891 Prolonged bleeding [rarediseases.info.nih.gov]

  People with this condition often experience prolonged bleeding following an injury, surgery, or having a tooth pulled. [icdlist.com]

  Bleeding from the umbilical cord in newborns is considered to be one of the principal symptoms of FXIII deficiency, while development of hematomas, soft-tissue bruising, and prolonged wound bleeding are common complaints as well. [symptoma.com]

  If the condition is not treated, affected individuals may have episodes of excessive and prolonged bleeding that can be life-threatening. Abnormal bleeding can occur after surgery or minor trauma. [ghr.nlm.nih.gov]

  Formerly, it was believed that heterozygotes are asymptomatic, but more recent evidence suggests they can have bleeding symptoms. 2 Symptoms include poor wound healing, umbilical stump bleeding, miscarriage, prolonged bleeding from superficial wounds, [mghlabtest.partners.org]

• Easy Bruising

  Factor X deficiency commonly causes nosebleeds, easy bruising, bleeding under the skin, bleeding of the gums, blood in the urine (hematuria), and prolonged or excessive bleeding following surgery or trauma. [icdlist.com]

  […] susceptibility Bruise easily Easy bruisability Easy bruising [ more ] 0000978 Congenital onset Symptoms present at birth 0003577 Ecchymosis 0031364 Intracranial hemorrhage Bleeding within the skull 0002170 Reduced factor XIII activity 0008357 Showing [rarediseases.info.nih.gov]

  Other signs and symptoms of inherited factor XIII deficiency include nosebleeds, bleeding of the gums, easy bruising, problems with wound healing, bleeding after surgery, and abnormal scar formation. [ghr.nlm.nih.gov]

  Other features included haematoma formation, easy bruising, post-traumatic bleeding, delayed wound healing, gastrointestinal bleeding and epistaxis. One child presented with intracerebral bleed. [jpma.org.pk]

• Subcutaneous Bleeding

  Physical Physical manifestations related to bleeding may include the following: Persistent bleeding from the stump of the umbilical cord in newborns [5] Soft tissue and subcutaneous bleeding Neurologic findings commensurate with CNS hemorrhage Bleeding [emedicine.medscape.com]

  1, 4, 12 ] The case we described here suffered from umbilical stump bleeding, and subcutaneous and muscle bleedings at very early age. [mjhid.org]

• Bleeding Gums

  Easy bleeding 0011889 Delayed onset bleeding 0040232 Epistaxis Bloody nose Frequent nosebleeds Nose bleed Nose bleeding Nosebleed [ more ] 0000421 Gingival bleeding Bleeding gums 0000225 Menorrhagia Abnormally heavy bleeding during menstruation 0000132 [rarediseases.info.nih.gov]

• Short Arm

  The present findings, in combination with earlier knowledge of PGM3 /GLO/HLA localization and gene distances, show that F13A is distal to HLA on the short arm of chromosome 6 in man [7]. [wikigenes.org]

  Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p24.2-p23” refers to bands 24.2-23 on the short arm of chromosome 6. [rarediseases.org]

• Delayed Wound Healing

  Other features included haematoma formation, easy bruising, post-traumatic bleeding, delayed wound healing, gastrointestinal bleeding and epistaxis. One child presented with intracerebral bleed. [jpma.org.pk]

  Thirty percent of the affected individuals may also experience spontaneous bleeding into the brain (intracranial hemorrhages), about 25% experience poor or delayed wound healing and others may have enhanced bleeding after trauma or surgery. [rarediseases.org]

  Surgery/Trauma - Bleeding after surgery/trauma is common, and delayed wound healing can also occur in up to 17% of patients. [rarebleedingdisorders.com]

• Suggestibility

  More importantly, no adverse effects or complications have been reported, suggesting that this form of therapy is safe to use. [symptoma.com]

  These observations have suggested physiologic and pathologic roles for factor XIII in angiogenesis, atherosclerosis, and inflammation. [emedicine.medscape.com]

  Evidence from GWASs suggests that common complex traits, such as coagulation and ischemic stroke, are polygenic, influenced by many SNPs each contributing a relatively small effect. [stroke.ahajournals.org]

