Practice Essentials

Factor XIII (FXIII), which was initially termed fibrin stabilizing factor, is involved in clot
preservation. FXIII deficiency, an autosomal recessive disorder, is a rare but potentially lifethreatening cause of a hemorrhagic diathesis. Paradoxically, alterations in FXIII may also
predispose to thrombosis. FXIII participates in other physiologic processes, including wound
repair and healing.

Essential update: FDA approves recombinant product for prophylaxis in factor

XIII deficiency
In December 2013, the FDA approved recombinant coagulation factor XIII A-subunit (Tretten)
for the prevention of bleeding in adults and children with congenital factor XIII A-subunit
deficiency. Approval was based on studies in 77 patients in which monthly treatment with the
coagulation factor effectively prevented bleeding in 90% of subjects.[1]

Signs and symptoms

The following symptoms should trigger an evaluation for FXIII deficiency:

Spontaneous miscarriages early in pregnancy

Bleeding from the umbilical cord 1-19 days after birth
Easy bruising and soft tissue bleeding, particularly in association with trauma, as the
infant starts to ambulate; bleeding following trauma may be immediate, delayed, and/or
recurrent
CNS hemorrhage is common, recurs in approximately 30% of patients, and may be the
initial manifestation in patients with severe FXIII deficiency
CNS bleeding may be preceded by head trauma in children, while adults may develop a
CNS bleed in the absence of obvious trauma
Symptoms typical of any CNS event may be present (eg, headaches, seizures, vomiting,
focal neurologic defects); symptoms may be acute at onset or may be superimposed on
residual findings of a past bleed
Menorrhagia and intra-abdominal bleeding during menses
Bleeding into joints
Poor wound healing, although described, is less common
Autoantibodies to FXIII are an acquired cause of a bleeding diathesis; these may be
triggered by isoniazid, so a detailed drug history is essential

Bleeding into joints

May be precipitated by trauma

Reports exist of recurrent target joint bleeds, but destructive changes in the joints are
uncommon[2]
Spontaneous joint and extensive muscle bleeding, characteristic of patients with severe
hemophilia, are uncommon in patients with severe FXIII deficiency

Physical findings
Physical findings depend on the site at which bleeding develops and include the following:

Bleeding from the umbilical cord after birth usually manifests with persistent oozing,
which may start a few days after birth
Findings associated with CNS bleeding depend on the location of the bleeding; trauma
may precede the event, with additional findings, a new CNS bleed may be superimposed
on residual findings related to a prior bleed
Findings in patients with bruising and soft tissue bleeding are similar to those seen in
other patients; it is uncommon to find the large hematomas or joint bleeds characteristic
in patients with severe hemophilia
Female patients may present with vaginal spotting or bleeding during early pregnancy,
preceding a spontaneous miscarriage
Persistent, delayed, or recurrent bleeding may occur at sites of trauma or surgery
Poor wound healing may be noted
Acquired causes of FXIII deficiency, such as DIC and liver disease, present in a wellrecognized manner

See Clinical Presentation for more detail.

Diagnosis
The following routine tests are the first step in the evaluation of any bleeding disorder:

aPTT
PT
Thrombin
Clottable fibrinogen level
Platelet count
Bleeding time (after ascertaining that the patient was not on antiplatelet drugs for at least
the preceding 5 d)

However, these tests cannot be used to screen for FXIII deficiency because the results would be
within reference ranges in a patient with isolated severe FXIII deficiency.[3]
Qualitative screening test for severe FXIII deficiency

Assessment of clot solubility in 5M urea or 1% monochloroacetic acid

Lysis of thrombin and Ca2+ - induced clot within a few hours suggests severe FXIII
deficiency, provided that fibrinogen levels are qualitatively and quantitatively within
reference range
The thrombin-clottable fibrinogen test can be used to exclude hypofibrinogenemia and
dysfibrinogenemia, which cause false-positive results on the 5M urea solubility test

Quantitive testing

If the 5M urea solubility test demonstrates positive results, this finding should be confirmed by
quantitating FXIII activity using a monodansylcadaverine or putrescine incorporation assay.
A new sensitive assay used to quantitate FXIII activity is based on monitoring the amount of
ammonia (NH3) released by using glutamate dehydrogenase and nicotinamide adenine
dinucleotide phosphate during the transamidation reaction (cross-linking) by FXIII. Another new
and sensitive colorimetric assay is based on incorporation of 5-(biotinamido) pentylamine into
fibrin/fibrinogen.[4]
In addition, a2PI and plasminogen activator inhibitor-1 assays should be performed to exclude
abnormalities in the fibrinolytic pathway, which accelerate clot lysis. Sodium dodecylsulfate
polyacrylamide gel electrophoresis under reducing conditions has been used to assess the
presence of cross-linked g or a chains of fibrin, which is a reflection of FXIII activity. The
studies must be performed by laboratory personnel with special expertise.
Testing for inhibitors

Repeat the urea solubility test with mixtures containing varying proportions of patient
and normal plasma to differentiate between a deficiency or an inhibitor as the cause of a
positive result; serum may be substituted for plasma in the test
Semiquantitation of the susceptibility of the fibrin clot to fibrinolysis can be obtained by
adding iodine-125-labeled fibrinogen, tissue plasminogen activator, thrombin, and Ca2 +
to the patient's plasma, with measurement of the time to 50% clot lysis

Prenatal diagnosis

Chorionic villous sampling at approximately 10-12 weeks of gestation or amniocentesis

at 16-20 weeks of gestation can be performed to obtain fetal cells for DNA analysis or for
linkage studies
If DNA analysis cannot be performed, fetal blood obtained by fetoscopy at approximately
20 weeks of gestation can be used
Perform these procedures only after intense genetic and obstetric counseling of the
parents

See Workup for more detail.

Management
FXIII replacement is used to treat bleeding, to prevent perioperative bleeding during elective
surgical procedures or, prophylactically, to prevent recurrent bleeding, as in CNS or joint
hemorrhages. Serial monitoring of achieved FXIII levels is essential to document the adequacy
of any therapy.
FXIII concentrates for replacement are as follows:

Plasma-derived virus-inactivated human FXIII concentrate (Corifact, in the United

States; Fibrogammin P in Europe, South America, South Africa, and Japan); a second
FXIII concentrate (Bio Products Laboratory, Elstree, Hertfordshire, UK) is available on a
per-patient request
Recombinant FXIII A-subunit, recombinant (Tretten)

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as
pressure, ice, and use of antifibrinolytic drugs. Avoidance of trauma and nonsteroidal antiinflammatory drugs (NSAIDs) is helpful in reducing bleeding events.
Treatment of patients with inhibitors

FXIII dose depends on the characteristics of the inhibitor

Also treat the underlying disorder and, when appropriate, use immunosuppressive agents,
including the newer B-cell-directed monoclonal antibodies.
Note that spontaneous disappearance of acquired inhibitors is part of their natural history,
and the use of milder less toxic immunomodulators, such as steroids, may suffice
Simple immediate ancillary measures of ice, pressure, ace wrap, immobilization of the
affected joint, and avoidance of NSAIDs may suffice in some cases

See Treatment and Medication for more detail.

Image library

Coagulation reactions leading to thrombin generation and

activation of factor XIII.

Background
The hemostatic system, consisting of blood vessels and blood, plays a crucial role in human
survival. The importance of the plasma coagulation system in protecting life and preventing
further blood loss following transection of a blood vessel has been understood for a long time.
Blood normally is maintained in a fluid state, without evidence of bleeding or clotting. The
presence of a bleeding diathesis in families with an X-linked pattern of inheritance of the
disorder has been recognized for hundreds of years.
The recognition of factor deficiencies as the cause of hemophilias spurred investigations into the
causes of other bleeding disorders and led to progress in understanding normal hemostasis.
Knowledge of the fact that blood clots that are formed in the presence of calcium are stronger,
insoluble in alkali, and resistant to proteolytic degradation led to the concept of insoluble clots in

the earlier part of the last century. In 1948, Laki and Lorand recognized that a serum factor,
termed fibrin stabilizing factor, was responsible for the characteristics of insoluble fibrin clots.[5]
In 1960, Duckert et al described the first case of an "undescribed congenital haemorrhagic
diathesis probably due to fibrin stabilizing factor deficiency," which was a description of the
consequences of severe factor XIII (FXIII) deficiency.[6, 7]
The importance of FXIII in the process of coagulation is underscored by symptoms borne by
patients who are homozygously deficient in FXIII or who have an antibody that disrupts FXIII
function. Paradoxically, alterations in FXIII may predispose patients to thrombosis. Based on all
available data, FXIII is clearly involved in the clot preservation side of the delicate balance
between clot formation and stability and clot degradation. FXIII participates in other physiologic
processes, including wound repair and healing. The many functions of FXIII and the disruptions
of those functions by mutations in the genes coding for FXIII are the subjects of on-going
investigations.[8, 9, 10]
Gene polymorphisms are being evaluated for their influence on susceptibility to venous and
arterial thromboembolism.[11] Variants of coagulation factors, including factor XIII Val34Leu,
have been implicated in influencing susceptibility to thromboembolic diseases.[12]
There is a question as to whether factor XIII Val34Leu polymorphism is protective against
idiopathic venous thromboembolism.[13] The substitution of leucine for valine at amino acid
position 34 of the factor XIII gene, commonly referred to as FXIII Val34Leu polymorphism, has
been reported to confer protection against venous thromboembolism. However, the results of a
recent study of white Canadian study population do not support an independent association of the
FXIII Val34Leu polymorphism with idiopathic venous thromboembolism.
An association may exist between the factor XIII Leu allele and a modest protective effect
against AMI and may provide useful information in profiling susceptibility to myocardial
infarction.[14]
Factor XIII has a variety of uses, potential and real. Plasma levels of factor XIII were found
decreased in children with HenochSchnlein purpura having severe abdominal symptoms.
Thus, it has been suggested that measurement of factor XIII level may be of value to detect the
vasculitic process of HenochSchnlein purpura before the rash occurs or long after it has
disappeared in patients with isolated abdominal or scrotal problems.[15, 16]
Immunohistochemistry may show factor XIIIa (FXIIIa).[17] FXIIIa-positive dermal dendritic cells
were increased in a variety of skin tumors, including dermatofibromas.
Severe factor XIII deficiency, a rare autosomal recessive coagulation disorder, is associated with
a relatively common prevalence of F13B gene defects, at least within the German population.
The regions in and around the cysteine disulphide bonds in the FXIII-B protein at the sites of
frequent mutations.[18]
FXIIIs aids immobilization and killing of bacteria as well as phagocytosis by macrophages,
likely functioning as part of the innate immune system.[19]

