Review article 199
Factor XIII deficiency management: a review of the literature Jodie E. Odamea, Anthony K. Chanb,c, John K. Wud,e and Vicky R. Breakeyb,c Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder estimated to affect 1 in 2 million live births. Treatment often involves prophylaxis with FXIII concentrate and is especially important in preventing intracranial hemorrhage (ICH) and maintaining pregnancy in women of childbearing age. The rarity of this condition and lack of good quality evidence has resulted in a literature largely based on case reports/case series. A review of the literature was conducted in order to provide information about the optimal management of FXIII deficiency. Articles were identified by searching MEDLINE from 1961 to June 2012. Eligible studies included details on patients with FXIII deficiency that received treatment. Information collected included dose, frequency, duration, hemostatic efficacy and adverse events. Of 606 abstracts reviewed, 43 articles, including a total of 328 patients met the selection criteria. Common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Patients were generally placed on prophylactic factor replacement therapy upon diagnosis of severe or symptomatic FXIII deficiency, which decreased and/or prevented bleeding episodes. Patients with FXIII deficiency that received prophylactic treatment successfully maintained pregnancies. Alternative treatments included the use of cryoprecipitate or frozen plasma when FXIII concentrate was not available or
Introduction Factor XIII (FXIII) is a hetero-tetramer zymogen activated by thrombin in the presence of calcium that catalyzes g-g cross-linking of glutamine-lysine residues of adjacent g fibrin chains, and a 2 antiplasmin onto a fibrin chain (Fig. 1). This is important in the final stages of blood coagulation [1–3]. The FXIII complex is composed of two A subunits (FXIIIA) and two B subunits (FXIIIB) [3]. The A subunits have four domains: an Nterminal activation peptide, a b sandwich, catalytic core and two b-barrels [3,4]. FXIIIA also exists as a homodimer intracellularly in platelets and monocytes in the uterus [3,5]. FXIIIB has 10-sushi domain repeats that bind to the a subunits and prolong their survival [3,6]. In the presence of calcium, thrombin leaves the Arg37Gly38 peptide bond in FXIIIA, releasing the activation peptide from its N-terminus, and FXIIIB disassociates [6]. FXIIIA2 is then activated, can cross-link fibrin chains and allow for clot formation. FXIIIA also acts to stabilize the fibrin chains and prevents fibrinolysis [6]. Deficiency of factor XIII
FXIII deficiency is a rare bleeding disorder with an estimated frequency of one in every 2 million people [8]. The FXIIIA gene is located on chromosome 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
affordable. Recent studies of a new recombinant FXIII concentrate show promising results in regards to safety and efficacy. There are limited data to guide the optimal treatment of FXIII deficiency. Larger patient registries and international collaborations are needed to improve the evidence and enhance clinical outcomes in this rare bleeding disorder. Blood Coagul Fibrinolysis 25:199–205 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:199–205 Keywords: blood coagulation disorders, factor 13 deficiency, factor XIIIa, factor XIIIb, factor XIII deficiency, hemorrhagic disorders, inherited a Department of Physiology, University of Toronto, Toronto, Ontario, bDepartment of Pediatrics, McMaster University, Hamilton, Ontario, cDivision of Hematology/ Oncology, McMaster Children’s Hospital, Hamilton, Ontario, dDepartment of Pediatrics, University of British Columbia, Vancouver, British Columbia and e Division of Pediatric Hematology/Oncology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
Correspondence to Vicky R. Breakey, MD, MEd, FRCPC, Pediatric Hematologist/ Oncologist, Assistant Professor, Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, HSC 3N27a – 1280 Main St. W, Hamilton, Ontario L8S 4K1, Canada Tel: +1 905 521 2100 x73080; fax: +1 905 521 1703; e-mail: [email protected] Received 3 April 2013 Revised 22 October 2013 Accepted 13 November 2013
6p24-p25, and the FXIIIB gene on 1q31–32.1 [8]. There are more than 94 mutations identified in FXIIIA and six in FXIIIB [3,9]. FXIII deficiency is inherited in an autosomal recessive mode, and thus is more prevalent in countries where consanguineous marriages are common, such as Middle Eastern countries, Pakistan and South India [3,6,10]. Inherited FXIII deficiency can be a result of FXIIIA or FXIIIB deficiency [6]. FXIIIA deficiency can be due to a reduction in FXIIIA synthesis (Type I) or decreased FXIIIA function (Type II) [6]. FXIIIB deficiency is much less common and tends to be associated with milder bleeding symptoms [6,11]. Clinical symptoms can range from mild-to-severe [6]. In general, there are lack of data about individuals that are heterozygous for FXIII deficiency. These people are most often asymptomatic, but may have prolonged bleeding after minor traumas [6]. Patients with FXIII less than 1U/dl have the highest risk of experiencing severe spontaneous bleeding [1]. Patients with levels between 1and 4U/dl have moderate-to-severe bleeding. Patients with levels more than 5U/dl may bleed occasionally, however, the relationship between FXIII levels and clinical features is difficult to DOI:10.1097/MBC.0000000000000029
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200 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 3
Fig. 1
Role of factor XIII in the coagulation cascade.
establish [12]. Severe deficiencies often present in the newborn period. Umbilical cord bleeding is one of the most common symptoms, occurring in 80% of cases of severe FXIII deficiency [3,6]. There is also a significant risk of intracranial hemorrhage (ICH), which has been reported in approximately 30% of FXIII deficiency newborns, and is the leading cause of death in this group [13]. Other symptoms in older children and adults with severe FXIII deficiency include intramuscular and subcutaneous hematomas, ecchymoses, postoperative bleeding and prolonged bleeding after trauma [6]. As FXIII is one of the few coagulation factors that does not rise during pregnancy, complications in pregnant women with FXIII deficiency are common [14]. FXIII deficiency may be diagnosed following multiple spontaneous abortions. It has been shown that women with FXIIIA deficiency have a poorly formed cytotrophoblastic and Nitabuch’s layer, affecting early placental adhesion and increasing the chance of placental detachment and miscarriage [7].
partial thromboplastin time (aPTT) and fibrinogen. However, these tests do not detect FXIII deficiency [15]. If FXIII deficiency is suspected, qualitative screening can be done using the clot solubility test. Plasma samples are clotted by excess calcium, then placed in 5 mol/l urea or 2% acetic acid (or 1% monochloracetic acid) and observed for 24 h. If inadequate levels of FXIII are present, the clot will dissolve within minutes to 2 h [16]. Unfortunately, clot solubility only detects severe FXIII deficiency (FXIII levels two patients) cases (Table 1) [6,13,18–22] whereas eight publications reported pregnancy outcomes (Table 2) [14,23–28]. The additional 19 small case reports were also reviewed and summarized [1,11,29–45]. General treatment approach
Over the last few decades, the treatment of patients with FXIII deficiency has been recorded in case reports and case series. The most common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Reported cases revealed that patients are generally placed on prophylactic replacement therapy once the diagnosis of severe or symptomatic FXIII deficiency
FXIII deficiency review selection criteria. FXIII, factor XIII.