  The structural analyses suggest that the mutations are most likely interfering with proper folding and stability of the protein, which is in agreement with the observed absence of detectable FXIIIA antigen. [lup.lub.lu.se]

• Epistaxis

  Other features included haematoma formation, easy bruising, post-traumatic bleeding, delayed wound healing, gastrointestinal bleeding and epistaxis. One child presented with intracerebral bleed. [jpma.org.pk]

  […] chromosome 1 Clinical features Variable bleeding tendency, from mild to severe depending on factor levels Umbilical cord stump bleeding, intracranial hemorrhage, soft tissue hematoma, bleeding after circumcision, gastrointestinal bleeding, gingival bleeding, epistaxis [pathologyoutlines.com]

  Bleeding within a joint Hemarthrosis [ more ] 0005261 Oral cavity bleeding Bleeding from mouth 0030140 Spontaneous hematomas 0007420 5%-29% of people have these symptoms Bleeding with minor or no trauma Easy bleeding 0011889 Delayed onset bleeding 0040232 Epistaxis [rarediseases.info.nih.gov]

  Symptoms commonly associated with factor XIII deficiency include chronic nosebleeds (epistaxis), bleeding from the gums, discoloration of the skin due to bleeding underneath the skin (ecchymoses), and solid swellings of congealed blood (hematomas). [rarediseases.org]

• Intracranial Hemorrhage

  Prophylactic therapy with FXIII concentrate should be indicated to prevent recurrent bleedings such as intracranial hemorrhage. Prognosis Intracranial hemorrhage can be life threatening, but prognosis is favorable if adequate treatment is provided. [orpha.net]

  A frequent and often devastating symptom is bleeding into the brain, also known as intracranial hemorrhage. Female carriers may have frequent miscarriages. [hemaware.org]

  A factor XIII polymorphism (Val34Leu), present in nearly half of the population, is suspected to protect against deep venous thrombosis and is somewhat more frequent in patients with intracranial hemorrhage. 3,4 Factor XIII has a long half-life of 10- [mghlabtest.partners.org]

  Up to 30% of patients sustain a spontaneous intracranial hemorrhage, a brain bleed, which is the leading cause of mortality. [hemophilia.org]

  Severely affected individuals have an increased risk of bleeding inside the skull (intracranial hemorrhage), in the lungs (pulmonary hemorrhage), or in the gastrointestinal tract, which can be life-threatening. [ Read More ] Prothrombin deficiency Prothrombin [icdlist.com]

Signs and symptoms that are encountered in these patients immediately point to a disorder of impaired coagulation, suggesting that a careful physical examination should be performed in order to assess the extent of symptoms and signs. It must be emphasized, however, that the entire coagulation cascade is not affected, which may mislead the physician away from the diagnosis. A quantitative FXIII activity assay is the ultimate tool for the diagnosis when impaired coagulation is observed without an identifiable cause. Additional testing to determine the levels of both subunits may also be performed [10].

Initial management of patients comprises of administration of cryoprecipitate, fresh frozen plasma (FFP) a plasma-derived FXIII concentrate [8] [11]. The recent introduction of recombinant FXIII, however, has dramatically improved long-term care of patients suffering from a deficiency of this clotting factor, primarily because of its long half-life of approximately 11.8 days [2] [8]. More importantly, no adverse effects or complications have been reported, suggesting that this form of therapy is safe to use [11].

The prognosis of FXIIID patients is very good with early initiation of treatment and prophylaxis using currently recommended agents [2]. Unfortunately, the diagnosis is still missed throughout the world, which leads to potentially fatal bleeding complications, the reasons being lack of awareness and low clinical suspicion [14]. Nevertheless, this condition should be considered in patients experiencing bleeding episodes without an identifiable cause.

FXIII is a heterotetramer that is composed of two paired A and B subunits and genes coding for these subunits have been identified on chromosomes 6 (p24-25) and 1 (q31-32.1), respectively [4] [12]. Up to now, approximately 36 mutations involving the FXIII gene have been identified [3], and the A subunit is affected in the vast majority of cases [11]. Missense (comprising about 50% of all mutations), nonsense, deletions and insertions have all been discovered [5]. Studies have confirmed that FXIIID is transmitted by autosomal recessive patterns of inheritance [11], but which mechanisms lead to the development of genetic mutations remain unknown.