Use of relatively new specific FXIII assays are pivotal to avoid missing the diagnosis of FXIII
deficiency, a rare but potentially life-threatening disorder.[20]

Pathophysiology
Structure, production, and half-life of FXIII
Plasma FXIII is a heterotetramer consisting of 2 identical proenzyme subunits (A2) and 2
identical carrier protein subunits (B2). Subunit A contains the catalytic site, the activation
peptide, a calcium-binding site, and free sulfhydryl (SH) groups. Subunit B, a glycoprotein, acts
as a carrier protein that stabilizes subunit A, binds the zymogen (subunit A) to fibrinogen, and
acts as a brake on FXIII activation.[21, 22] Subunit B circulates in plasma as part of the tetramer A2
B2 and as a free B2 dimer; all of plasma subunit A is complexed with subunit B. The
concentration of subunit A in plasma is 15 mg/mL, while that of subunit B is 21 mg/mL. Much
of FXIII circulates in blood in association with fibrinogen.[23, 24]
Platelet FXIII (an A2 homodimer) constitutes approximately 50% of total FXIII activity in blood.
Plasma FXIII has a long half-life of approximately 9-14 days. A similarity exists between a
portion of the carboxy terminal (C terminal) domain of FXIII and the receptor-binding region of
a2 -macroglobulin. The complex of a2 -macroglobulin and its substrate protease is removed from
the circulation by binding to its receptor in the liver and other tissues; therefore, as has been
suggested, FXIII also may be removed from the circulation by a similar mechanism.[25, 26] Some
features of the A and B chains of FXIII are listed below. Monoclonal antibodies and naturally
occurring inhibitors are used to elucidate structure-activity relationships.
Bone marrow cells, megakaryocytes, and monocytes/macrophages synthesize FXIII, with a
possible role for hepatocytes in the synthesis of subunit A. Subunit B is synthesized by the liver.
Tissue transglutaminase, the intracellular form of FXIII, consists of the A2 subunit (an A2
homodimer) and is present in a variety of cells including platelets, megakaryocytes,
monocytes/macrophages, and in the liver, placenta, uterus, prostate, and dermal dendrocytes.[27]
Red cells contain a transglutaminase that is activated by Ca2+ but is different from plasma
transglutaminase in its cross-linking activity and can cross-link fibrinogen as well as fibrin.
Trapped erythrocytes release FXIII when red cells lyse, providing additional cross-links to the
aging thrombus.[21]
Table. Some Features of the A and B Chains of Factor XIII (Open Table in a new window)
Properties
Plasma FXIII
Plasma level
Chains are free in plasma
Chain contains the catalytic
site

A Chain
Has 2 A chains
Approximately 15 mg/mL
No. All bound to B chain and
present as an A2 B2 tetramer
Yes

B Chain
Has 2 B chains
Approximately 21 mg/mL
Yes. Excess B chain present in
plasma as a B2 dimer
No

Chain is the carrier protein

Chain acts as a brake on
FXIII activation
Cellular FXIII
Mutations can lead to
decreased FXIII activity

No
No

Yes
Yes

Has 2 A chains (A2 dimer)

Yes

Has no B chains
Yes

Comparative biology shows that transglutaminases are distributed widely in nature and may
represent the prototype for the evolution of clotting enzymes.[28] Partial homology of plasma
FXIII exists with several proteins including tissue and keratinocyte transglutaminases,
erythrocyte transglutaminase, and the hemocyte transglutaminase of the horseshoe crab and other
zymogens of the same family.
A recent example is from the crystal structure of transglutaminase of the Red Sea bream, which
shows that its active site and overall structure resemble that of human FXIII.[29] These
homologies attest to conservation of the enzyme during evolution. Since the gene structures are
similar, it is believed that they evolved from a common ancestor. Subunit B contains 10
repeating "sushi" units linked by disulfide bonds; the function of the sushi unit is unknown.
Sushi structures are present in at least 26 proteins, including proteins in the horseshoe crab and in
the vaccinia virus.

Activation
Thrombin, generated by reactions initiated by activated tissue factor VII/factor IX pathways (as
illustrated in the first diagram below), leads to clot formation. Thrombin releases fibrinopeptide
A from the a chain of fibrinogen, then fibrinopeptide B from the b chain of fibrinogen. Fibrin
monomers (formed following the release of fibrinopeptides) polymerize spontaneously; this is
followed by development of a complex branching clot as a result of the actions of activated
FXIII (FXIIIa).[30] The sequence of these final steps is found in the second chart below.

Coagulation reactions leading to thrombin generation and

activation of factor XIII.

article: Factor XIII).

Final steps in clot formation (from

Thrombin starts the process of FXIII activation by cleaving an activation peptide from subunit A.
The subsequent Ca2+ -dependent dissociation of subunit B allows FXIII activation to proceed.
Calcium is important for activation of the zymogen (both FXIII and tissue transglutaminase
require Ca2+), conformational changes, and opening of the catalytic site of FXIII to its substrate.
Calcium also provides physical stability as determined by x-ray crystallography, computer
modeling, and other studies; all of the changes allow the active subunit A to perform its
functions optimally.[21, 31, 32]
When activated by thrombin, tissue FXIII functions in the same manner as plasma FXIIIa.
Platelet FXIII undergoes nonproteolytic activation following the platelet activation-induced rise
in cytosolic Ca2+. Activation of the red cell enzyme occurs upon exposure to Ca2+, and red cells
that are present in the fibrin clot lyse and release their FXIII as the clot ages. Several controls in
the complex activation process focus the actions of FXIIIa on fibrin rather than on fibrinogen.
Cross-linking of polymerized soluble fibrin by FXIIIa is the final step in hemostasis, as
illustrated in the following chart. For extensive details of this activation process, the reader is
referred to two recent reviews by Lorand.[21, 28] Note the image below.

Activation of factor XIII and generation of insoluble cross-linked

fibrin. Adapted from Lorand L. Ann N Y Acad Sci. 2001;936:291-311.

Role of FXIII in cross-linking and resistance to lysis

FXIIIa cross-links the lysine of one g chain in the fibrin polymer with the glutamine of another g
chain by transamidation, releasing ammonia in the process. Additional cross-links occur between
a-a chains, a-g chains, a chains-a2 -plasmin inhibitor (a2 PI), and a chains-fibronectin. As a result
of the extensive cross-linking actions of FXIIIa, the clot structure of fibrin polymers increases in
complexity from dimers to trimers to tetramers.
The g chains of fibrinogen and fibrin normally bind to the platelet membrane glycoprotein
IIb/IIIa complex. The same g chains are subject to cross-linking by FXIIIa; therefore, crosslinking also occurs between fibrin and the platelet membrane. Both plasma FXIIIa and platelet
FXIIIa cross-link fibrin polymers, but under physiologic conditions, platelet FXIII is believed to
play a minor role.[33] Red cell FXIII is responsible for hybrid cross-linking of a-g chains, in
contrast to the actions of plasma FXIII.
Dysfibrinogenemias and dyshypofibrinogenemias result in alterations in fibrin (substrate for
FXIIIa), which can interfere with the ability of FXIII to cross-link fibrin. A reduction in
available fibrin resulting from afibrinogenemia can have the same effect. Conversely, increased
fibrinogen levels have been identified as a risk factor for thrombosis.
Mechanisms of this risk were elucidated by a fibrinolysis assay containing purified components.
The assay showed that lysis of fibrin decreased as fibrinogen levels increased, and the presence
of a minor common variant of fibrin (g') is associated with accelerated cross-linking, which made
the clot resistant to proteolysis by both plasmin and trypsin. Increased clot stability also was
believed to result from increased concentration of FXIII in the clot. Non-cross-linked fibrin
potentiates activation of FXIII by thrombin; thus, the substrate potentiates its enzyme, further
contributing to clot stability.[24, 34, 35]
Cross-linking of a2 PI to a chains of fibrin by FXIIIa brings the principal inhibitor of plasmin to
the site of the clot, ensuring resistance of the clot to proteolysis. Inhibition of a2 PI in in vitro
systems leads to enhanced clot lysis. In humans, deficiency of a2 PI results in a bleeding disorder
because of vulnerability of the fibrin clot to prompt degradation by plasmin. The formation of
highly cross-linked a-fibrin polymers in the presence of high concentrations of FXIIIa produces
clots that are highly resistant to fibrinolysis.[36]
Fibronectin, an adhesive protein, is a large component (approximately 4%) of the proteins in a
fibrin clot, is present in plasma and cells, and is subject to cross-linking by both plasma and
cellular FXIII. Cross-linking of fibronectin to fibronectin and fibronectin to fibrin is
accomplished by FXIIIa, with fibronectin contributing to increased fiber size, density, and
strength of the clot. FXIIIa also cross-links actin to fibrin and actin to myosin. Cross-linking of
intracellular structural proteins is involved in clot retraction and cell migration. This complex gel
network created by the actions of FXIII plays an important role in wound healing, cell adhesion,
and cell migration. All of these cross-linking reactions impart increased mechanical strength to
the clot, contributing to clot retraction and resistance of the clot to degradation by plasmin and
providing an explanation for the known plasmin resistance of older clots.

Many other proteins function as substrates for FXIIIa, including von Willebrand factor (vWF),
factor V (FV), thrombospondin, gelsolin, vitronectin, vinculin, lipoprotein (a), and collagen
(FXIIIa cross-links collagen with fibronectin and vWF, attaches the clot to the vessel wall,
impacts tissue repair, increases resistance of collagen to proteolysis, and modulates synthesis of
collagen by fibroblasts). Thus, FXIII plays a role in a wide array of cross-linking reactions
involving plasma proteins at the intracellular level, impacting many different functions.