has been confirmed, as experience has suggested much better outcomes than in patients who received on demand therapy [17]. Plasma-derived FXIII concentrate (commercially available as Fibrogammin P; CSL Behring, Hayward’s Heath, West Sussex, UK) is currently considered standard therapy for congenital FXIII deficiency [3]. In adults, the standard dosing is 10– 35 U/kg of FXIII concentrate infused every 4–6 weeks. This results in few or no further bleeding episodes [6,8]. Common alternatives for FXIII deficiency treatment in countries where FXIII concentrate is not available include cryoprecipitate and FFP. Standard dosing for FFP in adults is 15–20 ml/kg, and 1 bag/10 kg for cryoprecipitate [46]. Twenty-two cases were reviewed wherein alternate forms of treatment were used. These were reported prior to the development of plasma-derived FXIII concentrates, or in areas that do not have access to FXIII concentrates. Padmanabhan et al. [27] described two separate cases in India wherein women received cryoprecipitate in order to maintain their pregnancies. FFP treatment was also used in a case reported by Rodeghiero et al. [24], but the patient was later switched to Fibrogammin P. Generally, plasma-based forms of treatment
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202 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 3
Table 1
Larger case series (>two patients) and prospective trials to review the treatment of factor XIII deficiency
Author, year
N
Treatment indication
Sex/age (years)
Acharya 2004 [19]
32
Hemorrhages, surgical wounds and joint/muscle bleeds
Unspecified
Eshghi 2004 [20]
13
Unspecified
Nugent 2006 [6]
61
Umbilical bleeding, bruises and hematoma most common Unspecified
Eshghi 2009 [21]
127
Lusher 2009 [22]
7
Dreyfus 2011 [18]
19
Unspecified
Inbal 2012 [13]
41
Unspecified
FXIII source, dose, frequency (if reported)
Outcome
Adverse events
45% FFP, 24% cryoprecipitate, 24% FXIII concentrate, 6% EACA, 34% long-term prophylaxis Prophylactic treatment with cryoprecipitate
Not reported
One patient developed an inhibitor, some died from ICH
No further bleeding
None reported
1–74 years
FXIII concentrate, dose not reported
Headaches, some myalgias, two unrelated deaths
Umbilical cord bleeding and deep soft tissue hematoma most common
66 M, 61 F, 0–23 years
Those on prophylactic treatment either received 1–15 ml/kg FFP or 1 U/10 kg cryoprecipitate every 4–6 weeks
Umbilical cord bleeding, hematomas, ICH, mouth thigh and gum bleeds
4 M, 2 F, 1 unspecified, 10 months– 19 years Unspecified, 18 days– 47 years Unspecified, 7–60 years
15–45 IU/kg FXIII concentrate every 3–4 weeks
No major bleeds during prophylaxis; bleeds in five patients noncompliant with treatment 14 of 19 died from ICH due to no prophylactic treatment; one patient receiving prophylactic treatment had major bleeding episode Annual spontaneous bleeding rate reduced during prophylactic FXIIIA concentrate therapy rFXIII efficacy rated as moderate (1), good (11) or excellent (3) rFXIII well tolerated, 4 of 41 patients had bleeds requiring treatment
1.55–14.8 IU/kg rFXIII concentrate a week every 4–6 weeks 35 IU/kg rFXIII every 4 weeks
None reported
None reported
None reported
Four patients developed nonneutralizing antibodies
EACA, epsilon aminocaproic acid; F, female; FFP, fresh frozen plasma; FXIII, factor XIII; ICH, intracranial hemorrhage; M, male; N, number of patients; rFXIII, recombinant FXIII.
also resulted in positive outcomes, and no further bleeds. However, a case reported by Perez et al. [45] revealed a 25-year-old woman died due to a thalamic ICH with ventricular extension despite treatment with Vitamin K Table 2
and FFP. It was suggested that the use of FXIII concentrates may have been a better choice, as it would be a more disease-specific approach to prophylactic treatment, and has fewer risks.
Summary of the publications addressing the treatment of factor XIII deficiency in pregnancy Age (years)
Author, year
N
Treatment indication
Fisher 1966 [23]
1
29
Rodeghiero 1987 [24]
1
Twelve spontaneous abortions Spontaneous abortions after severe decidual bleeding during early gestation
Boda 1989 [25]
1
34
Kobayashi 1990 [26]
1
Eight spontaneous abortions Spontaneous abortion at 6 weeks gestation
Burrows 2000 [14]
1
ICH (initially diagnosed at age 3 years)
22
Padmanabhan 2004 [27]
1
Seven spontaneous abortions
29
Padmanabhan 2004 [27]
1
Vaginal bleeding during early gestation
22
Dargaud 2008 [28]
1
Three spontaneous miscarriages
34
25
20
FXIII source, dose, frequency
Outcome
Adverse events
Plasma transfusion; 300 ml every 10 days FFP: 300–450 ml every 2 weeks; FXIII concentrate: 500 IU every 3 weeks 40 ml FFP every 10 days
Healthy baby delivered near term Delivered two healthy babies near term
None reported
Healthy baby delivered
None reported
500 IU FXIIIA concentrate every 7 days, 100 IU before delivery FXIIIA concentrate 500 IU every 7 days, 100 IU before delivery One unit cryoprecipitate every 4 weeks, later increased to two units Two units cryoprecipitate during first evacuation, four units during second evacuation Third pregnancy: 10 IU FFP FXIII concentrate: 20 U/kg 2–4 weeks, 1250 U before delivery
Delivered baby with no complications
None reported
Delivered baby with no complications
None reported
One spontaneous abortion, increased dose led to successful pregnancy Evacuation was done on both pregnancies
Oozing from uterine cavity postpartum
No early genital hemorrhage or fetal loss
Cervical premature membrane rupture led to preterm delivery and subsequent neonatal death
None reported
None reported
FXIII, factor XIII; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; N, number of patients.
