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CHAPTER 122 INHERITED DEFICIENCIES OF COAGULATION FACTORS II, V, VII, XI, AND XIII AND THE COMBINED DEFICIENCIES OF FACTORS V AND VIII AND OF THE VITAMIN K-DEPENDENT FACTORS

CHAPTER 122 INHERITED DEFICIENCIES OF COAGULATION FACTORS II, V, VII, XI, AND XIII AND THE COMBINED DEFICIENCIES OF FACTORS V AND VIII AND OF THE VITAMIN K-DEPENDENT FACTORS
Williams Hematology

CHAPTER 122 INHERITED DEFICIENCIES OF COAGULATION FACTORS II, V, VII, XI, AND XIII AND THE COMBINED DEFICIENCIES OF FACTORS V AND VIII AND OF THE VITAMIN K-DEPENDENT FACTORS

URI SELIGSOHN
GILBERT C. WHITE, II

Introduction
Factor II (Prothrombin) Deficiency

Definition

Molecular Features and Biochemistry

Genetics

Clinical Manifestations

Differential Diagnosis

Therapy
Factor VII Deficiency

Definition and History

Biochemistry and Molecular Features

Genetics

Clinical Features

Laboratory Features

Differential Diagnosis

Therapy
Factor X Deficiency

Definition

Biochemistry and Molecular Features

Genetics

Clinical Manifestations

Differential Diagnosis

Therapy
Combined Deficiency of the Vitamin K–Dependent Factors
Factor V Deficiency

Definition

Biochemistry and Molecular Features

Genetics

Clinical Manifestations

Differential Diagnosis

Therapy
Combined Deficiency of Factors V and VIII

Definition

Biochemistry and Molecular Features

Genetics

Clinical Manifestations

Differential Diagnosis

Therapy
Factor XI Deficiency

Definition and History

Biochemistry and Molecular Features

Genetics

Clinical Features

Laboratory Features

Therapy
Factor XIII Deficiency

Definition

Biochemistry and Molecular Features

Genetics

Clinical Manifestations

Differential Diagnosis

Therapy
Chapter References

Bleeding tendencies caused by inherited deficiencies of one or more coagulation factors are rare disorders distributed worldwide. Homozygotes or compound heterozygotes for the mutant genes responsible for these defects exhibit bleeding manifestations that are of variable severity and usually related to the extent of the decreased activity of the particular coagulation factor. Heterozygotes for the various deficiencies very rarely display a bleeding tendency. Numerous mutations have been identified in genes encoding coagulation factors II, V, VII, X, XI, and XIII. For some factors, such as factors II, VII, and X, mutations giving rise to dysfunctional proteins are common, while for other factors, such as factors V, XI, and XIII, true deficiencies are more common. Combined factor V and factor VIII deficiency, inherited as an autosomal recessive trait, can result from mutations in the gene encoding a transport protein of the endoplasmic reticulum–Golgi intermediate compartment. The very rare combined deficiency of the vitamin K–dependent coagulation factors can be caused by mutations in the gene that encodes for a carboxylase that g-carboxylates glutamic acid residues in these proteins. Treatment of patients with the various coagulation factor deficiencies may be necessary during spontaneous bleeding episodes, during and after surgical procedures, and to prevent intracranial hemorrhage. In most deficiency states, plasma replacement has been used, but specific concentrates of all the vitamin K–dependent factors and of factors VII, XI, and XIII are also available.

Acronyms and abbreviations that appear in this chapter include: aPTT, activated partial thromboplastin time; BHK, baby hamster kidney; CRM–, cross-reacting material negative; CRM+, cross-reacting material positive; CRMred, cross-reacting material reduced; DIC, disseminated intravascular coagulation; EGF, epidermal growth factor; ERGIC-53, endoplasmic reticulum–Golgi intermediate compartment 53; Gla, g-carboxyglutamic acid; HK, high-molecular-weight kininogen; PK, prekallikrein; PT, prothrombin time; TAFI, thrombin-activatable fibrinolysis inhibitor; TAFIa, activated TAFI.

INTRODUCTION
Inherited deficiencies of coagulation factors other than factor VIII (hemophilia A) and factor IX (hemophilia B) are rare bleeding disorders that have been described in most populations. The severity of the bleeding manifestations in affected patients, who are usually homozygotes or compound heterozygotes for a mutant gene, is variable and usually relates to the extent of the deficiency. While some patients may only have mild bruising or display excessive bleeding only following trauma, others, such as patients with less than 1 percent of normal factor VII, XIII, or X activities, may exhibit intracranial hemorrhages and hemarthroses similar to those of patients with severe hemophilia A and B.
The study of these disorders has significantly advanced the understanding of the pathophysiology of blood coagulation mechanisms (see Chap. 112). Following the characterization of the genes encoding for the coagulation factors, a host of mutations causing the various deficiencies have been identified. The use of molecular genetic techniques has established the molecular basis for two disorders that have constituted enigmas for several decades. Thus, the inherited combined deficiency of factors V and VIII was shown in most instances to be caused by mutations in a gene encoding for a transport protein carrying factors V and VIII from the endoplasmic reticulum to the Golgi apparatus, and the combined deficiency of all vitamin K–dependent factors was shown to result from a mutated gene encoding for the carboxylase that introduces g-carboxyl groups into these coagulation factors.
This chapter reviews the clinical, biochemical, and genetic aspects of the inherited deficiencies of coagulation factors that cause bleeding tendencies other than the hemophilias (see Chap. 123) and von Willebrand disease (see Chap. 135).
FACTOR II (PROTHROMBIN) DEFICIENCY
DEFINITION
Inherited hypoprothrombinemia and dysprothrombinemia are rare, genetically heterogeneous, autosomal recessive disorders characterized by mild to moderate bleeding. Both abnormalities of prothrombin impair the generation of thrombin, the central enzyme of the blood coagulation system.
MOLECULAR FEATURES AND BIOCHEMISTRY
Prothrombin is a protein of approximately 72,000 Mr that is structurally homologous with other members of the vitamin K–dependent proteins; factors VII, IX, and X; protein C; protein S; and bone g-carboxyglutamic acid (Gla) protein. Prothrombin is synthesized in the liver as a pre-propeptide of 622 amino acids and is composed of the following domains: propeptide (residues –43 to –1), Gla (residues 1–40), kringle (residues 41–271), and catalytic (residues 272–579).1,2 and 3 The propeptide domain is responsible for protein processing, targeting, and carboxylation, and is removed prior to secretion from the cell. The Gla domain constitutes the amino terminus of the mature prothrombin molecule and contains the 10 glutamic acid residues that are posttranslationally modified through the action of vitamin K–dependent carboxylase to Gla. As a result of this modification, prothrombin acquires the capacity to bind calcium and to bind to membranes containing acidic phospholipids. The kringle domain contains two extensively folded, disulfide-bonded kringle motifs, each consisting of approximately 79 amino acids,4 that are present in diverse proteins and are thought to mediate protein-protein interactions. The second kringle mediates the interaction of prothrombin with activated factor V.5 The catalytic domain contains the enzyme’s active site, which is responsible for cleavage of fibrinogen. The residues characteristic for the serine protease family, His363, Asp419, and Ser525, constitute a charge relay system responsible for bond cleavage.
The prothrombin gene is located on chromosome 11 near the centromere.6 The organization of the 26,930-bp gene consists of a 6544-bp upstream 5′ flanking sequence, a 20,241-bp coding region composed of 14 exons separated by 13 intervening sequences, and a 145-bp 3′ flanking sequence.7 A comparison of the organization of the prothrombin gene shows homology with the organization of other vitamin K–dependent serine protease genes, with the highest degree of homology in the part encoding the Gla domain. An unusual feature of the prothrombin gene is the presence of 41 copies of Alu-repetitive sequences in the upstream and intervening sequences.7,8 The function, if any, of these sequences is unknown.
Prothrombin plays a central role in coagulation, functioning in both tissue factor- and surface-activated pathways. Prothrombin is converted to its proteolytically active form, thrombin, by activated factor X in the presence of activated factor V and phospholipid surfaces provided by platelets and other cells (see Chap. 112). In addition to conversion of fibrinogen to fibrin (see Chap. 124) thrombin also (1) induces aggregation of platelets; (2) activates coagulation factor XIII, resulting in cross-linking of fibrin; (3) converts plasminogen to plasmin, thereby activating the fibrinolytic system; (4) activates thrombin-activatable fibrinolysis inhibitor; (5) activates coagulation factors V, VIII, and XI, promoting generation of additional thrombin; and (6) activates protein C in the presence of thrombomodulin (see Chap. 113). Thrombin also stimulates wound healing through its action as a growth factor and regulates vascular tone.
GENETICS
Abnormalities of prothrombin are inherited in an autosomal recessive manner. Among individuals with true prothrombin deficiency, heterozygotes exhibit prothrombin levels that are approximately 50 percent of normal, while homozygotes display levels that are typically less than 10 percent of normal. Prothrombin activity and antigen levels are reduced concordantly in these patients, and they are therefore designated as cross-reacting material negative (CRM–). Heterozygotes for dysprothrombinemias exhibit prothrombin activity levels that are around 50 percent of normal, with antigen levels that are normal or nearly normal. Prothrombin activity in homozygotes for dysprothrombinemia varies between 1 and 20 percent of normal, while antigen levels are either normal (CRM+) or partially reduced (CRMred). Compound heterozygotes bearing one prothrombin deficiency allele and one dysprothrombin allele have been reported and typically have prothrombin activity levels between 1 and 20 perecnt, with antigen levels between 13 and 50 percent of normal.
The molecular defects responsible for inherited prothrombin deficiency have not been extensively studied. In contrast, dysprothrombinemias have been shown to result almost exclusively from missense mutations. These mutations can be further divided into (1) mutations in which the defect results in abnormally slow activation of prothrombin and (2) mutations in which prothrombin activation is normal but the thrombin formed is abnormal and has an altered ability to clot fibrinogen. Table 122-1 lists examples of each type of inherited dysprothrombinemia.9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 and 31 Mutations in which prothrombin activation is abnormal include prothrombin San Juan, where there is an inability to bind calcium; prothrombins Madrid and Barcelona, where cleavage by activated factor X is abnormal; and prothrombin Segovia, where there is a possible defect in prothrombin fragment 2.11 Missense mutations that affect the function of thrombin encode for defects that interfere with the catalytic activity of thrombin or its interaction with fibrinogen. In prothrombins Molise, Tokushima, and Metz, point mutations are present in the catalytic domain, resulting in production of defective thrombin molecules. The activation of prothrombin by factor Xa is normal, but the thrombin that is generated is unable to cleave fibrinogen and exhibits abnormal catalytic activity toward small peptide substrates. In prothrombin Molise and Tokushima, Arg418 is replaced by tryptophan.22,23 This amino acid is located next to the aspartic acid of the catalytic site, and the substitution appears to interfere with the catalytic activity of thrombin. In prothrombin Quick I, where Arg382 is replaced by cysteine,27 and in prothrombin Quick II, where Gly558 is replaced by valine,30 the catalytic activity of thrombin toward small peptide substrates is intact, yet there is defective interaction with fibrinogen.