FXIIID is considered to be an extremely rare bleeding disorder, with estimated prevalence rates of 1 per 2 million individuals worldwide [7]. Studies have determined that the Sistan and Baluchistan provinces in Iran possess the highest prevalence rates in the world (12-fold higher compared to the rest of the world), but the cause remains unknown, although high rates of consanguineous marriages in these areas may explain the incidence[6] [7]. All genders and ethnic groups are equally affected [3].

The A and B subunits of FXIII are synthesized in the bone marrow and liver, respectively, and together they form a heterotetrameric structure that exerts various functions in the body [12] [13]. Under physiological conditions, the principal role of factor XIII is to convert loosely created fibrin into a firm and highly organized cross-linked mesh that possesses a high tensile strength, enabling it to create a stable clot that is resistant to fibrinolysis and the activity of plasmin [3] [12]. As it is present in platelets, monocytes, and monocyte-derived macrophages, various additional functions have been identified, such as downregulation of thrombospondin-1, an antiangiogenic protein, and mediation of leukocyte interaction with the extracellular matrix, contributing to wound healing and repair [1] [12] [13]. Additionally, its role in maintaining pregnancy has been well-established [13], and women suffering from homozygous mutations are not able to maintain pregnancy [13]. To perform these functions, this pro-transglutaminase must be converted into its active form (FXIIIa) in the presence of thrombin and Ca2+, which results in dissociation of the two subunits and release of the B subunit, thus leading to exposure of active sites on the A subunit [12]. In the presence of various mutations that cause impaired FXIII formation, affecting the A subunit in virtually all cases, the newly formed fibrin clot is not able to form a rigid structure and an increased bleeding risk, as well as the appearance of characteristic symptoms ensues.

Apart from genetic counselling of couples with family history positive for FXIIID, other preventive strategies are unknown.

Hereditary factor XIII A subunit deficiency (FXIIIAD) is a genetic disease in which various mutations cause reduced activity of factor XIII, a transglutaminase enzyme in the plasma responsible for initiation of the final step of the coagulation cascade [1]. Factor XIII is responsible for cross-linking of fibrin [1], mainly through the activity of the A subunit, making the formed blood clot stable and resistant to fibrinolysis [2] [3]. In the body, FXIII exists as a proenzyme composed of two paired subunits - A (containing the active site) and B, the stabilizing unit [4]. In the absence of the active subunit, the fibrin clots become unstable and patients are prone to bleeding. Locations of subunits A and B have been confirmed on chromosomes 6 and 1, respectively, and dozens of missense, nonsense, deletion and insertion mutations have been confirmed [3] [5]. FXIIIAD is shown to be very rare in the general population, as prevalence rates are estimated to be 1 in 2 million individuals, with certain Iranian provinces being the most prevalent areas [6] [7]. In the setting of FXIIIAD and inability of the clot to remain stable, various symptoms may be present. The clinical presentation ranges from mild bleeding episodes to possibly life-threatening central nervous system (CNS) hemorrhage [6] [8], but one of the most important manifestations is bleeding from the umbilical cord [9]. Because of the fact that FXIII has shown to be vital in maintaining pregnancy, recurrent spontaneous abortions may be reported in FXIIIAD[2]. To make the diagnosis, it is necessary to exclude all other coagulopathies as potential causes and evaluate the activity of FXIII through quantitative assays [10]. Earlier treatment principles included cryoprecipitate and fresh frozen plasma (FFP), which contain a fraction of FXIII, but the recent introduction of recombinant FXIII has drastically improved long-term management of patients with this disorder [11]. Due to its prolonged half-life (approx. 12 days) and absence of side-effects, rFXIII is safe for use and is now becoming the mainstay of therapy [11]. Although FXIIIAD is shown to be rarely encountered in clinical practice, it should be considered as a potential cause of bleeding when all other conditions have been excluded, primarily because it may cause life-threatening bleeding.