Factors affecting level and activity of FXIII

When quantitative amine incorporation assays became available, healthy people were found to
have an 8-fold spread in FXIIIa activity.[37] In recent studies of FXIII antigen and activity in
humans, no correlation was found between these two parameters. During the search for an
explanation, 23 unique FXIIIa genotypes were found. The Leu34 and Leu564 variants gave rise
to increased specific activity; the Phe204 variant lowered specific activity. Other mutations gave
rise to low, high, or median FXIII-specific activity, and some variants had no effect.[38, 39]
In a study of the variability of FXIII levels in racial groups, FXIII activity was found to be higher
in Asian Indians (male and female) than in their Chinese counterparts, accounting for
approximately one fourth of the variability. Common genetic polymorphisms in the A and B
chains appeared to contribute to the differences.[40] An influence exerted by acquired factors was
evident in the higher FXIII levels found in women who smoked 20 or more cigarettes per day
during a normal pregnancy than was found in nonsmokers, with a lesser drop in the second half
of pregnancy.[41]

Role of FXIII in pregnancy

In the latter half of pregnancy, some drop in FXIII levels is normal, but severe (homozygous)
FXIII deficiency is a cause of recurrent miscarriages. In a study of gestational tissues, FXIII was
found in the decidual layer of the placenta, while FXIII secretion was evident in cultures of
round-shaped endometrial cells. A study of early (7-8 wk) gestational tissues obtained from
women without FXIII deficiency and from a woman who was homozygous for FXIII deficiency
showed poorly formed cytotrophoblastic shells and Nitabuch layers, along with absence of
FXIIIa in tissues obtained from the woman with FXIII deficiency. Low plasma levels of FXIII
appear to correlate with low placental levels of FXIII with poor trophoblastic development,
which may be the cause of spontaneous miscarriages.
It has been suggested that preventing miscarriage in patients who are severely deficient requires
FXIII supplementation beginning at approximately 5 weeks of gestation because FXIII,
fibrinogen, and fibronectin are necessary to anchor cytotrophoblasts invading the
endometrium.[42, 43] Reduced FXIII activity resulting from the Tyr204Phe mutation has been
associated with repeated miscarriages.[44]

Role of FXIII in wound healing

Physiologically, hyperpermeability induced by severe metabolic inhibition of porcine aortic
endothelial cells is prevented by FXIIIa, which is similar to the maintenance of endothelial

barrier function by FXIIIa despite depletion of energy or during reperfusion of ischemic rat
hearts.[45] In a different system, FXIII induced epithelial wound healing by increasing cell growth
by approximately 2.5 fold, leading to replacement of damaged cells.[46] Smooth muscle cell
migration, an integral part of the healing process, is facilitated by FXIII. Migration of smooth
muscle cells in cross-linked fibrin gels was twice the migration seen in noncross-linked gels,
demonstrating the importance of the 3-dimensional clot structure created by cross-linking in
smooth muscle cell migration.[47] In humans, Fibrogammin was shown to contribute to the
healing of venous leg ulcers by reducing endothelial permeability.[48]

Effects of other agents on FXIII

Nitric oxide (NO), an important diffusible molecular messenger, is increasingly recognized as
having an impact on coagulation proteins. Activity of plasma transglutaminase is inhibited by
NO via nitrosylation of critical thiol groups (reactive cysteine residue), resulting in inhibition of
both g-chain cross-linking and insoluble clot formation. NO donors and carriers inhibit FXIII
activity in a dose-dependent manner, in a purified system and in plasma. Tissue
transglutaminases are involved in apoptosis, and inhibition of their activity by NO prevents
apoptosis.[49, 50]
Venoms and toxins can affect clot stability. Excessive bleeding resulting from envenomation can
affect the functions of FXIII in different ways. Acuthrombin A, one of two proteases in the
venom of Agkistrodon acutus (five-pace snake), activates FXIII.[51] Ancrod, obtained from the
venom of Agkistrodon species, causes defibrination, thereby removing the substrate for FXIII.
A severe systemic bleeding disorder may develop several hours after initial contact with 2 types
of caterpillars in the Saturniidae family (from Brazil and Venezuela). Intracranial and
intracerebral bleeding and renal failure may follow. In this case, FXIII reduction results from
generalized disseminated intravascular coagulation (DIC) induced by several activities directed
against the hemostatic mechanism, including a FXIII proteolytic-urokinaselike activity.[52]
Tridegin, a peptide inhibitor of FXIII present in the saliva of an Amazon leech (Haementeria
ghilianii) accelerates fibrinolysis by inhibiting FXIIIa; tridegin is under investigation as a
potential new antithrombotic agent. Destabilase, an enzyme present in the leech, hydrolyzes g-g
fibrin cross-links and breaks down blood clots.[53]
Simvastatin is a commonly used cholesterol-lowering agent. A nonantibody-mediated druginduced reduction in FXIII activity as part of a broader reduction in hemostatic activation has
been suggested to be the reason for the proven antithrombotic efficacy of simvastatin in clinical
trials.[54] Blood samples were obtained sequentially every 30 seconds from a bleeding time cut in
patients with coronary artery disease, before and 3 months after simvastatin treatment. Samples
were analyzed for the time-course drop in fibrinogen levels and activation of factors II, V, and
XIII by quantitative Western blot analyses. Simvastatin, independent of its effects on cholesterol,
significantly reduced the rate of blood clotting, as evidenced by reduced formation of several
activation products including FXIIIa.
Several selective synthetic inhibitors have been shown to prevent the ability of FXIIIa to
stabilize a clot, thereby reducing clot strength (clot stiffness, viscoelastic modulus) to

approximately 20% of normal (values similar to those seen in patients with severe FXIII
deficiency). Rapid lysis of these clots occurred following in vitro exposure to thrombolytic
agents.[28] Imidazolium derivatives, a new class of compounds, specifically inhibit both FXIIIinduced formation of a-chain polymers and the incorporation of a2 PI into the a chain of fibrin,
resulting in accelerated clot lysis.[10, 55]
Specific monoclonal antibodies to FXIII have provided similar benefits by reducing the
viscoelastic properties and by enhancing clot lysis. They also have been used to modify disease
states. The beneficial effect of the absence of cross-linked fibrin on pathophysiologic processes
was proven in an animal model of widespread thrombosis. FXIIIa deficiency induced in rabbits
by pretreatment with a specific monoclonal antibody before induction of a generalized
Schwartzman reaction protected them from the deleterious effects of widespread microvascular
thrombosis. The protection resulted from the ability of the fibrinolytic system to effectively
degrade noncross-linked thrombi.[56] These data add support to the author's speculation many
years ago of the potential use of drugs that inhibit cross-linking as a method of prophylaxis in
venous thromboembolic disease.
The biochemical basis and potential for using modifiers of fibrin stabilization in improved
thrombolytic therapies are discussed in a recent review by Lorand.[28] Similar ideas have been
proposed by others, expanding on the importance of fibrin structure in thrombus formation and
dissolution.[57] Prospective clinical trials must prove any thromboprophylactic efficacy of altering
fibrin structure using specific drugs.

Other functions of FXIII

Plasma and tissue transglutaminases have been reported to promote cell adhesion through
specific integrins for 2 different tumor cell types, MOLT-3 human lymphocytelike leukemia
and melanoma cells and SW480 colon cancer cells transfected with a ligand.[58] In contrast, FXIII
did not stimulate growth of cultured human tumor cells.[59] An intriguing observation is the
potential use of subunit A of FXIII and FXIII activity as a tumor marker in malignant brain
tumors; its presence may distinguish benign from malignant brain tumors.[60] Recently, it was
shown for the first time that intranuclear accumulation and cross-linking activity of FXIIIa
occurred in maturing monocytes, supporting the hypothesis that FXIIIa may be involved in cell
proliferation/differentiation, chromatin structure remodeling, and even cell death.[61] Further data
are needed to unravel the role of FXIII in malignancies.
An unexpected role has been postulated for FXIII in degenerative brain disorders. In Alzheimer
disease and spongiform encephalopathies, the brain contains fibrils that develop from native
proteins containing a discordant a helix. Human FXIII was found to form fibrils in buffered
saline, suggesting that FXIII, in addition to several other proteins, can be a source of this
abnormal fibrillar protein.[62]

Possible interactions between deficiencies of FXIII and thrombin-activatable

fibrinolytic inhibitor

Thrombin-activatable fibrinolytic inhibitor (TAFI), a single-chain carboxypeptidase Blike

zymogen, is activated by thrombin to become activated TAFI (TAFIa).[63] The importance of
TAFIa in fibrinolysis is emphasized by the fact that the conversion of only 1% of the zymogen to
TAFIa is sufficient to suppress fibrinolysis by approximately 60%.
TAFIa suppresses fibrinolysis by removing C-terminal lysine and arginine residues exposed in
the partially degraded fibrin clot produced by plasmin. Removal of C-terminal lysine residues
from fibrin reduces the rate of plasminogen activation by a number of mechanisms, attenuating
fibrinolysis. This effect is counterbalanced in normal plasma by activation of protein C, which
has profibrinolytic properties because of its ability to suppress thrombin generation via its major
effect of degrading activated factor V (FVa), and to a lesser extent, activated factor VIII
(FVIIIa).[63, 64, 65]
As illustrated in the chart below, a delicate balance usually exists between thrombus formation
and thrombus resolution; thrombin secures survival of the thrombus created by its action on
fibrinogen by activating TAFI, thereby inhibiting fibrinolysis. Cross-linking of fibrin induced by
FXIIIa (activated by thrombin) renders the clot insoluble. FXIII deficiency results in absence of
cross-linked fibrin, leading to premature lysis of the clot by the fibrinolytic system; adverse
consequences result, including bleeding. Theoretically, a deficiency of TAFI leading to
decreased suppression of fibrinolysis (enhanced clot lysis) can potentiate bleeding resulting from
FXIII deficiency (also associated with enhanced clot lysis). Note the image below.

Postulated interaction between factor XIII and thrombinactivatable fibrinolytic inhibitor.