TABLE 122-1 INHERITED DYSPROTHROMBINEMIAS

A number of polymorphisms have been identified in the prothrombin gene. One of these, a G-to-A change at nucleotide 20210 in the 3′-untranslated region of the prothrombin gene, is associated with increased plasma levels of prothrombin and an increased tendency to venous thrombosis.32,33,34,35 and 36 Its effect on the risk of arterial thrombosis is controversial.37,38 and 39 The prothrombin 20210 G­A polymorphism appears to be common in Caucasian populations,40,41 and evidence was provided for a founder effect.42 The polymorphism is very rare in individuals of African and Asian descent.40,41
CLINICAL MANIFESTATIONS
Inherited hypoprothrombinemia and dysprothrombinemia are characterized by mild to moderate mucocutaneous and soft-tissue bleeding that usually correlates with the degree of functional prothrombin deficiency. With prothrombin levels of less than 1 percent of normal, bleeding may occur spontaneously or following trauma. Surgical bleeding may be significant. Menstrual bleeding in females, epistaxis, gingival bleeding, easy bruising, and subcutaneous hematomas may occur. Hemarthroses can occur but are less frequent than in the hemophilias. In patients with prothrombin activities of 2 to 5 percent of normal, bleeding may be quite variable. Some individuals may bleed following minimal trauma, while others may be asymptomatic. Patients with prothrombin activity of 5 to 50 percent usually bleed only following major trauma and surgery, or do not bleed at all.
DIFFERENTIAL DIAGNOSIS
The activated partial thromboplastin time (aPTT) and prothrombin time (PT) are variably prolonged in inherited hypoprothrombinemia and dysprothrombinemia, but thrombin time is normal. The diagnosis of a prothrombin abnormality is established by the demonstration of decreased functional levels of prothrombin. Both functional and antigenic levels of prothrombin should be determined in cases of possible prothrombin deficiency in order to establish the presence of a dysprothrombinemia. Although acquired prothrombin deficiency is infrequent (e.g., in patients with antiphospholipid antibodies who have a bleeding tendency), family studies are helpful in establishing the diagnosis of an inherited deficiency.
Prothrombin can be activated by several snake venoms, and the pattern of activation by these enzymes may provide clues to the nature of the prothrombin abnormality. Activation of prothrombin by Taipan viper venom and by Pseudonaja textilis venom is independent of factor V. Thus, a normal Taipan viper venom or Pseudonaja textilis venom time with an abnormal classical one-stage assay for prothrombin implies a defect in the region of prothrombin that binds factor V. Echis carinatus venom activates prothrombin in the absence of factor V, phospholipid, and calcium and can therefore be used together with other prothrombin activators to test the requirement for each of these components. Plasma prothrombin immunoelectrophoresis is also useful in the diagnosis of dysprothrombinemias. Prothrombins Canberra, Segovia, and Denver show reduced anodic migration, while prothrombins Barcelona, San Juan, and Habana show enhanced anodic migration.
Prolonged aPTT and PT with a normal thrombin time are also seen in inherited factor V and factor X deficiency, in acquired conditions such as vitamin K deficiency, with therapeutic or surreptitious use of warfarin, in liver disease, and with lupus anticoagulants. These various disorders are readily distinguished by taking the patient’s history and by performing additional factor assays (see Chap. 115).
THERAPY
Replacement therapy in patients with inherited prothrombin deficiency and dysprothrombinemia is with prothrombin complex concentrates containing coagulation factors II, VII, IX, and X. These concentrates are heated or treated with solvent-detergent, processes that remove HIV, hepatitis B, hepatitis C, and other viruses but do not remove parvovirus, hepatitis A virus,43,44,45 and 46 and other possible bloodborne agents, such as Creutzfeldt-Jakob disease and its new variant. Thus, these concentrates are not without risk. In addition to the zymogen forms of factors II, VII, IX, and X, prothrombin complex concentrates also contain small amounts of activated forms of some of these factors. As a result, their administration may cause venous thromboembolism, myocardial infarction, or stroke.47 The risk of thrombosis appears to increase with the dose, and, thus, repeated administration of small doses is probably safer.
Fresh-frozen plasma is also effective but confers a very low, but measurable, risk of HIV and hepatitis B and C virus transmission. Solvent-detergent-treated fresh-frozen plasma has been developed and can provide increased safety from these infections. However, since it is prepared from large pools of plasma, it may increase the risk of transmitting agents that are not destroyed by solvent-detergent treatment.
In many cases, the decision is not what to use for treatment but whether treatment is needed. Bruises and mild superficial bleeding do not generally require replacement therapy. Since the biologic half-life of prothrombin is approximately 3 days, in many cases a single treatment is all that is needed.
FACTOR VII DEFICIENCY
DEFINITION AND HISTORY
Hereditary deficiency of factor VII, first described by Alexander et al in 1951,48 is a rare autosomal recessive disorder that occurs throughout the world. Its prevalence is not precisely known, except for that of one mutation responsible for the disease that is frequently observed among Iranian and Moroccan Jews (see below). The disorder is symptomatic only in homozygotes or compound hererozygotes, and the symptoms vary greatly from mild to severe. A presumptive diagnosis can be easily established, since factor VII deficiency is the only coagulation disorder that produces a prolonged PT and a normal aPTT.
BIOCHEMISTRY AND MOLECULAR FEATURES
Human factor VII is a single-chain glycoprotein (Mr »50,000) that is secreted from the liver parenchymal cells as a zymogen. The mature protein consists of 406 amino acids and is organized in three main domains: a Gla domain at the N terminus, a growth factor domain in the center, and a serine protease domain at the C terminus.49 Vitamin K is required for the formation of the Gla residues that bind calcium ions and permit interactions with phospholipid membranes. The factor VII gene spans about 12.8 kb50 and is located on chromosome 13q34,51,52 2.8 kb upstream from the factor X gene.53 The gene contains one exon that encodes for a preproprotein leader sequence and eight exons that encode for the mature protein. Promoter and silencer elements of the 5′ flanking region have been characterized.54,55 Factor VII zymogen circulates in blood at an extremely low concentration (»500 ng/ml)56 and has the shortest half-life of all coagulation factors (5 h).57
Factor VII is converted to activated factor VII (factor VIIa) by cleavage of an Arg152-Ile153 bond, resulting in a two-chain molecule held together by a disulfide bond. This cleavage can be caused by factor Xa,58 factor IXa,59 factor XIIa,59,60 thrombin,58 and factor VIIa in an autoactivation process.61 Binding of factor VII to tissue factor strikingly enhances these reactions.62,63,64,65 and 66
Factor VIIa can be detected in plasma by a sensitive assay employing a recombinant soluble form of tissue factor.67 The mean concentration of plasma factor VIIa is 3.6 ng/ml in normal individuals, which represents 0.76 percent of the total factor VII mass in plasma. The half-life of factor VIIa is relatively long (»2.5 h)68 compared to other activated coagulation factors. Factor IXa is probably responsible for the basal levels of plasma factor VIIa in normal individuals, since patients with severe hemophilia B, unlike patients with severe hemophilia A, have a very low concentration of circulating factor VIIa.69,70 Moreover, hemophilia B patients acquire normal levels of factor VIIa within a few hours of infusion of purified factor IX.71
Current theories are that blood coagulation is initiated when blood is exposed to tissue factor present in the subendothelium, in the tissues, or on the surface of stimulated monocytes (see Chap. 112). The exposed tissue factor forms a complex with circulating factor VIIa, which can activate factors X and factor IX.72 The rate of factor X activation by this pathway is, however, 50 times lower than the rate achieved by the combined effects of factor IXa, factor VIIIa, phospholipid, and calcium ions.73 It thus seems that factor VIIa plays a role in maintaining a low-key coagulant activity in the normal state and in the initial generation of thrombin once tissue factor becomes exposed. The sources of factor Va, which is essential for thrombin formation, and factor IXa, which is essential for maintaining the basal levels of factor VIIa, are unclear.74
When factor VII is completely lacking, as in knock-out mice, fatal hemorrhage occurs perinatally.75 It is interesting to note that mice lacking tissue factor die during the embryonal phase due to abnormalities in the vascular wall,76 while transgenic mice, rescued by incorporation of about 1 percent human tissue factor activity, develop normally and exhibit normal hemostasis.77
GENETICS
Factor VII deficiency is inherited as an autosomal recessive trait. The disorder manifests only in homozygotes or compound heterozygotes, of whom some are also homozygotes for polymorphisms associated with reduced factor VII levels.78,79