Hereditary factor XIII A subunit deficiency (FXIIIAD) is a genetic disease of impaired blood clot clotting that arises due to mutations that impair the A subunit of factor XIII, which is vital for the last step in clot formation. FXIII is composed of two subunits - A (the active component) and B (stabilizing component) and in the absence of subunit A, FXIII is not able to perform its function. FXIIIAD is very rare, approximately affecting 1 in 2 million individuals and the condition is transferred through an autosomal recessive pattern of inheritance. This means that parents, who each carry a single copy of the mutated gene and are not ill, transfer both genes to their child, resulting in the presence of two mutated genes and consequent deficiency of this clotting factor. The clinical presentation may be evident as early as birth and bleeding from the umbilical (belly button) cord may frequently be encountered in newborn babies. Pronounced bruising, development of hematomas and prolonged bleeding from wounds are also typical symptoms. One of the most dangerous manifestations of FXIIIAD is bleeding into the central nervous system, which may often be fatal. For this reason, a timely recognition of the disease can save the patient's life. The diagnostic workup should exclude all other causes of abnormal bleeding before testing for FXIIIAD. If the cause remains unknown, a test that determines the amount of FXIII in blood is needed for confirmation. Until recently, treatment principles relied on the administration of fresh frozen plasma (FFP) and cryoprecipitate containing all coagulation factors, including FXIII, but the use of recombinant FXIII (rFXIII) has revolutionized the care of patients suffering from this condition. Because of minimal adverse effects and a prolonged duration of effect compared to FFP and cryoprecipitate, rFXIII is now becoming the mainstay of treatment in general practice. Current preventive strategies may include genetic counseling for families with family members who possess mutations of the A subunit, but the exact reason why these mutations occur remains to be elucidated. Because long-term therapeutic measures are now safe and ensure a satisfying quality of life, it is important to recognize this condition early on, in order to reduce the number of deaths from this rare disease.

1. Anwar R, Minford A, Gallivan L, Trinh CH, Markham AF. Delayed umbilical bleeding--a presenting feature for factor XIII deficiency: clinical features, genetics, and management. Pediatrics. 2002;109(2):E32.
2. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia. 2008;14(6):1190-200.
3. Anwar R, Miloszewski A. Factor XIII deficiency. Rev Br J Haematol 1999;107:468–484.
4. Dickneite G, Herwald H, Korte W, Allanore Y, Denton CP, Matucci Cerinic M. Coagulation factor XIII: a multifunctional transglutaminase with clinical potential in a range of conditions. Thromb Haemost. 2015;113(4):686-697.
5. Board P, Webb GC, McKee J, Ichinose A. Localization of the coagulation factor XIII A subunit gene to chromoso me bands 6p24-p25. Cytogene t Cell Genet. 1988;48:25–27.
6. Naderi M, Alizadeh S, Kazemi A, et al. Central nervous system bleeding in pediatric patients with factor XIII deficiency: a study on 23 new cases. Hematology. 2015;20(2):112-118.
7. Dorgalaleh A, Naderi M, Hosseini MS, et al. "Factor XIII Deficiency in Iran: A Comprehensive Review of the Literature. Seminars in thrombosis and hemostasis. 2015;41:3:41:323–329.
8. Lovejoy A, Reynolds T, Visich J, Butine M, Young G, Belvedere M, et al. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency.Blood. 2006;108(1):57–62.
9. Muszbek, L et al. Blood coagulation factor XIII: structure and function.Thrombosis Research. 1999;94(5):271–305.
10. Karimi M, Bereczky Z, Cohan N, Muszbek L. Factor XIII Deficiency. Semin Thromb Hemost. 2009;35(4):426-438.
11. Inbal A, Oldenburg J, Carcao M, Rosholm A, Tehranchi R, Nugent D. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood. 2012;119(22):5111-5117.
12. Muszbek L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation and function. Crit Rev Clin Lab Sci. 1996;33:357–421.
13. Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: structure and function. Thromb Res. 1999;94(5):271-305.
14. Schroeder V, Kohler HP. Factor XIII deficiency: an update. Semin Thromb Hemost. 2013;39(6):632-641.