Cell surfacedirected hemostasis

The concept of coagulation as a waterfall or cascade effect has been acknowledged for a long
time, with platelets and other cell surfaces providing the anionic phospholipids needed for
complex formation, so that reactions can proceed efficiently. One review proposed that
coagulation is essentially a cell surfacebased event.[66] Platelet FXIII is positioned appropriately
to influence the process. (See the diagram below.)

Cell surfaceddirected hemostasis. Initially, a small amount of

thrombin is generated on the surface of the tissue factorbearing (TF-bearing) cell. Following
amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot)
formation (from article: Factor XIII). Adapted from Hoffman and Monroe. Thromb Haemost.
2001;85(6):958-65.

Conclusion
Much work is needed, even in the clinical arena, to clarify the relationship between the exact
levels of FXIII and hemorrhagic or thrombotic phenotypes. Establishing an international registry
of patients deficient in FXIII would be of value in improving understanding of the protean
manifestations of this uncommon disorder.

Frequency
United States
Overall estimated frequency of the autosomal recessive disorder involving a severe deficiency of
subunit A is approximately 1 case per 2 million population. Previously, consanguinity was
believed to be necessary, but the detection of compound heterozygotes by the application of
molecular techniques is changing that perception. Approximately 200 cases of FXIII deficiency
have been described thus far.[67] See Other Problems to be Considered for a discussion of
acquired FXIII deficiency related to diseases or inhibitors.

International
FXIII deficiency has been reported in many ethnic groups around the world, including persons
from Canada, Europe, India, Israel, Japan, Kuala Lumpur, Pakistan, Papua New Guinea, South
America, Thailand, Turkey, and the United States.
Diagnosis of disorders of FXIII inhibitors, which may have been missed in the past, is increasing
as more laboratory support becomes available around the world. An increasing use of isoniazid
(INH) to combat a worldwide rise in incidence of tuberculosis could contribute to an increased
incidence of FXIII inhibitors in patients.
Variability in the distribution of mutations is exemplified by existing data, ie, significant ethnic
heterogeneity was found in a Brazilian population in which the Val34Leu mutation was present

in 51.2% of American Indians, 44% of whites, 28.9% of Africans, and in only 2.5% of Japanese
Asians.[68]

Mortality/Morbidity
Umbilical bleeding starting in the first few days after birth, recurrent intracranial bleeding, and
recurrent early miscarriages are hallmarks of FXIII deficiency.
Approximately 30% of central nervous system (CNS) bleeding is recurrent, and approximately
50% of CNS bleeding may be fatal, but the severity of bleeding varies from family to family.
Posttraumatic bleeding may be immediate, delayed, or recurrent. Traumatic joint bleeding may
develop. Poor wound healing has been described, although this is not a universal finding.
Cryoprecipitate and fresh frozen plasma (FFP) provide a source of FXIII for most patients. All
plasma-derived products carry risks of transmitting hepatitis, HIV, parvovirus B19, transfusion
transmitted virus (TTV), and prion-induced (new variant Creutzfeldt-Jacob disease [nvCJD])
illnesses (see Complications and Medscape Reference article Factor VIII for more information).
Plasma-derived FXIII concentrates are being tested at centers. Recombinant factor XIII (rFXIII)
subunit A concentrates are yet to be tested widely.
Development of FXIII inhibitors (alloantibodies or autoantibodies) is associated with significant
morbidity and mortality.
Pregnant women with FXIII deficiency have a significant risk of miscarriage, placental
abruption, and postpartum hemorrhage without prophylaxis.[69]

Race
No predilection exists for FXIII deficiency. FXIII deficiency has been reported widely. The
restriction of certain polymorphisms to specific populations should be expected.

Sex
Since it is an autosomal disorder, homozygous FXIII deficiency occurs in either sex. Acquired
inhibitors to FXIII can present in either males or females.

Age
Physiologically, reduced levels of FXIII are found in healthy newborns, with a gradual rise in
levels into the reference range. Premature infants have lower values than full-term neonates.
FXIII levels drop in the latter half of a normal pregnancy.
Severe FXIII deficiency may present with bleeding from the umbilical cord after birth. Easy
bruising and delayed and recurrent bleeding after trauma begin in childhood. Oral bleeding can
begin with teething and cuts or abrasions to the lips, tongue, and frenulum. Bleeding remains a

problem throughout life and requires replacement therapy. FXIII deficiency acquired as a result
of autoantibodies has been reported in the older population, as has acquired hemophilia A. Both
drug-induced autoantibodies and alloantibodies have been reported in patients who are severely
deficient and receiving replacement therapy.

History
The following symptoms should trigger an evaluation for FXIII deficiency:

Spontaneous miscarriages occur early in pregnancy.

Bleeding from the umbilical cord has been reported to develop from 1-19 days after birth.
Easy bruising and soft tissue bleeding, particularly in association with trauma, occur as
the infant starts to ambulate. Bleeding following trauma may be immediate, delayed,
and/or recurrent.
CNS hemorrhage is common, recurs in approximately 30% of patients, and may be the
initial manifestation in patients with severe FXIII deficiency.
CNS bleeding may be preceded by head trauma in children, while adults may develop a
CNS bleed in the absence of obvious trauma.
Symptoms typical of any CNS event may be present, eg, headaches, seizures, vomiting,
and focal neurologic defects. Symptoms may be acute at onset or may be superimposed
on residual findings of a past bleed.
Menorrhagia and intra-abdominal bleeding during menses may be present.
Bleeding into joints may be precipitated by trauma. Although reports exist of recurrent
target joint bleeds, destructive changes in the joints are uncommon.[2] Spontaneous joint
and extensive muscle bleeding, characteristic of patients with severe hemophilia, are
uncommon in patients with severe FXIII deficiency.
The severity of bleeding is variable. An unusual example is the history of a very mild
bleeding disorder in 2 sisters despite severely reduced levels of FXIII (< 1%). One of the
sisters had 2 successful pregnancies without product replacement (see Causes for
details).[70]
Poor wound healing, although described, is less common.
Heterozygous parents of a propositus with severe bleeding usually are asymptomatic,
although some cases of bleeding in heterozygotes have been reported.
Development of alloantibodies is a serious complication that results in increased bleeding
and a lack of response to usual therapy. This condition can be fatal (see Other Problems
to Be Considered for more information).
Autoantibodies to FXIII are an acquired cause of a bleeding diathesis. A detailed drug
history is essential in assessing the possible contribution to inhibitor development. As the
frequency of tuberculosis rises worldwide and the use of INH increases, the number of
patients with inhibitors may increase (see Other Problems to Be Considered for more
information).
Patients may have acute and/or chronic viral illnesses transmitted by less pure products,
such as FFP or cryoprecipitate, that are used to treat bleeding. HIV-related illnesses,
AIDS, chronic hepatitis, progressive hepatic failure, and parvovirus-related illnesses
present in the usual manner.

Physical
Physical findings depend on the site at which bleeding develops and include the following:

Bleeding from the umbilical cord after birth usually manifests with persistent oozing,
which may start a few days after birth.
Findings associated with CNS bleeding depend on the location of the bleeding. Trauma
may precede the event, with additional findings. A new CNS bleed may be superimposed
on residual findings related to a prior bleed.
Findings in patients with bruising and soft tissue bleeding are similar to those seen in
other patients; it is uncommon to find the large hematomas or joint bleeds characteristic
in patients with severe hemophilia.
Patients may present with vaginal spotting or bleeding during early pregnancy, preceding
a spontaneous miscarriage.
Persistent, delayed, or recurrent bleeding may occur at sites of trauma or surgery.
Poor wound healing may be noted.
Acquired causes of FXIII deficiency, such as DIC and liver disease, present in a wellrecognized manner.

Causes
To date, most identified mutations leading to severe FXIII deficiency and a bleeding disorder
involve subunit A, with very few mutations reported involving subunit B. The gene for subunit A
is located on chromosome 6 bands p24-25. The gene is 160 kilobases in length and has 15 exons
and 14 introns with specific structural and functional domains. Catalytic activity is encoded in
the second exon, and the active cysteine is encoded by the seventh exon. The 2 Ca2+ -binding
sites and a thrombin-inactivation site have been identified at other locations. The gene for
subunit B is located on chromosome 1 bands q31-32.1, is 28 kilobases in length, and has 12
exons and 11 introns.[9, 71] (See the image below.)

Gene, messenger RNA, and protein for subunit A of factor XIII.

Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical
Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III,
Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.
Detailed characteristics of complementary ribonucleic acid (cRNA) and messenger ribonucleic
acid (mRNA) of the placental subunit A are known. The presence of an acetylated amino
terminal end and the absence of glycosylation and disulfide bonds apparently are features typical

of secreted cytoplasmic proteins. The presence of these characteristics makes it conducive for
subunit A expressed in yeast systems to make a recombinant product.
Substitutions in the core domain of the enzyme, affecting highly conserved residues, result in a
serious defect in structure and function. Missense mutations in the A chain are a common cause,
accounting for approximately 50% of cases of severe FXIII deficiency. The defects result in an
absence of subunit A protein but also are accompanied by a reduction in subunit B carrier protein
(type II defect).
Nonsense mutations are an equally common cause of A chain defects, resulting in a frameshifttype, splice-type, or termination-type mutation. The few defects that have been reported in the B
chain lead to a deficiency of the carrier protein (subunit B), which then leads to instability and
reduction of plasma subunit A levels despite the presence of functional intracellular subunit A
(type I defect).[72] Therefore, patients who are homozygous for subunit B mutations have a
bleeding disorder. Most recently, impaired intracellular transport from the endoplasmic reticulum
to the Golgi apparatus, with failure of secretion of the truncated FXIII subunit B produced by a
single-base deletion, was reported to be the cause of severe FXIII deficiency in 3 unrelated
patients.[73]
Many kinds of mutations have been (and continue to be) identified, with some mutations unique
to certain families. The finding of compound heterozygotes has eliminated the mandatory search
for consanguinity in all parents of patients with severe FXIII deficiency.[74, 75, 44]
An unusual mutation has been described in 2 Finnish sisters with a very mild bleeding disorder.
One sister had 2 successful pregnancies without regular replacement therapy. The sisters had no
detectable subunit A activity (< 1%) using plasma screening tests; however, using the 3Hputrescine incorporation assay, subunit A showed 0.35% of normal activity, with partial g-g
dimerization of fibrin in clotted plasma. A full-length subunit A was detected in the patients'
platelets using Western blot analysis.
The sisters had an Arg661-->stop mutation on one allele and a T-->C transition on the other
allele. These data showed that a mutation in the splice donor site of intron C can result in
different variant mRNA transcripts and that small amounts of correctly processed mRNA can
produce a type of FXIII that can produce, at least, dimerization of fibrin, thus minimizing the
clinical consequences.[70]
Various reported mutations are spread throughout the gene coding for FXIII without specific hot
spots. In many patients, low steady-state mRNA levels have been found, which result in
inefficient production of the abnormal protein.[10]
Data in the literature conflict regarding the impact of the common FXIII subunit A Val34Leu
mutation (associated with higher plasma transglutaminase activity) on thrombotic disease. Note
the following:

The Val34Leu mutation continues to be studied in different populations because current

data provide conflicting evidence about its causal role in coronary artery disease. The

Val34Leu mutation appears to protect whites but not Asian Indians from myocardial
infarction. However, in the Asian Indian population in Britain, a strong link was found
between FXIII subunit B levels and risk factors for cardiovascular disease and, possibly,
insulin resistance.[76]
In separate studies, a higher frequency of the Val34Leu mutation was found in whites
with primary intracerebral hemorrhage; however, the mutation reportedly was associated
with a reduction in brain infarcts.

A possible cooperative interaction between the Val34Leu mutation and other known
thrombophilic mutations also has been explored. Note the following:

In a study of patients from southern France, a higher than usual odds ratio was found for
the association between carriers of an angiotensin receptor mutation and coronary artery
disease, but no association was found between the disease and any of the FXIII
polymorphisms that were studied.[77]
A study of the contribution of the Val34Leu mutation to thrombotic risk in a large
number of carriers of factor V Leiden (who were relatives of thrombotic propositi with
factor V Leiden) found a very modest contribution of the Val34Leu mutation to venous
thrombotic disease.[78]
This study contrasts with a report of a protective role of the mutation in venous
thrombosis.[79]
A recent review discusses the possible role of FXIII in vascular diseases.[80] The FXIII
Val34Leu mutation does not appear to influence the induction or modification of the
course of inflammatory bowel disease.

Genetic polymorphisms affecting both the A and B subunits have been reported, but because
they do not involve conserved amino acids or are not important for protein structure, they do not
result in FXIII deficiency and bleeding. Based on an analysis of polymorphisms in the gene for
FXIII subunit A and their products in a northern Portuguese population, it has been stated that
the evolutionary order of appearance of the main protein alleles for FXIII is 1B-->2B-->1A-->2A
and that intragenic combinations are likely to have played a role in the molecular diversity in the
main FXIII subunit A alleles.[81]
Genetic polymorphisms and, particularly, intragenic polymorphisms are useful in genetic
counseling of families with unknown mutations. For example, 80% of whites are heterozygous
for a tetrameric repeat in intron 1 of subunit A, which can help differentiate defects in subunit A
from defects in subunit B.[9, 10, 71, 4] Some polymorphisms are universal, while others appear to be
restricted to particular ethnic groups. The latter situation will change as ethnic intermarriages
increase in this global society. Families with severe FXIII deficiency associated with a serious
disabling bleeding disorder have access to all of the genetic tools available to patients with
hemophilia A and B.
Disorders of fibrin stabilization can affect the activity of FXIII or its substrates fibrin and
fibrinogen. A proposed classification of disorders leading to a positive urea solubility test result
is presented below.

Disorders of fibrin stabilization (positive urea solubility test) are as follows:

Abnormalities of FXIII (enzyme) are as follows:

o Genetic mutation - (1) Subunit A, (2) subunit B, (3) subunit A and B
o Acquired - (1) Decreased production, ie, liver disease; (2) increased loss due to
excessive activation, ie, DIC, exposure to snake venoms and caterpillar toxins; (3)
secondary to inhibitors, ie, alloantibodies and autoantibodies
Abnormalities of the substrate for FXIII (fibrin/fibrinogen) are as follows:
o Genetic mutation - (1) Afibrinogenemia, (2) dyshypofibrinogenemia
o Acquired - (1) Decreased production, ie, acute massive hepatic necrosis or severe
chronic liver disease, (2) increased loss resulting from defibrination syndromes,
ie, DIC, exposure to snake venoms and caterpillar toxins, and systemic
hyperfibrinolysis (drug induced or disease induced)

Although gene therapy has not been used as a treatment modality in patients with FXIII
deficiency thus far, the reader is referred to a review of gene therapy in the hemophilias[82] and a
review on the use of gene therapy in malignancy, which provides an excellent overview of the
advantages and disadvantages of various approaches to gene therapy.[83]

Differential Diagnoses

Disseminated Intravascular Coagulation

Dysfibrinogenemia
Factor II
Factor IX
Factor V
Factor VII
Factor VIII
Factor XI Deficiency
Glanzmann Thrombasthenia
Menorrhagia
von Willebrand Disease

Proceed to Workup

Laboratory Studies
The following routine tests are the first step in the evaluation of any bleeding disorder: aPTT,
PT, thrombin-clottable fibrinogen level, platelet counts, and bleeding time (the latter after
ascertaining that the patient was not on antiplatelet drugs for at least the preceding 5 d).
However, these tests cannot be used to screen for FXIII deficiency because the results would be
within reference ranges in a patient with isolated severe FXIII deficiency.[3]

The next test performed is a qualitative screening test for severe FXIII deficiency that assesses
clot solubility in 5M urea or 1% monochloroacetic acid. If the thrombin and Ca2+ -induced clot
lyses within a few hours, severe FXIII deficiency is suggested provided fibrinogen levels are
qualitatively and quantitatively within reference range. Excluding hypofibrinogenemia and
dysfibrinogenemia is important, since these conditions cause false-positive results on the 5M
urea solubility test. The thrombin-clottable fibrinogen test can be used to exclude
hypofibrinogenemia and dysfibrinogenemia.
If the 5M urea solubility test demonstrates positive results, this finding should be confirmed by
quantitating FXIII activity using a monodansylcadaverine or putrescine incorporation assay,
which must be performed by laboratory personnel with expertise.
TEG is an old method used to assess clotting and lysis of fresh whole blood, and it has been used
as an early tool in the initial evaluation, and as a simple laboratory test, of the mechanical
strength (effect of FXIII) of fibrin sealants.[94] However, TEG cannot supplant any of the
qualitative or quantitative tests discussed in this section.
A new sensitive assay used to quantitate FXIII activity is based on monitoring the amount of
ammonia (NH3) released by using glutamate dehydrogenase and nicotinamide adenine
dinucleotide phosphate during the transamidation reaction (cross-linking) by FXIII. Note the
following:

Reportedly, this test is sensitive over a wide range of activities, from a low of 1 U/L
(0.1%) to a high of 470 U/L (47%), with an impressive coefficient of variation (CV) of
less than 8%, even at very low FXIII activity levels. Note that a low CV in the low range
of FXIII activity is a desirable feature of assays of this enzyme.[95]
Compared to the cumbersome conventional quantitative amine incorporation assays, the
new method appears to be simple, rapid, and reproducible not only in the assessment of
inherited or acquired reductions of FXIII activity levels but also in the ability to measure
increased FXIII activity levels resulting from certain mutations. The test fulfills the need
for a simpler method to quantify FXIII activity.
The same group also has published results of a simple, quick (2 h), 1-step, enzyme-linked
immunoassay (ELISA) to determine the presence of the plasma tetramer (A2 B2). Results
demonstrated high sensitivity and low CVs within batches and in day-to-day
variations.[96]

Another new and sensitive colorimetric assay based on incorporation of 5-(biotinamido)

pentylamine into fibrin/fibrinogen was compared to a photometric method based on ammonia
release and an ELISA of FXIII subunit A to quantitate FXIII activity. The test was shown to be
sensitive to both reductions and increases in activity; the increases resulted from the FXIII
Val34Leu mutation.[4]
In addition, a2 PI and plasminogen activator inhibitor-1 assays should be performed to exclude
abnormalities in the fibrinolytic pathway, which accelerate clot lysis.

Sodium dodecylsulfate polyacrylamide gel electrophoresis under reducing conditions has been
used to assess the presence of cross-linked g or a chains of fibrin, which is a reflection of FXIII
activity. The studies must be performed by laboratory personnel with special expertise.
If the presence of an inhibitor is suspected in a patient with a positive urea solubility test result,
the next step is to repeat the urea solubility test with mixtures containing varying proportions of
patient and normal plasma to differentiate between a deficiency or an inhibitor as the cause of a
positive result. Since FXIII activity is present in serum, serum also may be substituted for plasma
in the test.
Semiquantitation of the susceptibility of the fibrin clot to fibrinolysis can be obtained by adding
iodine-125-labeled fibrinogen, tissue plasminogen activator, thrombin, and Ca2+ to the patient's
plasma, with measurement of the time to 50% clot lysis. This method is useful in evaluating
inhibitors but must be performed by laboratory personnel with special expertise.
See Lorand for a recent review of further details of the sequence of necessary testing to confirm
the presence of a FXIII inhibitor.[87]
Acquired systemic disorders, including decompensated DIC and liver disease, require standard
tests to confirm the diagnosis.
Caution is warranted in obtaining blood samples for any coagulation assays from heparinized
central lines because of the effect of large amounts of heparin on any coagulation test that
depends on thrombin generation.
Prenatal diagnosis is as follows:

Use of several diagnostic procedures has been well established in the evaluation of
patients with FVIII and factor IX (FIX) deficiencies. In one case report, a short tandem
repeat marker that was closely linked to subunit A was used antenatally to identify the
presence of a severe bleeding disorder in a subsequent pregnancy in a family in which an
older sibling had severe FXIII deficiency.[97]
Chorionic villous sampling at approximately 10-12 weeks of gestation or amniocentesis
at 16-20 weeks of gestation can be performed to obtain fetal cells for DNA analysis or for
linkage studies. If DNA analysis cannot be performed, fetal blood obtained by fetoscopy
at approximately 20 weeks of gestation can be used. In general, these procedures carry
risks ranging from a low of approximately 0.5% maternal-fetal complications to a high of
approximately 1-6% fetal death for fetoscopy.
Perform these procedures only after intense genetic and obstetric counseling of the
parents.