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Management of factor XIII deficiency Odame et al. 203
Perioperative care
There were seven reports of perioperative management of patients with FXIII deficiency. These patients were treated with FXIII concentrate (four), FFP (two) or cryoprecipitate (one). In four of these cases, patients received therapy both before and after surgery [30,36,40,41]. In one case, treatment was just given preoperatively [30]. In two cases, treatment was just received postoperatively [39,44]. No further bleeds were seen after treatment in any of the reported cases. Prophylaxis
Twenty-five articles reported the use of prophylactic therapy in patients with FXIII deficiency, with 13 out the 25 articles reporting the use of FXIII concentrate. Only three of these cases reported adverse events related to treatment [13,40,42]. In a prospective multicenter study conducted by Dreyfus et al. [18], the efficacy of Fibrogammin P long-term replacement therapy in treating hemorrhages and preventing further bleeds was rated as good or excellent in 95% of cases. A multinational prospective study was conducted by Inbal et al. [13] to assess the efficacy of long-term replacement therapy with rFXIII. The frequency of bleeds was lower in patients receiving rFXIII than those on normal regular replacement therapy, with 37 of 41 patients having no bleeds requiring treatment during the trials. Pregnancy
Case reports of FXIII deficiency treatment in pregnancy were also summarized (Table 2). Although many pregnancies were established in FXIII-deficient patients without replacement therapy, a study conducted by Burrows et al. [14] revealed 10 of the 16 individuals with FXIII deficiency had recurrent abortions. There were a number of patients that presented with cases of recurrent abortions. Reviews that discussed the management of FXIII deficiency during pregnancy strongly recommended prophylactic therapy to prevent spontaneous abortions [47–49]. Asahina et al. [7] reported eight successful pregnancies in patients with FXIIIA deficiency who received replacement therapy. They described two cases in which vaginal bleeding began around 5–6 weeks of gestation, but bleeding control was achieved before abortion occurred following administration of FXIII concentrate. The cases reported increasing the standard dose of FXIII concentrate to 500 IU every 3–6 weeks during pregnancy. Another case reported doubling the dose again at 23 weeks of gestation to account for the drop in FXIII levels to about 5%. The mode of delivery varied with case, and seemed to be determined on an individual basis. In three cases, four vials (1000 IU) were administered prior to delivery [7]. Most women that received this treatment course delivered healthy babies. There were also some postpartum complications reported, most commonly bleeding from the uterine cavity [27]. Huq et al. [47] also reported that FXIIIA-deficient and
FXIIIB-deficient patients are at high risk of developing postpartum hemorrhage. Complications and adverse events
The development of adverse events after treatment was rare. In many cases, the complications reported were due to bleeding and were not related to therapy. In a case reported by Abbondanzo et al. [32], the patient developed cranial nerve palsies due to ICH despite treatment. In another case reported by Ugur et al. [35], the patient developed paralysis in the lower limbs and nerve damage in the right arm, as well as a spastic bladder due to intraspinal hemorrhage. A case reported by Almeida et al. [1] also spoke of a patient who developed blindness due to neurological damage. In these cases, the damage was extensive before treatment was given, and therefore could not be reversed. Complications reported during pregnancy included oozing form uterine cavity and premature cervical membrane rupture [27,28]. The most dreaded adverse event was the development of inhibitors, although its incidence was rare. A rare bleeding disorder registry created in North America discovered that 3% of FXIII-deficient patients that received FFP or FXIII concentrate treatment developed inhibitors [19]. A case reported by Kim et al. [42] revealed that a 9-year-old girl developed an inhibitor after receiving three units of cryoprecipitate and one unit of red blood cells. A study conducted by Inbal et al. [13] testing the efficacy of rFXIII found four patients developed nonneutralizing antibodies. As a result, three of these patients were removed from the study and restarted on the plasmaderived product. However, in one of the cases, an 8-yearold boy continued to receive monthly rFXIII treatment despite developing nonneutralizing antibodies after second exposure. These antibodies subsequently diminished to below detection levels 4 months later.
Discussion As of 2013, plasma-derived FXIII concentrate (Fibrogammin P) has been approved (licensed) in 14 countries worldwide (Argentina, Austria, Brazil, Colombia, France, Georgia, Germany, Great Britain, Indonesia, Israel, Japan, Luxembourg, Switzerland and United States) (Josephine Cybulski, plasma products specialist, personal communication, 1 October 2013). In Canada, FXIII concentrate is available through Health Canada approval [50]. Recently, the United States received further Food and Drug Administration approval to include perioperative management in February 2013 [51]. FXIII concentrate has been recommended as a safer treatment alternative to cryoprecipitate or FFP for FXIII deficiency. Many case reports have shown improved bleeding symptoms in patients on prophylactic therapy [18]. In countries where plasma-derived FXIII concentrates are not available, or the resources needed to purchase or manufacture this product are limited, treatment
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204 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 3
with FFP or cryoprecipitate is still common and usually efficacious [17]. It remains important that good manufacturing processes and viral inactivation of plasma products are practiced. Recently, the use of mini-pool solvent pathogen inactivation performed by blood establishments has been described, and provides a form of viral inactivation of plasma products at an affordable price [17]. This new technology can provide safer plasma-derived products for the treatment of FXIII deficiency in developing countries until FXIII concentrate becomes more affordable.
Conflicts of interest
There are no conflicts of interest.
References 1 2
3 4
The general availability of rFXIII is within sight. A recent multinational open-label trial suggested safety and efficacy of a new rFXIII, produced by Novo Nordisk (Denmark) for use in patients with congenital FXIII deficiency [13]. rFXIII is currently approved for FXIIIA deficiency in the European Union, Canada and Switzerland. Inhibitors are only rarely reported in patients with congenital FXIII deficiency, but nonneutralizing antibodies were noticed in some of the patients [13]. Patients should be carefully monitored once the use of rFXIII is more widespread.
10
Future directions
11
There is still much that is not well understood about FXIII deficiency. Clinicians should continue to educate their colleagues of the possible symptoms, as FXIII deficiency is not detected upon routine assessments of coagulation with INR/aPTT/fibrinogen/platelet count and cannot be diagnosed unless it is suspected. This is particularly important in newborns with umbilical bleeding and in women that present with recurrent abortions.
5 6 7
8 9
12
13
14
15
Further work is needed to improve the treatment of patients with FXIII deficiency. Plasma-derived FXIII concentrate has been the mainstay of therapy for many years, but as rFXIII becomes better-studied and more widely available, it may replace the plasma-derived product. In order to safely treat patients in both developing and developed countries, access and cost issues must be addressed. To expand our knowledge of FXIII deficiency, patient information should be gathered in registries and analyzed to better understand the clinical presentation, diagnosis and treatment of this small, but important group of patients. By pooling our experiences and working together on international trials, we can improve the care of these patients.
Acknowledgements This work was supported by the Canadian Hemophilia Society (CHS) Summer Studentship in Inherited Bleeding Disorders Research. Special thanks to Ivan Stevic for providing Figure 1. Work supported by: Canadian Hemophilia Society Inherited Bleeding Disorders summer studentship.