The heterogeneity of factor VII deficiency was already apparent in 1971, when two of four patients studied were found to have dysfunctional factor VII demonstrable by the presence of antibody-neutralizing material.80 Later studies confirmed these observations and classified subjects with factor VII deficiency into CRM–, CRM+ (having normal levels of factor VII antigen), and CRMred.81,82 The latter two categories predominated.82 Further complexity emanated from observations of variable reactivities of plasma from individuals with factor VII deficiency to bovine, rabbit, and human tissue factor.82 Following the characterization of the factor VII gene, the heterogeneity of factor VII deficiency was confirmed. Thirty-five mutations were reviewed in 1997,64 and many additional mutations have been published via the internet.83 Most of the mutations are single-base substitutions that are distributed throughout the gene. The majority of them are missense mutations, with a few splice-site and nonsense mutations. Short deletions have also been described.64 Two interesting single-base substitutions were recently described in the promoter region of the gene that disrupt the hepatocyte nuclear factor 4 and SP1 binding sites, respectively.84,85 Both probands bearing the respective mutations are homozygotes and exhibit a very severe bleeding tendency.
Most mutations causing factor VII deficiency have been observed in individual patients. However, one missense mutation Ala244Val, was detected in 23 unrelated subjects with factor VII deficiency studied in Israel.79 Most subjects were of Iranian and Moroccan Jewish origin and were found to share an identical haplotype, consistent with a founder effect. In the general Iranian Jewish and Moroccan Jewish populations, the prevalences of the Ala244Val allele are 0.023 and 0.025, respectively.79
Although the Dubin-Johnson syndrome was found to be associated with factor VII deficiency in Iranian and Moroccan Jews,86 this is probably simply a reflection of high consanguinity rates in these populations, since the gene of the canalicular multispecific organic anion transporter, which is impaired in Dubin-Johnson syndrome,87 is on chromosome 10q24,88 while the gene for factor VII is on chromosome 13q34.51,52
Three polymorphisms in the factor VII gene have been found to be associated with reduced plasma levels of factor VII. Since an increased level of factor VII was established as a risk factor for coronary heart disease in middle-aged men89 and was particularly found to be associated with fatal coronary events,90 the three polymorphisms have become the subject of intensive research. The first polymorphism, an Arg353Gln substitution, results in impaired secretion of factor VII from cells91 and gives rise to a 20 to 25 percent decrease in plasma factor VII level in heterozygotes and a 40 to 50 percent decrease in homozygotes.92,93 The allele frequency of the Arg353Gln polymorphism varies significantly in different populations. For example, in Japanese subjects the observed frequency is only 3.5 percent,94 while in Afro-Caribbeans it is 8 percent,95 in northern Europeans it is 9 percent,95 and in Italians it is 21 percent.96 The highest allele frequencies are in Gujaratis (25 percent) and Dravidian Indians (29 percent).97 While in all these studies an association between the 353Gln allele and reduced levels of factor VII and factor VIIa was evident,98 conflicting data exist regarding the relationship between the finding of the Arg353Gln polymorphism and the risk of coronary heart disease.96,99,100 Conceivably, the significant effects on factor VII level exerted by dietary intake of fats,101 serum cholesterol and triglyceride levels,102 body mass,103 age,103,104 and gender104 confound the effect conferred by the polymorphism. The second polymorphism associated with a diminished factor VII level is a decanucleotide insertion upstream from the 5′ end of the gene at –323. The insertion was shown to confer a 33 percent decrease in the promoter activity.55 The relative effects of this polymorphism and the Arg353Gln polymorphism on factor VII level are difficult to assess, since linkage disequilibrium exists between these markers.93 A third polymorphism associated with factor VII level is a hypervariable region 4 polymorphism in intron 7.105 The variable number of tandem repeats (five to eight copies of 37 bp) apparently influences the splicing efficiency. Although the effect of the variable repeats on factor VII level is less conspicuous than the decanucleotide insertion at the promoter region and the Arg353Gln polymorphism, a recent study showed that subjects bearing alleles with seven repeats, who had reduced factor VII levels, manifested a lower risk of myocardial infarction.96
CLINICAL FEATURES
Bleeding manifestations only occur in homozygotes and in compound heterozygotes for factor VII deficiency. Heterozygotes who have partial factor VII deficiency do not exhibit hemorrhagic manifestations, even following trauma.57,106 Patients who have factor VII levels of less than 1 percent frequently present with a disease that is indistinguishable from severe hemophilia A or hemophilia B. Such patients are afflicted by hemarthrosis, leading to severe arthropathy,57,107 and can present with life-threatening intracerebral hemorrhage.57,108 Patients with slightly higher levels of factor VII have also been reported to manifest such severe bleeding episodes, but this seems to be exceptional, since most patients with factor VII levels of 5 percent or more have a much milder disease, characterized by epistaxis, gingival bleeding, menorrhagia, and easy bruising. Dental extractions, tonsillectomy, and surgical procedures involving the urogenital tracts are frequently accompanied by bleeding when no prior therapy is instituted.57 In contrast, surgical procedures such as laparotomy, herniorrhaphy, appendectomy, and hysterectomy have been uneventful.57 This apparent discrepancy can be explained by different extents of local fibrinolysis exhibited by the respective traumatized tissues. Factor VII levels rise during pregnancy in healthy females109 but do not change in homozygous patients with the deficiency.110 Nevertheless, postpartum hemorrhage has not been observed in patients with factor VII deficiency, except for a few instances.57,111
Inhibitors to factor VII have not been described in patients with inherited factor VII deficiency. A spontaneous, acquired inhibitor to factor VII causing cerebral hemorrhage was, however, reported in one patient; this patient responded to immunosuppression.112
Venous thromboembolism has been described in several patients.113 This indicates that the deficiency of factor VII, like deficiencies of other coagulation factors, is not protective against venous thromboembolism.
LABORATORY FEATURES
A normal aPTT and a prolonged PT in a patient with a lifelong history of a mild or severe bleeding tendency is consistent with the diagnosis of factor VII deficiency (see Chap. 115). The prolonged PT is correctable by normal serum (containing factor VII) but not by absorbed plasma (devoid of factor VII). Making the diagnosis depends on a specific assay of factor VII activity using known factor VII–deficient plasma. Factor VII antigen can be measured by a radioimmunoassay.56,82 Factor VIIa is measurable by a clotting assay using soluble tissue factor, which is insensitive to native factor VII,67 or by an enzyme-linked immunoabsorbent assay using an antibody that exhibits 3000-fold greater reactivity with factor VIIa than with factor VII.114 Heterozygous carriers have reduced mean levels of factor VII activity, but the range of activity overlaps with normal values. Factor VII activity can also be decreased when the subject under investigation has vitamin K deficiency, which occurs quite frequently. Detection of heterozygotes can be facilitated by concomitant measurements of factor VII activity and antigen levels following administration of vitamin K. Since most factor VII deficiency states have been shown to be CRM+ or CRMred,81,82 a finding of reduced factor VII activity and significantly higher factor VII antigen level is consistent with heterozygosity.115 A more definitive approach is identification of the mutant gene in the involved family and tracking it among family members.
DIFFERENTIAL DIAGNOSIS
Before the diagnosis of inherited factor VII deficiency is made, the common causes for acquired factor VII deficiency must be excluded. These include liver disease, vitamin K deficiency, and use of warfarin and related anticoagulants. Very rare hereditary defects that need to be distinguished from factor VII deficiency are the combined deficiency of all vitamin K–dependent factors (see below), combined deficiency of factors VII and X,116 and combined deficiency of factors VII and IX.117
THERAPY
For minor bleeding episodes, replacement therapy is unnecessary. Local hemostasis for skin lacerations and administration of an antifibrinolytic agent for menorrhagia, epistaxis, and gingival hemorrhage are usually sufficient to arrest bleeding. Replacement therapy is essential in patients who present with severe hemorrhage, such as hemarthrosis or intracerebral bleeding. When surgery is required, the following should be considered:

1.
The tissue involved during surgery. Dental extractions, tonsillectomy, nose surgery, and urological interventions are likely to be associated with bleeding because of local fibrinolysis.

2.
The history of bleeding. Patients who have experienced hemarthroses, intracerebral hemorrhage, or other severe bleeding episodes have a much higher risk of bleeding than do those who have not had such symptoms.

3.
The basic level of factor VII. Patients with very low activities (<3 percent of normal) are more likely to bleed.

4.
A trough factor VII level of 20 to 25 percent of normal is probably sufficient, even when extensive trauma is inflicted.57,106,118

5.
Volume overload is to be expected if plasma is used as the replacement material.

6.
The half-life of factor VII is short (»5 h).57

7.
The safety of the blood component to be used.
When plasma is used for major surgery, a loading dose of 15 ml/kg should be administered, followed by 4 ml/kg every 6 h for 7 to 10 days. Diuretics or even plasmapheresis might be necessary because of volume overload.118 Prothrombin complex concentrates containing activated clotting factors68 can be used, but they confer a risk of thrombosis.119 Specific factor VII concentrates have been successfully used in series of patients.120,121 and 122 Another option is the use of recombinant factor VIIa, which was successfully used during seven surgical procedures in two patients with severe factor VII deficiency.123
FACTOR X DEFICIENCY
DEFINITION
Factor X deficiency, which is usually characterized by moderate to severe bleeding, is an autosomal recessive disorder first reported by Telfer and colleagues and by Hougie and coworkers.124,125
BIOCHEMISTRY AND MOLECULAR FEATURES
The gene encoding factor X is located on chromosome 13q34-qter, adjacent to the gene encoding for factor VII.126,127 The gene spans approximately 25 kb and is composed of eight exons.128 The factor X gene shows significant homology with the genes of other vitamin K–dependent serine proteases, suggesting that all of these multidomain genes have evolved from a common ancestral gene.129
The protein encoded by the factor X gene is 488 amino acids in length. At the N terminus is a 23–amino acid signal peptide, which targets factor X as a secretory protein and is removed by a signal peptidase. The Gla domain forms the N terminus of the mature protein and contains 11 Gla residues,130 which are responsible for calcium and phospholipid binding. Adjacent to the Gla domain is a short stack of predominantly hydrophobic amino acids, followed by the epidermal growth factor (EGF) domain, which contains two EGF motifs that are believed to mediate protein-protein interactions. The heavily glycosylated 52–amino acid activation peptide of factor X separates the EGF domain and the C-terminus catalytic domain.
Factor X undergoes proteolytic processing in the endoplasmic reticulum so that circulating factor X is a two-chain, disulfide-linked protein consisting of a 17-kDa light chain composed of the Gla and EGF domains, and a 40-kDa heavy chain composed of the activation and the catalytic domains.131 Factor X can be activated by a complex of phospholipid, factor IXa, and factor VIIIa through the intrinsic pathway of coagulation or by membrane-bound factor VIIa–tissue factor through the extrinsic pathway of coagulation.132 Factor X can also be activated by a component of Russell’s viper venom,133 by trypsin, and, in an autocatalytic reaction, by factor Xa. In each case, the activation of factor X is accomplished by proteolytic cleavage and subsequent removal of the activation peptide. Activated factor X, in turn, activates prothrombin to thrombin in a reaction that requires a phospholipid surface, divalent cations, and thrombin-activated factor V.
GENETICS
Factor X deficiency is inherited in an autosomal recessive manner, with males and females equally affected. Heterozygotes have factor X levels that are approximately 50 percent of normal and are generally asymptomatic. The genetic defects that cause a deficiency of factor X may be quantitative or qualitative and are classified as CRM+, CRMred, and CRM– according to the functional and immunological analysis of the abnormal factor X molecule.
As shown in Table 122-2, the molecular defects associated with factor X deficiency consist of large deletions, small frameshift deletions, nonsense mutations, and missense mutations.134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151 and 152 The deletion mutations result in the absence of protein synthesis or in the synthesis of unstable or dysfunctional proteins. CRM+ variants may affect factor X function in several ways. Activation through the intrinsic pathway may be preferentially affected, as with factor X Roma149 and factor X San Antonio,136 and activation by both pathways may be affected, as with factor X Friuli150 and some of the mutations in the Gla residues, such as factor X St. Louis II.139 Activation by Russell’s viper venom may be relatively preserved. For example, with factor X Friuli, there is 25 percent activation with Russell’s viper venom but only 3 percent activation through the intrinsic and extrinsic pathways. Similarly, with factor X Roma, there is full activation with Russell’s viper venom but impaired activation through the intrinsic and, to a lesser extent, extrinsic pathways. Missense mutations may also affect synthesis or secretion, thus producing CRM– phenotypes, as with factor X Santo Domingo138 and the Stuart mutation.