Perform liver function tests; kidney function tests; HIV-1 and HIV-2 antigen and antibody tests;
hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D, and hepatitis E
antigen/antibody levels; and other tests as needed.
Assess a-fetoprotein levels and other tumor markers as needed in patients with chronic hepatitis.

FXIII, which is involved in wound healing and angiogenesis, may be detectable by highly
sensitive chemiluminescent ELISAs in tiny volumes of tear. This concept may provide a tool for
monitoring FXIII subunit and complex levels in pathological conditions.[98]

Imaging Studies
MRI, CT scan, and ultrasound have been used to localize, quantify, and serially monitor the
location and response of bleeding to specific therapy. Perform other imaging tests as needed to
diagnose associated diseases.

Other Tests
Perform ECGs as needed.

Procedures
Diagnostic amniocentesis, chorionic villous sampling, or fetoscopy may be performed during
pregnancy. Perform other routine procedures when indicated. Perform arthrocentesis only when
infection is suggested. Any invasive procedure requires the appropriate factor replacement.
When indicated, perform other procedures, such as colonoscopy, in persons without hemophilia.
Evaluate persistent GI tract bleeding without an apparent cause using endoscopy and
colonoscopy to exclude underlying lesions. Persistent genitourinary tract bleeding requires
evaluation for nephrolithiasis, tumors, or obstruction. If a biopsy is needed, patients require
replacement therapy prior to and following the procedure until the biopsy site has healed.
Invasive lifesaving procedures should be performed in patients with inhibitors only in concert
with appropriate treatment.

Medical Care
FXIII replacement is used to treat bleeding, to prevent perioperative bleeding during elective
surgical procedures or, prophylactically, to prevent recurrent bleeding, as in CNS or joint
hemorrhages. Serial monitoring of achieved FXIII levels is essential to document the adequacy
of any therapy.
Prompt and adequate therapy for acute bleeding is essential along with immobilization of the
affected sites and pain relief. Most patients receive FFP or cryoprecipitate to treat bleeding.
Information regarding the amount of FXIII present in either of these products usually is not
available; therefore, monitoring the adequacy of FXIII levels is essential.
Two intermediate-purity FXIII concentrates are being tested in the United States and are
available in other countries. Note the following:

Virus-inactivated FXIII concentrates made from human plasma or placenta are an

improvement over traditional products.
Human factor XIII concentrate (Corifact by CSL Behring) is now approved in the United
States. The brand name Fibrogammin P (CLS Behring) is the plasma-derived virusinactivated concentrate marketed in Europe, South America, South Africa, and Japan. A
second FXIII concentrate (Bio Products Laboratory, Elstree, Hertfordshire, UK) is
available on a per patient request.

Factor XIII A-subunit, recombinant (Tretten) was approved by the FDA in December 2013.
Approval was based on results from a clinical study that demonstrated the safety and efficacy of
rFXIII A-subunit. The phase 3 trial included 41 patients and showed that when compared to an
historic control group of individuals who did not receive routine FXIII infusions preventive
treatment with monthly 35 IU/kg rFXIII A-subunit injections significantly decreased the number
of treatment-requiring bleeding episodes.[99]
The long half-life of FXIII of 6-19 days and the hemostatic efficacy of even small amounts of
FXIII of approximately 5% allow replacement therapy to be administered every 4-6 weeks. An
FFP dose of 2-3 mL/kg may be effective for up to 4 weeks.[100, 101] The dose of concentrate in
adults with deficiency is 35 U/kg every 4 weeks.[102, 103, 104]
A paucity of data exists concerning the pediatric population. Hemostatic evaluation following a
head trauma-induced large subcutaneous hematoma associated with recurrent postsurgical
bleeding led to a diagnosis of severe FXIII deficiency in a 22-month-old boy. Following initial
therapy, subsequent replacement with an FXIII concentrate dose of 50 U/kg every 5 weeks was
sufficient to prevent rebleeding and allow healing.[105] Serial monitoring of actual levels achieved
is important in children to determine adequacy of any therapy.
Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as
pressure, ice, and use of antifibrinolytic drugs. Avoidance of trauma and nonsteroidal antiinflammatory drugs (NSAIDs) is helpful in reducing bleeding events.
Several reports exist of the use of FXIII in unusual circumstances. Note the following:

Effectiveness of normalizing FXIII levels in the treatment of a cerebrospinal fluid leak,

which started 2 weeks after removal of a meningioma, was reported in a Japanese
patient.[106]
The potential use of transglutaminases to mechanically stabilize and allow cultured
epithelial autografts to take when used to repair extensive skin wounds supports a
possible role of FXIII in the formation of de novo dermoepidermal junctions, thereby
facilitating permanent skin replacement.[106]
Improved stability of surgical wounds has been reported following infusion of FXIII
concentrates.
Although a few reports exist concerning the use of FXIII replacement in patients with
scleroderma, Henoch-Schnlein purpura, and malignancies, the value of such
replacement therapy remains to be established by proper clinical trials.[10, 107, 108, 109]

Patients with acquired inhibitors to FXIII should be treated using well-established principles of
therapy. Note the following:

FXIII dose depends on the characteristics of the inhibitor. One patient was treated
preoperatively using a 10-fold dose of FXIII concentrate (350 U/kg) followed by a
similar postoperative dose resulting in adequate hemostasis after coronary bypass graft
surgery.[104]
In addition to administering an FXIII concentrate whenever available, treat the
underlying disorder and, when appropriate, use immunosuppressive agents, including the
newer B-cell-directed monoclonal antibodies.
Note that spontaneous disappearance of acquired inhibitors is part of their natural history,
and the use of milder less toxic immunomodulators, such as steroids, may suffice.
The proper choice of agent is dictated by clinical circumstances. Simple immediate
ancillary measures of ice, pressure, ace wrap, immobilization of the affected joint, and
avoidance of NSAIDs must not be forgotten.
The complexity of required treatment is exemplified by a patient with an INH-induced
inhibitor in whom INH was discontinued, cryoprecipitate and FXIII concentrate were
administered, the patient underwent plasma exchanges and treatment with an
immunoadsorption column to reduce the inhibitor's titer, and immunosuppressives were
administered before hemostatic success was achieved.[89, 87, 91]

To date, prophylactic factor replacement has been undertaken mainly in patients with intracranial
bleeding or recurrent miscarriages caused by severe FXIII deficiency. Successful prevention of
recurrent joint bleeds also has been accomplished using periodic transfusions of FFP and
cryoprecipitate.[2] FFP can be administered in a dose of 2-3 mL/kg every 4 weeks.
A literature review of bleeding risks and reproduction among patients with severe FXIII
deficiency suggests that patients with clinically significant bleeding should start receiving factor
replacement therapy in childhood to reduce early mortality from hemorrhages and to allow
patients to reach adulthood. During pregnancy, monthly replacement was found to be effective in
preventing miscarriages.[110] However, both short-term benefits and potential long-term adverse
consequences of prophylactic use of these products must be discussed, with full patient
participation in all decision making.
Advances in the types of available products improve care. Addition of Tween 20 makes a
reduction of the generation of soluble and insoluble aggregates of rFXIII possible when rFXIII is
subjected to freezing and thawing or agitation.[111] Another advance in the technology relates to
solving problems faced during freeze-drying and storing the dry solid. Improvement in storage
stability of therapeutic proteins has obvious advantages for both storage and transport.[112]
Pooled plasma treated with solvent-detergent (PLAS+SD) is available to treat any condition in
which FFP typically is used and for which no factor concentrate is available. Viral inactivation
using the solvent-detergent (SD) process has been used in preparation of coagulation factor
concentrates in the past. In vitro treatment of donor plasma with 1% of the solvent tri(n- butyl)
phosphate (TNBP) and 1% of the detergent Triton X-100 leads to significant inactivation of a
broad spectrum of lipid-enveloped viruses. Note the following:

Studies of viral inactivation using the SD process show significant inactivation of the
human pathogenic viruses hepatitis B and C and HIV. Other lipid-enveloped viruses (eg,
Sindbis virus, bovine viral diarrhea virus) also have been used to monitor inactivation.
PLAS+SD is ABO blood type specific, and SD-treated plasma should be ABO
compatible with the recipient's red cells.
The frozen product is supplied in 200-mL bags. Each 200-mL bag has been demonstrated
to raise factor levels by approximately 2-3%, with 4-6 bags raising the factor level of a
70-kg person by approximately 8-18%.
Monitoring of specific factor levels before and after product infusion is important to
ensure that hemostatically adequate levels are achieved and maintained to provide
adequate hemostasis.

Antifibrinolytic agents are not used commonly to treat patients with FXIII deficiency but may be
used as ancillary therapy. Note the following:

The hemostatic plug formed in the presence of adequate levels of FXIII at the time of
surgical trauma (as with dental procedures or with mucosal bleeding) can be preserved by
inhibiting fibrinolysis with -aminocaproic acid (EACA; Amicar) or trans-paminomethyl-cyclohexane carboxylic acid (AMCA; also termed tranexamic acid;
Cyklokapron) administered orally or, if needed, intravenously. EACA has been
administered in a dose of 5 g orally or intravenously slowly prior to the surgical
procedure, along with a dose of the appropriate FXIII replacement. This is followed by a
maintenance dose of 1 g/h postoperatively until it is appropriate to start tapering the dose
over the next several days.
AMCA is administered in a dose of 1.5 g intravenously every 6-8 hours and tapered, as
needed; however, it is not available in the United States.
Antifibrinolytic agents also can be used as a mouthwash for oral bleeding and have been
used to stop local intracavitary oozing.
Antifibrinolytic agents are contraindicated in patients with hematuria because of the
possible risk of development of a firm occluding clot in the ureters when administered
simultaneously with factor replacement. The drugs are not useful in the treatment of joint
bleeding (see Factor VIII for more information).