16
17 18
19
20
21
22
23 24
25
Almeida A, Khair K, Hann I, Liesner R. Unusual presentation of factor XIII deficiency. Haemophilia 2002; 8:703–705. Koseki-Kuno S. Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages. Blood 2003; 102:4410–4412. Muszbek L, Bagoly Z, Cairo A, Peyvandi F. Novel aspects of factor XIII deficiency. Curr Opin Hematol 2011; 18:366–372. Louhichi N, Medhaffar M, HadjSalem I, Mkaouar-Rebai E, Fendri-Kriaa N, Kanoun H, et al. Congenital factor XIII deficiency caused by two mutations in eight Tunisian families: molecular confirmation of a founder effect. Ann Hematol 2009; 89:499–504. Adany R, Muszbek L. Immunohistochemical detection of factor XIII subunit a in histiocytes of human uterus. Histochemistry 1989; 91:169–174. Nugent DJ. Prophylaxis in rare coagulation disorders: factor XIII deficiency. Thromb Res 2006; 118:S23–S28. Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv 2007; 62:255–260. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14:1190– 1200. Cooper DN, Stenson PD, Phillips AD, et al. Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. [Internet]. hgmdcfacuk http://www.hgmd.cf.ac.uk. [Accessed on 20 September 2013] Peyvandi F, Jayandharan G, Chandy M, MSrivastava A, Nakaya SM, Johnson MJ, et al. Genetic diagnosis of haemophilia and other inherited bleeding disorders. Haemophilia 2006; 12 (Suppl 3):82–89. Killick CJ, Barton CJ, Aslam S, Standen G. Prenatal diagnosis in factor XIIIA deficiency. Arch Dis Child Fetal Neonatal Ed 1999; 80:F238–F239. Bolton-Maggs PHB, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams MD, et al. The rare coagulation disorders: review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia 2004; 10:593–628. 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; 119:5111–5117. Burrows RF, Ray JG, Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature. Obstet Gynecol Surv 2000; 55:103–108. Lusher JM, Barnhart MI. Acquired bleeding disorders in children: platelet abnormalities and laboratory methods first edition, 1st ed. Aperture; 1985–04; 208 pages. Luo Y-Y, Zhang G-S. Acquired factor XIII inhibitor: clinical features, treatment, fibrin structure and epitope determination. Haemophilia 2011; 17:393–398. Magdy El Ekiaby MD. Improving the safety of plasma and its components for clinical transfusion. J Appl Hematol 2011; 2:280. Dreyfus M, Barrois D, Borg JY, Claeyssens S, Torchet M-F, Arnuti B, et al. Successful long-term replacement therapy with FXIII concentrate (Fibrogammin1 P) for severe congenital factor XIII deficiency: a prospective multicentre study. J Thromb Haemost 2011; 9:1264– 1266. Acharya SS, Coughlin A, Dimichele DM, the North American Rare Bleeding Disorder Study Group. Rare bleeding disorder registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2004; 2:248–256. Eshghi PP, Abolghasemi HH, Sanei-Moghaddam EE, Anwar R, Jazebi M, Amid A, Ala A. Factor XIII deficiency in south-east Iran. Haemophilia 2004; 10:470–472. Eshghi P, Mahjour SB, Naderi M, Dehbozorgian J, Karimi M. Long-term prophylaxis in patients with factor XIII deficiency complicated by intracranial haemorrhage in Iran. Haemophilia 2009; 16:383–385. Lusher J, Pipe SW, Alexander S, Nugent D. Prophylactic therapy with Fibrogammin 1P is associated with a decreased incidence of bleeding episodes: a retrospective study. Haemophilia 2009; 16:316–321. Fisher S, Rikover M, Naor S. Factor 13 deficiency with severe hemorrhagic diathesis. Blood 1966; 28:34–39. Rodeghiero F, Castaman GC, Di Bona E, Ruggeri M, Dini E. Successful pregnancy in a woman with congenital factor XIII deficiency treated with substitutive therapy. Report of a second case. Blut 1987; 55:45–48. Boda Z, Pfliegler G, Muszbek L, et al. Congenital factor XIII deficiency with multiple benign breast tumours and successful pregnancy with substitutive therapy. A case report. Haemostasis 1989; 19:348–352.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Management of factor XIII deficiency Odame et al. 205
26
27 28
29 30 31 32
33
34
35
36 37
38
Kobayashi TT, Terao TT, Kojima TT, Takamatsu J, Kamiya T, Saito H. Congenital factor XIII deficiency with treatment of factor XIII concentrate and normal vaginal delivery. Gynecol Obstet Invest 1990; 29:235– 238. Padmanabhan LD, Mhaskar R, Mhaskar A, Ross CR. Factor XIII deficiency: a rare cause of repeated abortions. Singapore Med J 2004; 45:186–187. Dargaud Y, De Mazancourt P, Rugeri L, Hanss M, Borg JY, Gaucherand P, et al. An unusual clinical presentation of factor XIII deficiency and issues relating to the monitoring of factor XIII replacement therapy. Blood Coagul Fibrinolysis 2008; 19:447–452. Francis J, Todd P. Congenital factor XIII deficiency in a neonate. BMJ 1978; 2:1532. Suzuki H, Kaneda T. Tooth extraction in two patients who had a congenital deficiency of factor XIII. J Oral Maxillofac Surg 1985; 43:221–224. Landman J, Creter D, Homburg R, Sirota L, Dulitzky F. Neonatal factor XIII deficiency. Clin Pediatr 1985; 24:352–353. Abbondanzo SL, Gootenberg JE, Lofts RS, McPherson RA. Intracranial hemorrhage in congenital deficiency of factor XIII. Am J Pediatr Hematol Oncol 1988; 10:65–68. Giraldi C, Creta S, Martini A, Ioppoli C, Valleriani A, Muratorio A. Spontaneous intracerebral hematoma in an adolescent with factor XIII deficiency. Case report. Ital J Neuro Sci 1989; 10:579–582. Larsen PD, Wallace JW, Frankel LS, Crisp D. Factor XIII deficiency and intracranial hemorrhages in infancy. [Internet]. Pediatr Neurol 1990; 6:277–278; http://www.sciencedirect.com/science/article/pii/ 088789949090123I. Ugur S, Uzel N, Dundar K, Kaya U, Ayan I, Gedikog˘lu G. Intraspinal hemorrhage in a child with factor XIII deficiency. Pediatric Emerg Care 1991; 7:231–233. Deshmukh RG, Bosco J. Claw toes correction and factor XIII deficiency: a case report. Med J Malaysia 1995; 50:417–419. Andreae MCM, Amanullah AA, Jamil SS, Main C. Congenital factor XIII deficiency: a patient report and review of the literature. Clin Pediatr 1997; 36:53–55. Gootenberg JE. Factor concentrates for the treatment of factor XIII deficiency. Curr Opin Hematol 1998; 5:372–375.
39
40
41
42 43
44
45
46 47 48 49 50 51
Karabulut AB, Aydin H, Mezdegi A, Ademoglu E. Recurrent bleeding following rhinoplasty due to factor XIII deficiency. Plast Reconstr Surg 2001; 108:808. Pernod G, Barro C, Arnutti B, Blanc-Jouvan F, Garrel S, Kahn P, et al. Surgery in severe factor XIII deficiency: report of a case of epilepsy neurosurgery and review. Haemophilia 2003; 9:121–124. Neeta S, Nupur G, Shikha S, Deka D, Mittal S. Corpus luteal hemorrhage: an unusual manifestation of congenital factor XIII deficiency. Haemophilia 2008; 14:667–668. Kim GB. Pulmonary hypertension in infants with bronchopulmonary dysplasia. Korean J Pediatr 2010; 53:688–693. Vural M, Yarar C, Durmaz R, Atasoy MA. Spontaneous acute subdural hematoma and chronic epidural hematoma in a child with F XIII deficiency. J Emerg Med 2010; 38:25–29. Nourbakhsh E, Anvari R, D’cunha N, Thaxton L, Malik A, Nugent K. Postoperative bleeding in a patient with normal screening coagulation tests. Am J Med Sci 2011; 342:262–264. Perez DL, Diamond EL, Castro CM, Diaz A, Buonanno F, Nogueira RG, Sheth K. Factor XIII deficiency related recurrent spontaneous intracerebral hemorrhage: a case and literature review. Clin Neurol Neurosurg 2011; 113:142–145. Karimi M, Bereczky Z, Cohan N, Muszbek L. Factor XIII deficiency. Semin Thromb Hemost 2009; 35:426–438. Huq FY, Kadir RA. Management of pregnancy, labour and delivery in women with inherited bleeding disorders. Haemophilia 2011; 17 (Suppl 1): 20–30. Pike GN, Bolton-Maggs PHB. Factor deficiencies in pregnancy. Hematol Oncol Clin North Am 2011; 25:359–378; viii-ix. Chi C, Kadir RA. Inherited bleeding disorders in pregnancy. Best Pract Res Clin Obstet Gynaecol 2012; 26:103–117. Canadian Blood Services - Plasma Protein Products [Internet] http:// www.blood.ca. [Accessed on 1 October 2013] Behring C. CSL Behring Receives FDA Approval to Expand the Indication for Corifact [Internet]. cslbehringcom http://www.cslbehring.com/ newsroom/FDA-approves-expanded-indication-for-Corifact. [Accessed on 20 September 2013]