TABLE 122-2 INHERITED FACTOR X DEFICIENCY*

CLINICAL MANIFESTATIONS
The clinical manifestations of factor X deficiency are related to the functional levels of factor X. Individuals with severe factor X deficiency having functional factor X levels less than 1 percent of normal bleed spontaneously and following trauma. Bleeding is primarily into joints and soft tissues and from mucous membranes.153 More unusual bleeding may also occur, including central nervous system hemorrhage; intramural intestinal bleeding, which can produce symptoms like those of an acute abdomen; urinary tract bleeding; and soft-tissue bleeding with the development of hemorrhagic pseudocysts or pseudotumors. Menorrhagia may be especially problematic in women with factor X deficiency. Umbilical cord bleeding after delivery is also common. In individuals with moderate or mild deficiencies of factor X and in heterozygotes, bleeding is less common, usually occurring only after trauma or during or after surgery. Such patients may experience easy bruising as the only clinical manifestation.
DIFFERENTIAL DIAGNOSIS
The diagnosis of factor X deficiency is suggested by the demonstration of prolonged PT and aPTT assays. The Russell’s viper venom time, which is based on the activation of factor X by the venom, is also prolonged. The thrombin time is normal. The diagnosis of factor X deficiency depends on the demonstration of an isolated deficiency of factor X by a specific factor X assay.
Prolonged PT and aPTT assays in conjunction with a normal thrombin time can also be observed in patients with prothrombin deficiency, factor V deficiency, multiple factor deficiencies, vitamin K deficiency, liver disease, and lupus anticoagulants. Factor X deficiency is distinguished from these disorders by measurements of the levels of factor X and other specific factors, including factors II, V, VII, and IX (see Chap. 115).
Inherited factor X deficiency must also be differentiated from various acquired causes of isolated factor X deficiency, such as systemic amyloidosis.154,155,156 and 157 Factor X deficiency that sometimes occurs in this disorder can be due to (1) selective binding of factor X to the amyloid fibrils that can be erroneously attributed to the presence of an inhibitor when exogenously infused factor X is rapidly removed from the circulation,155,156 or (2) presence of abnormal factor X molecules with reduced activity versus antigen level.157 Amyloidosis associated with factor X deficiency due to both causes is generally of the primary type. Acquired isolated factor X deficiency has also been reported in association with respiratory infections, spindle cell thymoma, fungicide exposure, renal and adrenal adenocarcinoma, acute myelogenous leukemia, and use of methylbromide. Acquired inhibitors of factor X have also been reported.158
THERAPY
The treatment of inherited factor X deficiency is usually with heated and solvent-detergent-treated prothrombin complex concentrates that contain factor X in addition to factors II, VII, and IX. The use of these concentrates carries a low risk of transmission of bloodborne viruses. There is, however, a risk of thrombosis, including venous thromboembolism, disseminated intravascular coagulation, and myocardial infarction,47,159 which is thought to be dose dependent. As a result, administration of doses over 2000 units is not recommended. If a larger dose is needed, it is recommended that divided doses be used.
For soft-tissue, mucous membrane, and joint hemorrhages, the aim of treatment should be to maintain a factor X level of at least 30 percent of normal. For more serious hemorrhages, a factor X level of 50 to 100 percent should be the goal. The biologic half-life of factor X is 24 to 40 h.160,161 Based on this, if continued treatment is needed, prothrombin complex concentrates should be administrated every 24 h until hemostasis is achieved. Fresh-frozen plasma that contains factor X at a concentration of 1 unit/ml can also be used to treat patients with factor X deficiency. The issue of volume overload with plasma and the relative merits of using solvent-detergent-treated plasma are discussed above (see “Therapy” under “Factor II and Factor VII Deficiency”).
COMBINED DEFICIENCY OF THE VITAMIN K–DEPENDENT FACTORS
In 1966 McMillan and Roberts reported the first case of severe hereditary deficiency of coagulation factors II, VII, IX, and X.162 The combined deficiency of these vitamin K–dependent factors is a very rare autosomal recessive disorder that can be manifested by a mild or severe bleeding tendency. Protein C and protein S levels have also been reduced in cases where these proteins were assayed.163,164 Evidence for impaired g-carboxylation of the affected factors was described in 1979,165 and a missense mutation in the g-glutamylcarboxylase gene was identified in one case as the cause of the combined deficiency in 1998.166
Administration of large doses of vitamin K has resulted in improved hemostasis and partial correction of the factors’ levels in several cases.162,164 In patients who do not respond to vitamin K administration, fresh-frozen plasma should be used for replacement therapy.167
FACTOR V DEFICIENCY
DEFINITION
Hereditary factor V deficiency, initially described as parahemophilia,168 is a rare autosomal recessive disorder that is manifested in homozygotes as a moderate bleeding tendency. The prevalence of the disorder is unknown, and no specific ethnic or population clusters have been reported.
BIOCHEMISTRY AND MOLECULAR FEATURES
Human plasma factor V is a high-molecular-weight (Mr »330,000) single-chain glycoprotein that consists of 2196 amino acids.169,170 Analysis of the approximately 7-kb factor V cDNA showed that the protein is organized according to the following domain structure: A1-A2-B-A3-C1-C2.171 The A and C domains have approximately 40 percent homology with analogous domains in factor VIII. The large B domain shows no homology with the corresponding B domain of factor VIII. The gene contains 25 exons171 and was mapped to chromosome 1q21-25.172 Factor V is converted to its activated form following several proteolytic cleavages by thrombin173 or factor Xa.174 These cleavages remove the B domain and yield factor Va, consisting of a heavy chain (A1-A2 domains) associated by Ca2+ with a light chain (A3-C1-C2 domains).169,170 The light chain contains the binding sites for membrane phospholipids, prothrombin, and activated protein C; both light and heavy chains are probably necessary for binding factor Xa.170
The assembly of factor Va and factor Xa on the phospholipid membrane of platelets in the presence of Ca2+ forms the prothrominase complex, which catalyzes the conversion of prothrombin to thrombin.169 The exclusion of factor Va from the prothrombinase complex reduces the rate of thrombin generation by four orders of magnitude.169 Factor V is synthesized by the liver175 and by megakaryocytes.176 Its plasma concentration is appproximately 7 µg/ml,177 and its half-life is 12 to 15 h.178 About 20 percent of factor V in whole blood is localized in the a granules of platelets,179 where it is complexed with an extremely large protein multimerin.180 Platelet factor V is partially fragmented,179 but full activity is preserved. Its release from platelets upon their activation exerts an important hemostatic effect, since patients with an inherited defect of a-granule proteins, including platelet factor V, have a severe bleeding tendency.181,182
Factor Va is inactivated by activated protein C through limited proteolysis in the presence of protein S, Ca2+, and either platelet or endothelial cell membrane phospholipids.183 Partial protection from this cleavage is provided by factor Xa when factor Xa is bound to factor Va.184 Partial resistance to inactivation by activated protein C occurs when the cleavage sites of factor Va (Arg306 and Arg506) are mutated (see Chap. 127).
GENETICS
Factor V deficiency is inherited as an autosomal recessive trait. Heterozygotes whose plasma factor V activity ranges between 26 and 60 percent of normal are usually asymptomatic.185
Assays of factor V antigen have shown that most homozygotes have a true deficiency. Only 2 of 21 patients examined in one study169 and 4 of 14 patients examined in another study186 were shown to possess dysfunctional factor V.
Candidate mutations responsible for factor V deficiency were reported only in a few unrelated subjects. In one report, two siblings were found to bear an Ala221Val missense mutation that seemed to code for a factor V molecule with reduced functional activity.187 In another study, a patient with partial factor V deficiency was found to bear a nt 5509 G®A change in exon 16 that predicted an Ala1779Thr substitution and perhaps a splicing abnormality.188 The third mutation identified was a 4-bp deletion in exon 13 that introduced a frameshift and a stop codon, which should lead to synthesis of a truncated form of factor V that lacks part of the B domain and domains A3, C1, and C2.189 It is remarkable that the homozygous proband, whose factor V antigen and activity were approximately 1 percent of normal, had only a mild bleeding tendency.