In recent years, the use of NSAIDs to relieve pain has increased in patients with bleeding
disorders. Although they provide relief from inflammatory pain, patients experience increased GI
tract or other bleeding because of the impact of the drugs on primary hemostasis, and they
require additional FXIII replacement to control bleeding. The problem is magnified by the
availability of over-the-counter NSAID pain relievers. Non-NSAIDs, such as acetaminophen and
codeine-type analgesics, are much less effective, and some are addictive.
Routine dental care is of the utmost importance in maintaining dental hygiene.
Other routine care, such as mammography in women older than 50 years or colonoscopy for
patients older than 50 years, must be provided as in nonbleeding patients.

Surgical Care

All elective procedures require proper perioperative management. Note the following:

Patients with severe FXIII deficiency require FXIII replacement both preoperatively and
postoperatively. Levels of as little as 3-5% may be sufficient to provide adequate
hemostasis, and a single dose is sufficient to last several weeks unless excessive blood
loss occurs. Serial factor levels must be performed to ensure adequacy of FXIII levels.
Procedures such as endoscopies, although considered routine for unaffected individuals,
require preprocedural product replacement so that patients do not bleed during or
following a needed biopsy. Postbiopsy replacement must continue until the biopsy site
has healed.
Dental extractions or mucosal procedures can be handled using a single preprocedure
dose of FXIII along with Amicar or AMCA. A standardized approach to dental
extractions, as has been proposed for patients with hemophilia, may be used in patients
with FXIII deficiency. Continuing antifibrinolytics on an outpatient basis for several days
after a dental extraction is routine practice, with gradual tapering of dosage.
Avoidance of NSAIDs and other platelet-inhibiting drugs perioperatively is essential to
minimize bleeding risk. Ice packs and pressure are always useful when feasible.
Application of fibrin glue as an ancillary measure is useful in helping control bleeding at
surgical sites. Fibrin glue consists of a mixture of fibrinogen, thrombin, and FXIII used to
cross-link freshly formed fibrin. Cryoprecipitate also has been used as a source of
fibrinogen and FXIII, with the use of bovine thrombin to clot fibrinogen. Some
preparations also incorporate antifibrinolytic agents to prevent clot lysis. In particular,
fibrin glue has been useful in orthopedic surgery and with surgical procedures in patients
with FXIII inhibitors. Bovine thrombin may elicit antibodies.
Bleeding from suture holes is a complication in a variety of invasive vascular procedures
(surgery, radiologic procedure, coronary angiography). In an experimental porcine
vascular graft model, fibrin sealant containing FXIII effectively reduced blood loss and
reduced the time to achieve adequate hemostasis more than fibrin alone or thrombincoated gelatin sponges.[113]

Consultations
A hematologist, orthopedist, physical therapist, dentist, social worker, psychologist, infectious
disease specialist, gastroenterologist/hepatologist, geneticist, and an appropriately equipped
special laboratory all play important roles in providing optimal care for patients with FXIII
deficiency and their families.
The efforts of the National Hemophilia Foundation and its regional chapters must be recognized
in helping to educate patients, assist service providers, foster dialog regarding problems and
solutions among patients with bleeding disorders, and improve conditions for the entire
community through support of legislation.

Diet
A healthy and nutritional diet should be encouraged.

Activity
Appropriate physical activity and physical therapy must be encouraged to maintain and preserve
muscle function.

Medication Summary
For FXIII replacement therapy, 2 intermediate-purity FXIII concentrates are being tested or are
commercially available for use. FFP and cryoprecipitate also are used. An FFP dose of 2-3
mL/kg every 4 weeks has been used for replacement therapy under steady-state conditions.
Dosing of cryoprecipitate is empiric, since no standardized amount of FXIII exists for
cryoprecipitate. Repeat dosing should be guided by the adequacy of a prior dose as determined
by FXIII assays. FXIII concentrate, human (Corifact) is commercially available in the United
States. In December 2013, a recombinant FXIII A-subunit product (Tretten) was approved for
preventing bleeding episodes in patients with congenital FXIII-a subunit deficiency.[114]
PLAS+SD is ABO blood type specific. As a result of treatment with 1% tri(n- butyl)phosphate
(or TNBP as the solvent) and 1% Triton X-100 (as the detergent), lipid-enveloped viruses (eg,
HIV, HBV, HCV, Hantavirus, Marburg virus, Ebola virus) are disrupted and killed in significant
numbers. The resulting fragments are inactive and cannot replicate or cause disease. PLAS+SD
has proven efficacy in treating coagulation factor deficiencies when factor concentrate is
unavailable. SD-treated plasma offers more protection to patients than is found in standard FFP.
Patients with FXIII deficiency have been specifically treated successfully with PLAS+SD.
Information regarding PLAS+SD can be found in the manufacturer's product circular.[115]
Traditionally, FFP has been the source of factors for the treatment of coagulation factor
deficiencies for which no concentrates are available; FXIII deficiency falls into this category.
Higher risks of virally transmitted illnesses remain among patients who are recipients of multiple
units of FFP. The greater degree of viral safety assured by this treatment has led to the exclusive
use of PLAS+SD instead of FFP in some countries (Norway and Belgium).
PLAS+SD delivers consistent and reproducible levels of coagulation factors. In contrast to the
extreme variability in FFP, PLAS+SD contains no leukocytes, and physiologic inhibitor levels
are mostly within reference range, with the exception of a moderate reduction in the levels of a2
PI (approximately 0.48 IU/mL) and protein S (approximately 0.52 IU/mL). In addition,
coagulation zymogens are not activated, reference range levels of other plasma proteins and
immunoglobulins are present, and all lots have anti-HAV antibody levels greater than 0.8 IU/mL,
providing passive administration of antibody that may neutralize HAV. PLAS+SD also lacks the
largest vWF multimers and has proven efficacy in the treatment of a variety of bleeding
disorders.
Disadvantages of PLAS+SD use include minor allergic reactions as observed with other blood
products but that respond to antihistamines. PLAS+SD is contraindicated in patients with known
IgA deficiency.

FXIII levels and efficacy of PLAS+SD: FXIII levels in 3 representative lots of pooled plasma
(starting material prior to SD and other treatments) were 1.18 0.05 U/mL (average standard
deviation), with levels of 1.23 0.06 U/mL in the final SD-treated, ultrafiltered, and sterilefiltered product.
Four patients with an inherited FXIII deficiency received successful prophylaxis with 1-2 U of
PLAS+SD administered every 21-40 days on a total of 39 occasions over 42 months (range in
each patient, 2-15 mo). PLAS+SD was proven to be equivalent to FFP in preventing
hemorrhages in patients with known FXIII deficiency. A fifth patient with FXIII deficiency was
treated successfully for soft tissue hemorrhages on an on-demand basis.[116]
When PLAS+SD was stored at -18C, FXIII activity was 1.14 0.09 U/mL at the start and 1.33
0.05 U/mL after 18 months of storage. Currently, based on additional data submitted,
PLAS+SD has a US Food and Drug Administration (FDA)-approved 2-year shelf life according
to F. Darr, MD, of the American Red Cross (Fred Darr, MD, e-mail, February 2002). Therefore,
evidence exists that FXIII activity remains stable during long-term storage.
All PLAS+SD units that are administered should be ABO compatible with each patient's red
cells. Adverse reactions include minor allergic reactions and volume overload. Rarely, citrate
toxicity, hypothermia, and other metabolic problems arise if large volumes are used rapidly.
Noncardiogenic pulmonary edema can occur. Antibody-induced positive results to the direct
antiglobulin test and hemolysis also may occur rarely.[116]
See the drug tables below for further details on the use of PLAS+SD instead of FFP.
Careful screening of blood donors and viral testing of donated blood (HBV surface antigen,
antibody to HBV core antigen, HCV, antibody to HIV-1 and HIV-2, HIV p24 antigen, antibodies
to human T-cell leukemia virus [HTLV] types I and II, and screening for elevated levels of
alanine aminotransferase [ALT]) have improved safety of blood products, but risks remain for a
variety of reasons including failure to detect infections during the "window" or incubation period
before currently available test results become positive.
Other types of infections in which screening currently is not performed, tests are not available, or
the presence of infection is unknown continue to cause concerns. Some of the emerging
pathogens previously referred to include HIV-2, HIV type O, hepatitis G, TTV, human
herpesvirus 8, the SEN family of viruses, and prions causing Creutzfeldt Jacob disease [CJD]
and nvCJD.[117, 118, 119]
Newer emerging technologies, such as those using nucleic acid chemistry, are being used to
inactivate viruses, bacteria, and parasites and to attempt to remove prions, thus making blood and
blood components safer than they are currently. These newer technologies attempt to preserve
clinically useful components of blood while improving its safety. Potentially, these
methodologies could be used to improve the safety of a wide variety of products.
Adjunctive role of inhibitors of fibrinolysis: Recognition of the importance of the lysine-binding
sites in various interactions in the fibrinolytic pathway led to the synthesis of lysine analogs such