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Factor XIII deficiency management: a review of the literature Jodie E. Odamea, Anthony K. Chanb,c, John K. Wud,e and Vicky R. Breakeyb,c Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder estimated to affect 1 in 2 million live births. Treatment often involves prophylaxis with FXIII concentrate and is especially important in preventing intracranial hemorrhage (ICH) and maintaining pregnancy in women of childbearing age. The rarity of this condition and lack of good quality evidence has resulted in a literature largely based on case reports/case series. A review of the literature was conducted in order to provide information about the optimal management of FXIII deficiency. Articles were identified by searching MEDLINE from 1961 to June 2012. Eligible studies included details on patients with FXIII deficiency that received treatment. Information collected included dose, frequency, duration, hemostatic efficacy and adverse events. Of 606 abstracts reviewed, 43 articles, including a total of 328 patients met the selection criteria. Common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Patients were generally placed on prophylactic factor replacement therapy upon diagnosis of severe or symptomatic FXIII deficiency, which decreased and/or prevented bleeding episodes. Patients with FXIII deficiency that received prophylactic treatment successfully maintained pregnancies. Alternative treatments included the use of cryoprecipitate or frozen plasma when FXIII concentrate was not available or
Introduction Factor XIII (FXIII) is a hetero-tetramer zymogen activated by thrombin in the presence of calcium that catalyzes g-g cross-linking of glutamine-lysine residues of adjacent g fibrin chains, and a 2 antiplasmin onto a fibrin chain (Fig. 1). This is important in the final stages of blood coagulation [1–3]. The FXIII complex is composed of two A subunits (FXIIIA) and two B subunits (FXIIIB) [3]. The A subunits have four domains: an Nterminal activation peptide, a b sandwich, catalytic core and two b-barrels [3,4]. FXIIIA also exists as a homodimer intracellularly in platelets and monocytes in the uterus [3,5]. FXIIIB has 10-sushi domain repeats that bind to the a subunits and prolong their survival [3,6]. In the presence of calcium, thrombin leaves the Arg37Gly38 peptide bond in FXIIIA, releasing the activation peptide from its N-terminus, and FXIIIB disassociates [6]. FXIIIA2 is then activated, can cross-link fibrin chains and allow for clot formation. FXIIIA also acts to stabilize the fibrin chains and prevents fibrinolysis [6]. Deficiency of factor XIII
FXIII deficiency is a rare bleeding disorder with an estimated frequency of one in every 2 million people [8]. The FXIIIA gene is located on chromosome 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
affordable. Recent studies of a new recombinant FXIII concentrate show promising results in regards to safety and efficacy. There are limited data to guide the optimal treatment of FXIII deficiency. Larger patient registries and international collaborations are needed to improve the evidence and enhance clinical outcomes in this rare bleeding disorder. Blood Coagul Fibrinolysis 25:199–205 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:199–205 Keywords: blood coagulation disorders, factor 13 deficiency, factor XIIIa, factor XIIIb, factor XIII deficiency, hemorrhagic disorders, inherited a Department of Physiology, University of Toronto, Toronto, Ontario, bDepartment of Pediatrics, McMaster University, Hamilton, Ontario, cDivision of Hematology/ Oncology, McMaster Children’s Hospital, Hamilton, Ontario, dDepartment of Pediatrics, University of British Columbia, Vancouver, British Columbia and e Division of Pediatric Hematology/Oncology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
Correspondence to Vicky R. Breakey, MD, MEd, FRCPC, Pediatric Hematologist/ Oncologist, Assistant Professor, Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, HSC 3N27a – 1280 Main St. W, Hamilton, Ontario L8S 4K1, Canada Tel: +1 905 521 2100 x73080; fax: +1 905 521 1703; e-mail: [email protected] Received 3 April 2013 Revised 22 October 2013 Accepted 13 November 2013
6p24-p25, and the FXIIIB gene on 1q31–32.1 [8]. There are more than 94 mutations identified in FXIIIA and six in FXIIIB [3,9]. FXIII deficiency is inherited in an autosomal recessive mode, and thus is more prevalent in countries where consanguineous marriages are common, such as Middle Eastern countries, Pakistan and South India [3,6,10]. Inherited FXIII deficiency can be a result of FXIIIA or FXIIIB deficiency [6]. FXIIIA deficiency can be due to a reduction in FXIIIA synthesis (Type I) or decreased FXIIIA function (Type II) [6]. FXIIIB deficiency is much less common and tends to be associated with milder bleeding symptoms [6,11]. Clinical symptoms can range from mild-to-severe [6]. In general, there are lack of data about individuals that are heterozygous for FXIII deficiency. These people are most often asymptomatic, but may have prolonged bleeding after minor traumas [6]. Patients with FXIII less than 1U/dl have the highest risk of experiencing severe spontaneous bleeding [1]. Patients with levels between 1and 4U/dl have moderate-to-severe bleeding. Patients with levels more than 5U/dl may bleed occasionally, however, the relationship between FXIII levels and clinical features is difficult to DOI:10.1097/MBC.0000000000000029
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200 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 3
Fig. 1
Role of factor XIII in the coagulation cascade.
establish [12]. Severe deficiencies often present in the newborn period. Umbilical cord bleeding is one of the most common symptoms, occurring in 80% of cases of severe FXIII deficiency [3,6]. There is also a significant risk of intracranial hemorrhage (ICH), which has been reported in approximately 30% of FXIII deficiency newborns, and is the leading cause of death in this group [13]. Other symptoms in older children and adults with severe FXIII deficiency include intramuscular and subcutaneous hematomas, ecchymoses, postoperative bleeding and prolonged bleeding after trauma [6]. As FXIII is one of the few coagulation factors that does not rise during pregnancy, complications in pregnant women with FXIII deficiency are common [14]. FXIII deficiency may be diagnosed following multiple spontaneous abortions. It has been shown that women with FXIIIA deficiency have a poorly formed cytotrophoblastic and Nitabuch’s layer, affecting early placental adhesion and increasing the chance of placental detachment and miscarriage [7].
partial thromboplastin time (aPTT) and fibrinogen. However, these tests do not detect FXIII deficiency [15]. If FXIII deficiency is suspected, qualitative screening can be done using the clot solubility test. Plasma samples are clotted by excess calcium, then placed in 5 mol/l urea or 2% acetic acid (or 1% monochloracetic acid) and observed for 24 h. If inadequate levels of FXIII are present, the clot will dissolve within minutes to 2 h [16]. Unfortunately, clot solubility only detects severe FXIII deficiency (FXIII levels two patients) cases (Table 1) [6,13,18–22] whereas eight publications reported pregnancy outcomes (Table 2) [14,23–28]. The additional 19 small case reports were also reviewed and summarized [1,11,29–45]. General treatment approach
Over the last few decades, the treatment of patients with FXIII deficiency has been recorded in case reports and case series. The most common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Reported cases revealed that patients are generally placed on prophylactic replacement therapy once the diagnosis of severe or symptomatic FXIII deficiency
FXIII deficiency review selection criteria. FXIII, factor XIII.