Subjects who are compound heterozygotes for factor V Arg506Gln (factor V Leiden) and for a factor V null allele have normal hemostasis (despite reduced factor V clotting activity), but since they are phenotypically homozygous for activated protein C resistance, they may present with thrombosis.188,190,191,192 and 193
Among several polymorphisms detected in the factor V gene, the His1299Arg in exon 13 is of particular interest, since it is associated with a reduced plasma factor V level.194 Moreover, in two heterozygotes for factor V R506Q (factor V Leiden) who presented with thrombosis, reduced factor V activity due to the His1299Arg polymorphism conferred a pseudohomozygous phenotype for activated protein C resistance.194
Factor V Quebec was initially described as an autosomal dominant disorder with severe bleeding manifestations.195 Affected patients had platelet factor V activity of 2 to 4 percent of normal, slightly reduced platelet factor V antigen, moderately decreased plasma factor V activity, and mild thrombocytopenia. The inactive platelet factor V in these patients is caused by abnormal proteolysis of several platelet a-granule proteins,181,182,196 including fibrinogen, von Willebrand factor, thrombospondin, and factor V complexed with multimerin.180 Thus, factor V Quebec, described in two unrelated families,195,196 is a deficiency of platelet factor V activity secondary to a generalized platelet defect.
CLINICAL MANIFESTATIONS
Gene-targeting experiments in mice have shown that total deficiency of factor V is incompatible with life.197 Mice die either during embryogenesis from vascular abnormalities or reach term but die within hours from massive hemorrhage. Homozygous patients whose factor V level ranges from less than 1 to 10 percent of normal exhibit a lifelong bleeding tendency. Manifestations include, in decreasing order of frequency, ecchymoses, epistaxis, gingival bleeding, hemorrhage following minor lacerations, and menorrhagia.178 Bleeding from other sites is less common, but instances of hemarthroses unrelated to trauma, and intracerebral hemorrhage have been reported.178,198 Trauma, dental extractions, and surgery confer a high risk of excessive bleeding.
Venous and arterial thromboses have been described in patients with factor V levels ranging between 2 and 14 percent of normal.199,200 and 201 These observations indicate that factor V deficiency, like deficiencies of other coagulation factors, does not provide protection against thrombosis.202 Factor V deficiency deprives activated protein C of one of its essential substrates, thereby down-regulating the inhibitory function of the protein C system. As already discussed, this is highlighted in patients with thrombosis who are compound heterozygotes for a factor V deficiency allele and an allele bearing the factor V Leiden mutation.188,190,191,192 and 193
DIFFERENTIAL DIAGNOSIS
Hereditary factor V deficiency must be distinguished from hereditary combined factor V and factor VIII deficiency, from acquired factor V deficiency associated with severe liver dysfunction or disseminated intravascular coagulation (DIC), and from a deficiency related to an acquired inhibitor to factor V. In both factor V and combined factor V and VIII deficiencies, the PT and aPTT assays are prolonged, inheritance is autosomal recessive, and bleeding manifestations are similar. An assay of factor VIII is therefore essential for distinction between these entities (see Chap. 115). The clinical manifestations of severe liver disease or DIC are sufficient for easy distinction between acquired and inherited factor V deficiency.
Acquired inhibitors to factor V are of three major classes: spontaneous, after transfusion in factor V–deficient patients, and after exposure to preparations of bovine thrombin. Belonging to the first class are spontaneously occurring inhibitors of unknown etiology that have been rarely reported in patients following surgery or in patients treated by aminoglycoside antibiotics or other drugs.203,204 Inhibitors in this class that were characterized were either IgGs or IgMs.204 Patients who develop such inhibitors are either asymptomatic or present with a severe bleeding tendency that, in at least two instances, was fatal.205,206 In most cases these inhibitors disappear spontaneously.203 Inhibitors in the second class have been reported in two patients with hereditary factor V deficiency, who developed the inhibitors following transfusions of plasma.207,208 In one of the patients, the inhibitor disappeared, while in the other patient a low titer of the inhibitor persisted.208 The third class of inhibitors consists of antibodies that develop in patients exposed to topical bovine thrombin.209 The afflicted patients may react not only to the bovine thrombin but also to bovine factor V that is present in the commercial preparations of bovine thrombin.210 The anti–bovine factor V antibodies cross-react with endogenous factor V and can cause an extremely low level of factor V.210,211 Bleeding manifestations are variable in such patients. In a review of 17 patients, 5 were asymptomatic, and 12 had bleeding manifestations ranging from minimal to life-threatening.212 A prolonged thrombin time with bovine thrombin that shortens when using human thrombin is consistent with the diagnosis of anti–bovine thrombin antibodies, and prolonged PT and aPPT suggest the presence of factor V inhibitors.
A recent study of 12 patients who developed autoantibodies of the first class or bovine thrombin–induced antibodies of the third class demonstrated that, in those patients who had significant bleeding manifestations, the antibodies reacted with a common epitope at the N-terminal region of the C2 domain of factor V.213 This domain was previously shown to be required for binding factor Va to phosphatidylserine, which is essential for the generation of prothombinase activity.214
THERAPY
Patients with epistaxis and gingival bleeding may respond to tranexamic acid (1g q.i.d), and local hemostatic measures may suffice for minor lacerations. If these measures fail, if severe spontaneous bleeding occurs, or if surgery is performed, fresh-frozen plasma replacement should be given. The following should be considered when planning plasma replacement therapy: (1) the half-life of factor V is approximately 12 to 14 h; (2) a factor V level of 25 percent is usually adequate even for major surgery215,216; and (3) surgical procedures at sites such as the urogenital tract, oral cavity, and nose, with high local fibrinolytic activity, are likely to result in excessive bleeding, and late bleeding may occur. Infusion of a loading dose of 20 ml/kg of fresh-frozen plasma followed by 5 to 10 ml/kg every 12 h for 7 to 10 days is usually adequate to ensure hemostasis during and after surgery.
Patients with inhibitors to factor V from any class may present a serious therapeutic challenge. Successful management of bleeding has been achieved in this situation in one patient by platelet transfusions, apparently due to greater hemostatic effects of platelet factor V,217 perhaps as a result of decreased access of the inhibitor to the factor V. Immunosuppressive therapy with or without plasma exchange was successful in elimination of the inhibitor in two patients,218,219 but it failed in another patient, who died of hemorrhage.206
COMBINED DEFICIENCY OF FACTORS V AND VIII
DEFINITION
Combined deficiency of factors V and VIII, first described in 1954,220 is a rare, moderate bleeding disorder that is transmitted as an autosomal recessive trait.221 Affected homozygotes have plasma levels of factors V and VIII in the range of 5 to 30 percent of normal.222 The disorder results in most cases from a deficiency of an intracellular protein found in the endoplasmic reticulum–Golgi intermediate compartment (ERGIC-53) that is required for the transport of factors V and VIII through the cellular secretory pathway.223 The disorder has been detected in many populations, but a relatively high frequency was observed among Tunisian and Middle Eastern Jews residing in Israel221 and among Iranians.224
BIOCHEMISTRY AND MOLECULAR FEATURES
Factor V and factor VIII are essential coagulation factors that circulate in plasma as precursors. Upon limited proteolysis by thrombin or by factor Xa, and in concert with negatively charged phospholipid surfaces, factor V and factor VIII exhibit profound cofactor activities for the activation of factor X by factor IXa and for the activation of prothrombin by factor Xa, respectively. Inactivation of factors Va and VIIIa is accomplished by activated protein C in the presence of protein S and phospholipids through several proteolytic cleavages at distinct sites. Factors V and VIII have similar domain organizations with partial homology (see “Factor V Deficiency” and Chap. 112), and both are synthesized by liver parenchymal cells.225,226 Distinct genes that encode for factor V and factor VIII are located on chromosomes 1 and X, respectively.227,228 Mutations in the factor VIII gene result in hemophilia A, afflicting about 1:5000 males, and mutations in the factor V gene cause hereditary factor V deficiency, which is a rare autosomal recessive disorder.