as EACA and AMCA. These synthetic lysine analogs induce a conformational change in
plasminogen when they bind to its lysine-binding site; plasminogen has the shape of a prolate
ellipsoid after EACA binds to it. The bound plasminogen-EACA elongates into a long structure
in which the interaction between the parts of plasminogen, as they existed, are lost. In vivo, the
structures probably prevent plasminogen activation and, in large doses, bind plasmin, thereby
preventing it from binding to its substrate fibrin. In the plasminogen-EACA binding sites, the
tightest binding is to kringle 1 followed by kringles 4 and 5. The interaction with kringle 2 is
weak, and kringle 3 does not interact at all.
A model of the structure of kringle 4 shows that the shallow trough formed by the hydrophobic
amino acids is surrounded by positively and negatively charged amino acids at a distance ideal
for EACA interaction. For further details regarding these interactions, please see Bachmann,
2001.[120] EACA is the most widely used antifibrinolytic drug in the United States. The minimal
dose needed to inhibit either normal or excessive fibrinolysis is unknown. EACA is absorbed
well orally, and 50% is excreted in the urine within 24 hours.
Generally, an initial loading dose is followed by a maintenance dose to adequately inhibit
fibrinolysis until excess bleeding is controlled. Then, the maintenance dose is tapered gradually
until it can be discontinued. Rarely, myopathy and muscle necrosis can develop. Lower doses are
adequate when bleeding involves the urinary tract, since drug concentrations are 75- to 100-fold
higher in urine than in plasma.
AMCA also is excreted rapidly in the urine, with more than 90% excreted within 24 hours.
However, its antifibrinolytic effect lasts longer than EACA. AMCA inhibits fibrinolysis at lower
plasma concentrations, although its serum half-life is similar to that of EACA. Therefore, AMCA
can be administered less frequently and at lower doses. EACA and AMCA doses must be
reduced when renal failure is present.
Aprotinin (Trasylol), a third antifibrinolytic drug obtained from bovine lung, is a nonhuman
protein inhibitor of several serine proteases, including plasmin. It is approved by the FDA for use
in patients undergoing open heart surgery to reduce operative blood loss. Aprotinin
administration also has reduced blood loss and transfusion requirements in patients undergoing
orthotopic liver transplantation or in patients undergoing elective resection of a solitary liver
metastasis originating from colon cancer. Aprotinin is the most expensive of the 3 drugs
discussed here. Aprotinin is now only available via a limited-access protocol. Fergusson et al
reported an increased risk for death compared with tranexamic acid or aminocaproic acid in
high-risk cardiac surgery.[121]
A novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency was evaluated as
safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit
deficiency.[114]

Clotting factors
Class Summary

FXIII is the terminal enzyme in the blood coagulation cascade; when activated by thrombin at
the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis
through cross-linking of fibrin and other proteins in the fibrin clot. FXIII is a proenzyme that is
activated, in the presence of calcium ion, by thrombin cleavage of the A-subunit to become
activated FXIII (FXIIIa). It promotes cross-linking of fibrin during coagulation and is essential to
the physiological protection of the clot against fibrinolysis.
View full drug information

Factor XIII A-subunit, recombinant (Tretten)

FXIII A-subunit recombinant is a human factor XIII-A2 homodimer composed of 2 FXIII Asubunits. It is indicated for routine prevention of bleeding in patients with congenital Factor XIII
A-subunit deficiency.
View full drug information

Factor XIII concentrate, human (Corifact)

Temporarily replaces missing clotting factor XIII which corrects and/or prevents bleeding. It is
indicated for routine prophylactic treatment of congenital factor XIII (FXIII) deficiency.

Antihemophilic agents
Class Summary
Use inhibitors of fibrinolysis together with FFP replacement for minor surgical procedures (eg,
dental extractions or sinus surgery) so that the surgery can be accomplished on an outpatient
basis with the use of a single dose of product.
Concern remains regarding the possible relationship to acute thrombotic events, although a
causal relationship is being questioned because the underlying disease state determines the site
and extent of thrombosis.

Pooled plasma, solvent-detergent treated (PLAS+SD)

Pooled plasma is treated using a procedure developed by the American Red Cross and V. I.
Technologies (see details under Medical Care). SD treatment of pooled human plasma disrupts
and kills lipid-enveloped viruses (eg, HIV, HBV, HCV). SD treatment is followed by

ultrafiltration and sterile filtration; however, these treatments do not remove all viruses from
plasma, nor is the method capable of totally eliminating viral infectivity from plasma-derived
products. However, such treatments improve safety compared to standard FFP. Efficacy and
safety have been proven in the treatment of several coagulopathies.
According to the package insert (ARC, 2000), the half-life of coagulation factors in recipients of
this product were similar to reference range values at the time of measurements. If available,
PLAS+SD can be used in patients with FXIII deficiency because no concentrate is widely
available to treat FXIII deficiency. As with any bleeding disorder, serial measurement of the
specific coagulation factor in question is essential to assure hemostatic adequacy of levels. On
average, 1 U of PLAS+SD raises factor levels by approximately 2-3%, while 4-6 U raise factor
levels by approximately 8-18% in a 70-kg person. These numbers do not specifically apply to
FXIII and are provided only as a general guideline.
PLAS+SD contains not less than 0.7 U/Ml of FXIII, and serial monitoring of FXIII levels is
necessary in patients. PLAS+SD should be stored at -18C or less and thawed at 30-37C in a
water bath with very gentle shaking; once thawed, keep at room temperature and use as soon as
possible and preferably within 24 hours. Do not store thawed material in the cold.

Antifibrinolytic agents
Class Summary
These agents are used as an ancillary measure and to diminish bleeding.
View full drug information

Aminocaproic acid (Amicar)

EACA diminishes bleeding by inhibiting lysis of hemostatic plugs. Can be used PO or IV.
View full drug information

Tranexamic acid (Cyklokapron)

AMCA diminishes bleeding by inhibiting fibrinolysis of hemostatic plug. Can be used PO or IV.

Further Inpatient Care

Patients should be hospitalized for serious complications, such as severe bleeding, or for major
surgical procedures, all which require complex interdisciplinary care including pharmacy and
laboratory support. Constant clinical evaluation and laboratory monitoring ensure adequacy of
product replacement, pain relief, and other supportive care. The hematologist must be centrally
involved to coordinate care.

Further Outpatient Care

Clinic-supervised outpatient care is an extremely important part of treatment. Complete annual
physical examinations and laboratory testing for inhibitors, hepatitis, and HIV infection, as well
as other tests, should be performed as needed. As in persons without hemophilia, routine care
should be provided to patients with FXIII deficiency, including examination of stool for blood,
rectal examination, colonoscopy, prostate-specific antigen determinations, mammography, and
dental care. Physical therapy may be needed for the long-term care of affected joints.
Prophylactic care includes vaccination for HAV[122] and HBV and other routine vaccines.
Notify the local chapter of the National Hemophilia Foundation regarding the patient so that
proper statistics can be provided to the appropriate agencies for adequate federal and state
funding of patient care.
Provide counseling and classes to encourage questions and to help solve problems, such as
possible ways to avoid transmission of HIV to an uninfected spouse and to children.[123]
An appointment with a psychosocial worker at the time of counseling ensures that other
psychological, social, and economic support is provided.

Inpatient & Outpatient Medications

Patients should avoid acetylsalicylic acid, NSAIDs, and any over-the-counter herbal medications
that can precipitate bleeding.

Transfer
If a qualified hematologist and laboratory personnel with expertise are available, patients may be
cared for in a setting close to home. Laboratory testing provided by community hospitals has
been improved by the existence of commercial referral laboratories.
Federal and state funding for programs may be available through a medical center. Costs of care
are much higher at tertiary medical centers.

Deterrence/Prevention
Avoidance of high-risk activities (eg, boxing, motorbike riding) and NSAIDs reduces the
frequency of bleeding.

Avoidance of alcohol helps protect liver function in patients with hepatitis.

Primary prophylaxis is the best way to prevent recurrent CNS bleeding, recurrent miscarriages
or, rarely, recurrent joint bleeding. Joint replacement may be needed in the older patient with
severe arthropathy.
HAV and HBV vaccines should be administered. Other routine vaccinations, such as those for
influenza and pneumonia, should be provided as in other persons.

Complications
Recurrent CNS bleeding is a major problem requiring prophylactic transfusions. Infections,
particularly HIV, AIDS, and chronic hepatitis, can lead to death. Interferon alfa has been used to
treat chronic viral hepatitis. Multidrug cocktails are used to treat HIV/AIDS, but protease
inhibitors can increase risk of bleeding. Some over-the-counter herbal remedies increase the risk
of bleeding.
Viral safety in products derived from plasma is ensured through several techniques, ie, heating,
pasteurization, SD treatment, and monoclonal antibody purification. These procedures currently
free products from HIV and HCV (lipid-enveloped viruses) but do not solve the problem of
transmission of nonlipid-enveloped viruses such as HAV, parvovirus B19, and TTV. Even with
recombinant products, a possibility exists of contamination with pathogens previously unknown,
including new murine viruses. A recent report shows the presence of TTV in first-generation
recombinant products, which is due to the use of human serum albumin that is contaminated with
TTV.[119] Thus, virus-induced illnesses of concern include hepatitis viruses A-E, GB virus C (or
hepatitis G virus), the SEN family of viruses,[118] and human herpesvirus 8,[117] all of which
constitute emerging pathogens related to transfusion-transmitted illnesses.
A recent review reports concerns about the transmission of CJD or its variant form (vCJD) in
recipients of blood products. The Transmissible Spongiform Encephalopathies Advisory
Committee of the FDA has suggested limiting the donor pool and excluding donors who have
lived or traveled for 5 years or longer in Europe or donors who have lived in the United
Kingdom for a total of 3 months or longer. The development of new tests to check for vCJD is
anticipated.[124, 117]
The presence of inhibitors adds another layer of complexity when alloantibodies develop as a
consequence of transfusion of blood products. Spontaneous disappearance is a typical feature of
autoantibodies, presumably as a response to removal of the antigenic stimulus. Bleeding
associated with inhibitors can be life threatening and requires complex care.
Severe economic and emotional problems occur as a result of the recurrent nature of the
bleeding.
Complex psychiatric issues arise in the treatment of patients with HIV/AIDS.[123]

Prognosis
Prognosis depends on the types of complications that develop, on the type of replacement
product the patient has received, and on the viral infections that the patient has accumulated over
the years. Newly diagnosed patients should, whenever possible, receive purer products to ensure
maximum safety.
The presence of inhibitors in patients poses a serious therapeutic challenge, and, currently,
surgery should be considered only as a lifesaving measure.

Patient Education
Encourage patients to register with the local chapter of the National Hemophilia Foundation and
to attend educational seminars. Provide one-on-one discussions of issues with patients and
family members. Early and complete genetic testing can help families plan future pregnancies.
For excellent patient education resources, visit eMedicineHealth's Pregnancy Center. Also, see
eMedicineHealth's patient education article Miscarriage.
Ca2+

A2B2