has been confirmed, as experience has suggested much better outcomes than in patients who received on demand therapy [17]. Plasma-derived FXIII concentrate (commercially available as Fibrogammin P; CSL Behring, Hayward’s Heath, West Sussex, UK) is currently considered standard therapy for congenital FXIII deficiency [3]. In adults, the standard dosing is 10– 35 U/kg of FXIII concentrate infused every 4–6 weeks. This results in few or no further bleeding episodes [6,8]. Common alternatives for FXIII deficiency treatment in countries where FXIII concentrate is not available include cryoprecipitate and FFP. Standard dosing for FFP in adults is 15–20 ml/kg, and 1 bag/10 kg for cryoprecipitate [46]. Twenty-two cases were reviewed wherein alternate forms of treatment were used. These were reported prior to the development of plasma-derived FXIII concentrates, or in areas that do not have access to FXIII concentrates. Padmanabhan et al. [27] described two separate cases in India wherein women received cryoprecipitate in order to maintain their pregnancies. FFP treatment was also used in a case reported by Rodeghiero et al. [24], but the patient was later switched to Fibrogammin P. Generally, plasma-based forms of treatment
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202 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 3
Table 1
Larger case series (>two patients) and prospective trials to review the treatment of factor XIII deficiency
Author, year
N
Treatment indication
Sex/age (years)
Acharya 2004 [19]
32
Hemorrhages, surgical wounds and joint/muscle bleeds
Unspecified
Eshghi 2004 [20]
13
Unspecified
Nugent 2006 [6]
61
Umbilical bleeding, bruises and hematoma most common Unspecified
Eshghi 2009 [21]
127
Lusher 2009 [22]
7
Dreyfus 2011 [18]
19
Unspecified
Inbal 2012 [13]
41
Unspecified
FXIII source, dose, frequency (if reported)
Outcome
Adverse events
45% FFP, 24% cryoprecipitate, 24% FXIII concentrate, 6% EACA, 34% long-term prophylaxis Prophylactic treatment with cryoprecipitate
Not reported
One patient developed an inhibitor, some died from ICH
No further bleeding
None reported
1–74 years
FXIII concentrate, dose not reported
Headaches, some myalgias, two unrelated deaths
Umbilical cord bleeding and deep soft tissue hematoma most common
66 M, 61 F, 0–23 years
Those on prophylactic treatment either received 1–15 ml/kg FFP or 1 U/10 kg cryoprecipitate every 4–6 weeks
Umbilical cord bleeding, hematomas, ICH, mouth thigh and gum bleeds
4 M, 2 F, 1 unspecified, 10 months– 19 years Unspecified, 18 days– 47 years Unspecified, 7–60 years
15–45 IU/kg FXIII concentrate every 3–4 weeks
No major bleeds during prophylaxis; bleeds in five patients noncompliant with treatment 14 of 19 died from ICH due to no prophylactic treatment; one patient receiving prophylactic treatment had major bleeding episode Annual spontaneous bleeding rate reduced during prophylactic FXIIIA concentrate therapy rFXIII efficacy rated as moderate (1), good (11) or excellent (3) rFXIII well tolerated, 4 of 41 patients had bleeds requiring treatment
1.55–14.8 IU/kg rFXIII concentrate a week every 4–6 weeks 35 IU/kg rFXIII every 4 weeks
None reported
None reported
None reported
Four patients developed nonneutralizing antibodies
EACA, epsilon aminocaproic acid; F, female; FFP, fresh frozen plasma; FXIII, factor XIII; ICH, intracranial hemorrhage; M, male; N, number of patients; rFXIII, recombinant FXIII.
also resulted in positive outcomes, and no further bleeds. However, a case reported by Perez et al. [45] revealed a 25-year-old woman died due to a thalamic ICH with ventricular extension despite treatment with Vitamin K Table 2
and FFP. It was suggested that the use of FXIII concentrates may have been a better choice, as it would be a more disease-specific approach to prophylactic treatment, and has fewer risks.
Summary of the publications addressing the treatment of factor XIII deficiency in pregnancy Age (years)
Author, year
N
Treatment indication
Fisher 1966 [23]
1
29
Rodeghiero 1987 [24]
1
Twelve spontaneous abortions Spontaneous abortions after severe decidual bleeding during early gestation
Boda 1989 [25]
1
34
Kobayashi 1990 [26]
1
Eight spontaneous abortions Spontaneous abortion at 6 weeks gestation
Burrows 2000 [14]
1
ICH (initially diagnosed at age 3 years)
22
Padmanabhan 2004 [27]
1
Seven spontaneous abortions
29
Padmanabhan 2004 [27]
1
Vaginal bleeding during early gestation
22
Dargaud 2008 [28]
1
Three spontaneous miscarriages
34
25
20
FXIII source, dose, frequency
Outcome
Adverse events
Plasma transfusion; 300 ml every 10 days FFP: 300–450 ml every 2 weeks; FXIII concentrate: 500 IU every 3 weeks 40 ml FFP every 10 days
Healthy baby delivered near term Delivered two healthy babies near term
None reported
Healthy baby delivered
None reported
500 IU FXIIIA concentrate every 7 days, 100 IU before delivery FXIIIA concentrate 500 IU every 7 days, 100 IU before delivery One unit cryoprecipitate every 4 weeks, later increased to two units Two units cryoprecipitate during first evacuation, four units during second evacuation Third pregnancy: 10 IU FFP FXIII concentrate: 20 U/kg 2–4 weeks, 1250 U before delivery
Delivered baby with no complications
None reported
Delivered baby with no complications
None reported
One spontaneous abortion, increased dose led to successful pregnancy Evacuation was done on both pregnancies
Oozing from uterine cavity postpartum
No early genital hemorrhage or fetal loss
Cervical premature membrane rupture led to preterm delivery and subsequent neonatal death
None reported
None reported
FXIII, factor XIII; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; N, number of patients.