The pathogenesis of combined deficiency of factors V and VIII has puzzled investigators for more than 40 years. The original hypothesis was that the disorder represents impaired synthesis of a precursor protein for both factors V and VIII.220 However, transfusion studies excluded this possibility.229,230 Accelerated degradation of factors V and VIII by activated protein C due to a deficiency of protein C inhibitor was proposed as an alternative mechanism for the disease231 but was incompatible with observations of a normal rate of factor VIII disappearance in patients with the combined deficiency following transfusion of cryoprecipitate and desmopressin infusion.222 Moreover, measurements of protein C inhibitor levels in plasma of affected patients disclosed normal values, thereby excluding a deficiency state.232,233 Functional impairments of factors V and VIII, presumably due to posttranslational processing, was also entertained. However, plasma factor V and factor VIII clotting activities in affected patients corresponded very well with antigen levels,234,235 and both factors were activated by thrombin as anticipated.236 Homozygosity mapping in nine unrelated Jewish families demonstrated that the gene for the deficiency of factors V and VIII was localized on the long arm of chromosome 18.237,238 Genetic linkage studies and recombination analysis localized the gene to an approximately 2.5 cm region,237 and ultimately the involved protein was identified as ERGIC-53,223 a 53-kDa transmembrane protein located in the intermediate compartment between the endoplasmic reticulum and Golgi.239,240 Analysis of ERGIC-53 mRNA in three affected patients disclosed two mutations predicting truncation of the protein, and indeed the protein was totally absent from EBV-transformed lymphocytes from the patients.223 ERGIC-53 may be involved in transport of glycoproteins from the endoplasmic reticulum to Golgi.241 Since no other protein abnormalities (including ceruloplasmin, which is partially homologous to factors V and VIII) have been identified in patients with combined factor V and factor VIII deficiency,222 it appears that the function of ERGIC-53 is confined to the transport of factors V and VIII. It seems likely that ERGIC-53, previously shown to exhibit affinity to mannose residues,242 interacts with the extensively glycosylated B domains of factors V and VIII by a lectin-like function.243
Since all patients with the combined deficiency have residual plasma levels of factors V and VIII ranging between 5 and 30 percent of normal, alternative mechanisms of intracellular transport of factors V and VIII probably exist. Moreover, other genetic defects are also likely to cause the combined deficiency, since no genetic linkage to the ERGIC-53 locus could be found in at least two of the afflicted families.244
GENETICS
The defect is inherited as an autosomal recessive trait, and thus, as expected, consanguinity in affected families is common.221,222,244 Coincidental association between hemophilia A and factor V deficiency is estimated to be extremely rare245 and has indeed been reported in only five families.246,247,248,249 and 250
In five unrelated families of Tunisian Jewish origin, a GT®GC change was detected at a donor splice site of the ERGIC-53 gene leading to loss of splicing and predicting a truncated protein.223 In five additional families of Middle Eastern Jewish origin (Iraq, Iran, and Egypt), a G insertion was identified in a stretch of four guanines from bases 86 to 89, predicting a frameshift and also leading to a truncated ERGIC-53. Allele-specific oligonucleotide hybridization analyses clearly distinguished between homozygotes and heterozygotes for each mutation.223 Distinct founder haplotypes were found for patients of Tunisian Jewish and Middle Eastern Jewish origin.237 Recently, 16 additional mutations were detected in 54 families studied.244,251
CLINICAL MANIFESTATIONS
Homozygous patients exhibit spontaneous as well as posttraumatic bleeding manifestations. Commonly observed are menorrhagia, epistaxis, easy bruising, and gingival hemorrhage.222,224 Hemarthrosis unrelated to trauma was described in about 20 percent of the cases.222,224 Less common are hematuria and gastrointestinal hemorrhage. Spontaneous intracranial hemorrhage was reported only in 1 patient.224 Dental extractions and surgical procedures are almost always accompanied by excessive bleeding when no replacement of the missing factors is provided. It is interesting that bleeding was noted only in 1 of 6 Jewish patients who underwent circumcision on the eighth day of life.221 In contrast, Muslim patients bled excessively following circumcision performed at age 5 to 7 years.224 Postpartum hemorrhage was noted in 13 of 17 women.222,224
Heterozygotes exhibit slight but significantly reduced mean levels of factor V and factor VIII.221 In a literature survey of 161 heterozygotes, 22 were reported to have significant bleeding manifestations.252 There was no correlation between factor V or VIII level and the bleeding tendency.222,252
DIFFERENTIAL DIAGNOSIS
Hemophilia A can be easily distinguished from combined deficiency of factors V and VIII by the X-linked mode of inheritance and by the normal PT observed in patients affected by hemophilia A. Hereditary factor V deficiency can be confused with combined deficiency of factors V and VIII, since both entities are inherited as autosomal recessive traits, have similar manifestations, and are characterized by prolonged PT and aPTT assays. Assays of factors V and VIII are therefore essential for making the distinction (see also Chap. 115). A coincidental association between mild or moderate hemophilia A and hereditary factor V deficiency should be borne in mind. Other features that are helpful in distinguishing between the two entities are (1) consanguinity, which is frequently present in parents of patients with the combined deficiency; (2) independent segregation of factor V and factor VIII deficiency among immediate relatives of patients with the coincidental association; and (3) concordant reductions in levels of factors V and VIII, which are more likely in patients afflicted by the combined deficiency.
THERAPY
An antifibrinolytic agent such as tranexamic acid or e-aminocaproic acid can be helpful in patients who exhibit menorrhagia, epistaxis, or gingival bleeding. Patients with severe bleeding episodes or patients undergoing surgical procedures, including dental extractions, should receive fresh-frozen plasma for replacement of factor V, and cryoprecipitate or factor VIII concentrate as a source of factor VIII. Desmopressin can also be used for achieving an increase of endogenous plasma factor VIII level,222 but this treatment sometimes fails.253 As with other clotting factor deficiencies, replacement therapy in patients undergoing major surgery should last for 7 to 10 days after the operation. Hemostatically safe levels of factor V and VIII have not been established, but given the significant bleeding experienced by patients with factor V and VIII levels of up to 30 percent of normal, it is reasonable to aim for trough factor levels of greater than 50 percent of normal during and after surgery. Volume overload can be a serious problem but can be circumvented by plasma exchange and concomitant use of a factor VIII concentrate.253
FACTOR XI DEFICIENCY
DEFINITION AND HISTORY
Factor XI deficiency was initially described as a “new hemophilia” in 1953 by Rosenthal et al254 in two sisters and their maternal uncle, and was erroneously thought to be transmitted as an autosomal dominant disorder with variable expressivity. Later studies, however, clearly established that the mode of transmission of factor XI deficiency is autosomal recessive.255,256 The disorder is exhibited in homozygotes or compound heterozygotes as a mild to moderate bleeding tendency that is mainly injury related. Affected subjects are rarely encountered in most populations, except for Jews, particularly of Ashkenazi origin, among whom the deficiency is common.256
Until recently, factor XI was regarded as one of the “contact” coagulation factors, functioning in the initiation of the intrinsic coagulation system. Numerous studies showed that, when blood or plasma is exposed to negatively charged surfaces in vitro, a series of reactions involving factor XII, high-molecular-weight kininogen (HK), and prekallikrein (PK) take place that yield a factor XIIa. Alpha factor XIIa then activates factor XI, and factor XIa, in turn, propagates the intrinsic coagulation system by activating factor IX in the presence of calcium ions. All attempts to ascribe to the contact activation pathway an essential function in vivo have been futile, since, unlike factor XI deficiency, severe deficiencies of factor XII, HK, and PK have not been shown to cause any hemostatic derangement. Recent studies demonstrated that factor XI can be activated by thrombin,257,258 thereby bypassing the contact reactions. This finding and new observations on the involvement of factor XI in the intrinsic coagulation system (see Chap. 112) and in the fibrinolytic system (see below) explain why factor XI is important for hemostasis, whereas factor XII, HK, and PK are probably not.