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Management of factor XIII deficiency Odame et al. 203
Perioperative care
There were seven reports of perioperative management of patients with FXIII deficiency. These patients were treated with FXIII concentrate (four), FFP (two) or cryoprecipitate (one). In four of these cases, patients received therapy both before and after surgery [30,36,40,41]. In one case, treatment was just given preoperatively [30]. In two cases, treatment was just received postoperatively [39,44]. No further bleeds were seen after treatment in any of the reported cases. Prophylaxis
Twenty-five articles reported the use of prophylactic therapy in patients with FXIII deficiency, with 13 out the 25 articles reporting the use of FXIII concentrate. Only three of these cases reported adverse events related to treatment [13,40,42]. In a prospective multicenter study conducted by Dreyfus et al. [18], the efficacy of Fibrogammin P long-term replacement therapy in treating hemorrhages and preventing further bleeds was rated as good or excellent in 95% of cases. A multinational prospective study was conducted by Inbal et al. [13] to assess the efficacy of long-term replacement therapy with rFXIII. The frequency of bleeds was lower in patients receiving rFXIII than those on normal regular replacement therapy, with 37 of 41 patients having no bleeds requiring treatment during the trials. Pregnancy
Case reports of FXIII deficiency treatment in pregnancy were also summarized (Table 2). Although many pregnancies were established in FXIII-deficient patients without replacement therapy, a study conducted by Burrows et al. [14] revealed 10 of the 16 individuals with FXIII deficiency had recurrent abortions. There were a number of patients that presented with cases of recurrent abortions. Reviews that discussed the management of FXIII deficiency during pregnancy strongly recommended prophylactic therapy to prevent spontaneous abortions [47–49]. Asahina et al. [7] reported eight successful pregnancies in patients with FXIIIA deficiency who received replacement therapy. They described two cases in which vaginal bleeding began around 5–6 weeks of gestation, but bleeding control was achieved before abortion occurred following administration of FXIII concentrate. The cases reported increasing the standard dose of FXIII concentrate to 500 IU every 3–6 weeks during pregnancy. Another case reported doubling the dose again at 23 weeks of gestation to account for the drop in FXIII levels to about 5%. The mode of delivery varied with case, and seemed to be determined on an individual basis. In three cases, four vials (1000 IU) were administered prior to delivery [7]. Most women that received this treatment course delivered healthy babies. There were also some postpartum complications reported, most commonly bleeding from the uterine cavity [27]. Huq et al. [47] also reported that FXIIIA-deficient and
FXIIIB-deficient patients are at high risk of developing postpartum hemorrhage. Complications and adverse events
The development of adverse events after treatment was rare. In many cases, the complications reported were due to bleeding and were not related to therapy. In a case reported by Abbondanzo et al. [32], the patient developed cranial nerve palsies due to ICH despite treatment. In another case reported by Ugur et al. [35], the patient developed paralysis in the lower limbs and nerve damage in the right arm, as well as a spastic bladder due to intraspinal hemorrhage. A case reported by Almeida et al. [1] also spoke of a patient who developed blindness due to neurological damage. In these cases, the damage was extensive before treatment was given, and therefore could not be reversed. Complications reported during pregnancy included oozing form uterine cavity and premature cervical membrane rupture [27,28]. The most dreaded adverse event was the development of inhibitors, although its incidence was rare. A rare bleeding disorder registry created in North America discovered that 3% of FXIII-deficient patients that received FFP or FXIII concentrate treatment developed inhibitors [19]. A case reported by Kim et al. [42] revealed that a 9-year-old girl developed an inhibitor after receiving three units of cryoprecipitate and one unit of red blood cells. A study conducted by Inbal et al. [13] testing the efficacy of rFXIII found four patients developed nonneutralizing antibodies. As a result, three of these patients were removed from the study and restarted on the plasmaderived product. However, in one of the cases, an 8-yearold boy continued to receive monthly rFXIII treatment despite developing nonneutralizing antibodies after second exposure. These antibodies subsequently diminished to below detection levels 4 months later.
Discussion As of 2013, plasma-derived FXIII concentrate (Fibrogammin P) has been approved (licensed) in 14 countries worldwide (Argentina, Austria, Brazil, Colombia, France, Georgia, Germany, Great Britain, Indonesia, Israel, Japan, Luxembourg, Switzerland and United States) (Josephine Cybulski, plasma products specialist, personal communication, 1 October 2013). In Canada, FXIII concentrate is available through Health Canada approval [50]. Recently, the United States received further Food and Drug Administration approval to include perioperative management in February 2013 [51]. FXIII concentrate has been recommended as a safer treatment alternative to cryoprecipitate or FFP for FXIII deficiency. Many case reports have shown improved bleeding symptoms in patients on prophylactic therapy [18]. In countries where plasma-derived FXIII concentrates are not available, or the resources needed to purchase or manufacture this product are limited, treatment
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204 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 3
with FFP or cryoprecipitate is still common and usually efficacious [17]. It remains important that good manufacturing processes and viral inactivation of plasma products are practiced. Recently, the use of mini-pool solvent pathogen inactivation performed by blood establishments has been described, and provides a form of viral inactivation of plasma products at an affordable price [17]. This new technology can provide safer plasma-derived products for the treatment of FXIII deficiency in developing countries until FXIII concentrate becomes more affordable.
Conflicts of interest
There are no conflicts of interest.
References 1 2
3 4
The general availability of rFXIII is within sight. A recent multinational open-label trial suggested safety and efficacy of a new rFXIII, produced by Novo Nordisk (Denmark) for use in patients with congenital FXIII deficiency [13]. rFXIII is currently approved for FXIIIA deficiency in the European Union, Canada and Switzerland. Inhibitors are only rarely reported in patients with congenital FXIII deficiency, but nonneutralizing antibodies were noticed in some of the patients [13]. Patients should be carefully monitored once the use of rFXIII is more widespread.
10
Future directions
11
There is still much that is not well understood about FXIII deficiency. Clinicians should continue to educate their colleagues of the possible symptoms, as FXIII deficiency is not detected upon routine assessments of coagulation with INR/aPTT/fibrinogen/platelet count and cannot be diagnosed unless it is suspected. This is particularly important in newborns with umbilical bleeding and in women that present with recurrent abortions.
5 6 7
8 9
12
13
14
15
Further work is needed to improve the treatment of patients with FXIII deficiency. Plasma-derived FXIII concentrate has been the mainstay of therapy for many years, but as rFXIII becomes better-studied and more widely available, it may replace the plasma-derived product. In order to safely treat patients in both developing and developed countries, access and cost issues must be addressed. To expand our knowledge of FXIII deficiency, patient information should be gathered in registries and analyzed to better understand the clinical presentation, diagnosis and treatment of this small, but important group of patients. By pooling our experiences and working together on international trials, we can improve the care of these patients.
Acknowledgements This work was supported by the Canadian Hemophilia Society (CHS) Summer Studentship in Inherited Bleeding Disorders Research. Special thanks to Ivan Stevic for providing Figure 1. Work supported by: Canadian Hemophilia Society Inherited Bleeding Disorders summer studentship.
16
17 18
19
20
21
22
23 24
25
Almeida A, Khair K, Hann I, Liesner R. Unusual presentation of factor XIII deficiency. Haemophilia 2002; 8:703–705. Koseki-Kuno S. Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages. Blood 2003; 102:4410–4412. Muszbek L, Bagoly Z, Cairo A, Peyvandi F. Novel aspects of factor XIII deficiency. Curr Opin Hematol 2011; 18:366–372. Louhichi N, Medhaffar M, HadjSalem I, Mkaouar-Rebai E, Fendri-Kriaa N, Kanoun H, et al. Congenital factor XIII deficiency caused by two mutations in eight Tunisian families: molecular confirmation of a founder effect. Ann Hematol 2009; 89:499–504. Adany R, Muszbek L. Immunohistochemical detection of factor XIII subunit a in histiocytes of human uterus. Histochemistry 1989; 91:169–174. Nugent DJ. Prophylaxis in rare coagulation disorders: factor XIII deficiency. Thromb Res 2006; 118:S23–S28. Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv 2007; 62:255–260. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14:1190– 1200. Cooper DN, Stenson PD, Phillips AD, et al. Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. [Internet]. hgmdcfacuk http://www.hgmd.cf.ac.uk. [Accessed on 20 September 2013] Peyvandi F, Jayandharan G, Chandy M, MSrivastava A, Nakaya SM, Johnson MJ, et al. Genetic diagnosis of haemophilia and other inherited bleeding disorders. Haemophilia 2006; 12 (Suppl 3):82–89. Killick CJ, Barton CJ, Aslam S, Standen G. Prenatal diagnosis in factor XIIIA deficiency. Arch Dis Child Fetal Neonatal Ed 1999; 80:F238–F239. Bolton-Maggs PHB, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams MD, et al. The rare coagulation disorders: review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia 2004; 10:593–628. 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; 119:5111–5117. Burrows RF, Ray JG, Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature. Obstet Gynecol Surv 2000; 55:103–108. Lusher JM, Barnhart MI. Acquired bleeding disorders in children: platelet abnormalities and laboratory methods first edition, 1st ed. Aperture; 1985–04; 208 pages. Luo Y-Y, Zhang G-S. Acquired factor XIII inhibitor: clinical features, treatment, fibrin structure and epitope determination. Haemophilia 2011; 17:393–398. Magdy El Ekiaby MD. Improving the safety of plasma and its components for clinical transfusion. J Appl Hematol 2011; 2:280. Dreyfus M, Barrois D, Borg JY, Claeyssens S, Torchet M-F, Arnuti B, et al. Successful long-term replacement therapy with FXIII concentrate (Fibrogammin1 P) for severe congenital factor XIII deficiency: a prospective multicentre study. J Thromb Haemost 2011; 9:1264– 1266. Acharya SS, Coughlin A, Dimichele DM, the North American Rare Bleeding Disorder Study Group. Rare bleeding disorder registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2004; 2:248–256. Eshghi PP, Abolghasemi HH, Sanei-Moghaddam EE, Anwar R, Jazebi M, Amid A, Ala A. Factor XIII deficiency in south-east Iran. Haemophilia 2004; 10:470–472. Eshghi P, Mahjour SB, Naderi M, Dehbozorgian J, Karimi M. Long-term prophylaxis in patients with factor XIII deficiency complicated by intracranial haemorrhage in Iran. Haemophilia 2009; 16:383–385. Lusher J, Pipe SW, Alexander S, Nugent D. Prophylactic therapy with Fibrogammin 1P is associated with a decreased incidence of bleeding episodes: a retrospective study. Haemophilia 2009; 16:316–321. Fisher S, Rikover M, Naor S. Factor 13 deficiency with severe hemorrhagic diathesis. Blood 1966; 28:34–39. Rodeghiero F, Castaman GC, Di Bona E, Ruggeri M, Dini E. Successful pregnancy in a woman with congenital factor XIII deficiency treated with substitutive therapy. Report of a second case. Blut 1987; 55:45–48. Boda Z, Pfliegler G, Muszbek L, et al. Congenital factor XIII deficiency with multiple benign breast tumours and successful pregnancy with substitutive therapy. A case report. Haemostasis 1989; 19:348–352.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Management of factor XIII deficiency Odame et al. 205
26
27 28
29 30 31 32
33
34
35
36 37
38
Kobayashi TT, Terao TT, Kojima TT, Takamatsu J, Kamiya T, Saito H. Congenital factor XIII deficiency with treatment of factor XIII concentrate and normal vaginal delivery. Gynecol Obstet Invest 1990; 29:235– 238. Padmanabhan LD, Mhaskar R, Mhaskar A, Ross CR. Factor XIII deficiency: a rare cause of repeated abortions. Singapore Med J 2004; 45:186–187. Dargaud Y, De Mazancourt P, Rugeri L, Hanss M, Borg JY, Gaucherand P, et al. An unusual clinical presentation of factor XIII deficiency and issues relating to the monitoring of factor XIII replacement therapy. Blood Coagul Fibrinolysis 2008; 19:447–452. Francis J, Todd P. Congenital factor XIII deficiency in a neonate. BMJ 1978; 2:1532. Suzuki H, Kaneda T. Tooth extraction in two patients who had a congenital deficiency of factor XIII. J Oral Maxillofac Surg 1985; 43:221–224. Landman J, Creter D, Homburg R, Sirota L, Dulitzky F. Neonatal factor XIII deficiency. Clin Pediatr 1985; 24:352–353. Abbondanzo SL, Gootenberg JE, Lofts RS, McPherson RA. Intracranial hemorrhage in congenital deficiency of factor XIII. Am J Pediatr Hematol Oncol 1988; 10:65–68. Giraldi C, Creta S, Martini A, Ioppoli C, Valleriani A, Muratorio A. Spontaneous intracerebral hematoma in an adolescent with factor XIII deficiency. Case report. Ital J Neuro Sci 1989; 10:579–582. Larsen PD, Wallace JW, Frankel LS, Crisp D. Factor XIII deficiency and intracranial hemorrhages in infancy. [Internet]. Pediatr Neurol 1990; 6:277–278; http://www.sciencedirect.com/science/article/pii/ 088789949090123I. Ugur S, Uzel N, Dundar K, Kaya U, Ayan I, Gedikog˘lu G. Intraspinal hemorrhage in a child with factor XIII deficiency. Pediatric Emerg Care 1991; 7:231–233. Deshmukh RG, Bosco J. Claw toes correction and factor XIII deficiency: a case report. Med J Malaysia 1995; 50:417–419. Andreae MCM, Amanullah AA, Jamil SS, Main C. Congenital factor XIII deficiency: a patient report and review of the literature. Clin Pediatr 1997; 36:53–55. Gootenberg JE. Factor concentrates for the treatment of factor XIII deficiency. Curr Opin Hematol 1998; 5:372–375.
39
40
41
42 43
44
45
46 47 48 49 50 51
Karabulut AB, Aydin H, Mezdegi A, Ademoglu E. Recurrent bleeding following rhinoplasty due to factor XIII deficiency. Plast Reconstr Surg 2001; 108:808. Pernod G, Barro C, Arnutti B, Blanc-Jouvan F, Garrel S, Kahn P, et al. Surgery in severe factor XIII deficiency: report of a case of epilepsy neurosurgery and review. Haemophilia 2003; 9:121–124. Neeta S, Nupur G, Shikha S, Deka D, Mittal S. Corpus luteal hemorrhage: an unusual manifestation of congenital factor XIII deficiency. Haemophilia 2008; 14:667–668. Kim GB. Pulmonary hypertension in infants with bronchopulmonary dysplasia. Korean J Pediatr 2010; 53:688–693. Vural M, Yarar C, Durmaz R, Atasoy MA. Spontaneous acute subdural hematoma and chronic epidural hematoma in a child with F XIII deficiency. J Emerg Med 2010; 38:25–29. Nourbakhsh E, Anvari R, D’cunha N, Thaxton L, Malik A, Nugent K. Postoperative bleeding in a patient with normal screening coagulation tests. Am J Med Sci 2011; 342:262–264. Perez DL, Diamond EL, Castro CM, Diaz A, Buonanno F, Nogueira RG, Sheth K. Factor XIII deficiency related recurrent spontaneous intracerebral hemorrhage: a case and literature review. Clin Neurol Neurosurg 2011; 113:142–145. Karimi M, Bereczky Z, Cohan N, Muszbek L. Factor XIII deficiency. Semin Thromb Hemost 2009; 35:426–438. Huq FY, Kadir RA. Management of pregnancy, labour and delivery in women with inherited bleeding disorders. Haemophilia 2011; 17 (Suppl 1): 20–30. Pike GN, Bolton-Maggs PHB. Factor deficiencies in pregnancy. Hematol Oncol Clin North Am 2011; 25:359–378; viii-ix. Chi C, Kadir RA. Inherited bleeding disorders in pregnancy. Best Pract Res Clin Obstet Gynaecol 2012; 26:103–117. Canadian Blood Services - Plasma Protein Products [Internet] http:// www.blood.ca. [Accessed on 1 October 2013] Behring C. CSL Behring Receives FDA Approval to Expand the Indication for Corifact [Internet]. cslbehringcom http://www.cslbehring.com/ newsroom/FDA-approves-expanded-indication-for-Corifact. [Accessed on 20 September 2013]
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