BIOCHEMISTRY AND MOLECULAR FEATURES
Factor XI is a glycoprotein that consists of two identical polypeptide chains of 80 kDa linked together by a disulfide bond.259 Each subunit contains 607 amino acids with a serine protease domain at the C terminus and 4 tandem repeats of 90 or 91 amino acids, designated apple domains, at the N terminus. A disulfide bond is formed between Cys321 residues, which are contained in the fourth apple domain of each monomer.260 In blood, factor XI is complexed noncovalently with HK through a binding region in the first apple domain.261 The normal plasma concentration of factor XI is about 4 µg/ml. The 23-kb gene encoding for factor XI consists of 15 exons and 14 introns262 and is on chromosome 4q34-35.263
Activation of factor XI involves cleavage of the Arg369-Ile370 bond, yielding a heavy chain containing the four apple domains linked by a disulfide bond to a light chain containing the catalytic domain.259 Each activated molecule thus contains two catalytic sites. Factor XI adhered to negatively charged surfaces by HK can be activated by a factor XIIa or through autoactivation by factor XIa.264 However, it is doubtful whether these reactions occur in vivo. The major activator of factor XI in vivo is probably thrombin,257,258 and the reaction can take place in the fluid phase,265 on the surface of platelets (see Chap. 112), or on the fibrin surface after a clot is formed.266 Once factor XIa is generated, it activates factor IX by limited proteolysis of two peptide bonds in the presence of calcium ions.267 Factor IXa then activates factor X in the presence of factor VIIIa, negatively charged phospholipids, and calcium ions. Thus, through thrombin-mediated activation of factor XI, additional thrombin is generated.
The presence of factor XI is also essential for activation of procarboxypeptidase B by thrombin. This protein, also named thrombin-activatable fibrinolysis inhibitor (TAFI), was first described in 1990268 and later fully characterized.269,270 Activated TAFI (TAFIa) removes terminal lysine residues from fibrin, leading to impaired binding of certain forms of plasminogen to fibrin, thereby disrupting the process of tissue plasminogen activator–induced plasmin generation in the blood clot.271 TAFIa is thus a strong inhibitor of fibrinolysis. Large amounts of thrombin are necessary for TAFI activation, but the reaction is substantially augmented when thrombin is bound to thrombomodulin.272 It follows that impaired generation of thrombin, for example, in inherited deficiencies of factors VIII, IX, or XI, not only delays clot formation but enhances premature lysis of clots.273 Activation of factor XI by thrombin, particularly within the blood clot, is essential for adequate TAFI activation and protection of the clot from lysis in vitro274,275 and in vivo.276 These data fit well with the clinical observations of bleeding in factor XI–deficient patients occurring commonly at sites rich in local fibrinolytic activity277 and with the effective prevention of such episodes by antifibrinolytic agents (see below).278
Factor XI is synthesized in the liver, and a case has been described of acquired factor XI deficiency due to liver transplantation from a donor who, in retrospect, was found to have the deficiency.279 A small amount of a 230-kDa protein with factor XI activity was found in platelets and was suggested to be derived from an alternatively spliced transcript found in megakaryocytes.280 However, another study showed a normally spliced transcript in platelets.281
GENETICS
INHERITANCE
Factor XI deficiency is inherited as an autosomal recessive trait that is characterized by plasma factor XI levels of less than 15 percent of normal in homozygotes and compound heterozygotes.255,277 In heterozygotes, factor XI levels frequently range between 25 and 70 percent of normal but can even be higher.256,282 Factor XI deficiency due to a dysfunctional molecule is exceedingly rare. In a study of 125 patients from various ethnic origins, none was found to have discordant levels of factor XI activity and antigen.283 Only two cases with severe deficiency of factor XI activity and seemingly normal antigen levels have been described.284,285
MUTATIONS
Three mutations, designated types I, II, and III, were first described in 1989 in six Ashkenazi Jewish patients who had severe factor XI deficiency.286 The type I mutation is a G-to-A change at the splice site of the last intron of the gene; type II is a G-to-T change in exon 5 at Glu117 leading to a stop codon TAA; and type III is a T-to-C change in exon 9 that results in a substitution of Phe283 by Leu in the fourth apple domain of the protein. A fourth mutation, designated type IV, was later identified in another Ashkenazi Jewish patient and was found to consist of a 14-bp deletion at the intron N–exon 14 junction.287 Of the four mutations among Jews, the predominant mutations are the type II and type III mutations (see below). Additional mutations have been reported in non-Jewish patients.83,260,288,289,290,291,292,293 and 294
The majority of mutations so far described are point mutations at the coding region or at intron-exon boundaries. Of six missense mutations that were expressed in BHK cells260,295 or COS-7 cells,288 five mutations involving the fourth apple domain of the protein exhibited impaired secretion of factor XI from the cells. Pulse chase experiments used in two of these studies identified impaired intracellular dimerization of factor XI as the probable cause for retarded secretion and intracellular degradation of the oligomers.260,295
ETHNIC DISTRIBUTION AND PREVALENCE
Most patients with factor XI deficiency are Jewish.255,256,277,282 Sporadically, patients have been described who are of English, German, Italian, French, Basque, Chinese, Japanese, Indian, Arab, and African American origin.282,283,296,297 and 298 Several instances of vertical transmission of severe factor XI deficiency in Ashkenazi Jewish families (consistent with pseudodominance) suggested that the gene frequency in this segment of Jews is very high. This indeed was found in two surveys of this population performed in Israel.256
Type II and type III are the predominant mutations causing factor XI deficiency in Ashkenazi Jews.277,296 Of 250 mutant alleles analyzed in 125 unrelated subjects with severe deficiency, 246 were either of the type II (123 alleles) or the type III (123 alleles).299 Screening the general Ashkenazi Jewish population for these mutations disclosed allele frequencies of 0.0217 for type II mutation and 0.0254 for type III mutation. Hence, the estimated frequency of subjects with severe factor XI deficiency in Ashkenazi Jews is 1:450 and of heterozygotes for both types of mutation, 1:11. These data indicate that factor XI deficiency is the most frequent hereditary disorder in this population. It is interesting to note that the type II mutation has also been observed in Iraqi Jews with a similar allele frequency, 0.0167,299 in Palestinian Arabs with a frequency of 0.0065, and in Sephardic and other Middle Eastern Jews with a frequency of 0.0027.300 In sharp contrast, the type III mutation was not detected in 1343 Jews of non-Ashkenazi origin or in 313 Palestinian Arabs.300
FOUNDER EFFECTS FOR THE TYPE II AND TYPE III MUTATIONS
Haplotype analysis based on examination of factor XI gene polymorphisms disclosed distinct founder effects for type II and type III mutations.300 In view of the similar prevalences of the type II mutation in Iraqi and Ashkenazi Jews, its presence in Palestinian Arabs and Sephardic Jews, and the historical information about the divergence of these populations 2000 to 2500 years ago, the type II mutation seems to have occurred in ancient times. Type III mutation, which is confined to Ashkenazi Jews, probably stemmed from a founder who lived in more recent times. Evidence supporting these hypotheses has been presented.301
CLINICAL FEATURES
BLEEDING MANIFESTATIONS IN HOMOZYGOTES AND COMPOUND HETEROZYGOTES
Most bleeding manifestations in homozygotes and compound heterozygotes are related to injuries. Excessive bleeding can occur at the time of injury or begin several hours or days following trauma. Some patients with severe factor XI deficiency may not bleed at all following trauma,255 and in others the bleeding tendency may vary from one hemostatic challenge to another.277,282 These apparent inconsistencies can now be partially explained by the genotype of the patient, which affects the extent of the deficiency, as well as by the variable sites of injury.282,302,303 Homozygotes for the type III missense mutation, whose mean factor XI level was 9.7 percent of normal, had significantly fewer injury-related bleeding events than did homozygotes for the type II mutation, with a mean factor XI level of 1.2 percent of normal. Surgical procedures that involve tissues with high fibrinolytic activity (the urinary tract, tonsils, nose, and tooth sockets) are frequently associated with excessive bleeding in patients with severe factor XI deficiency irrespective of the genotype.277 A significantly lower frequency of bleeding complications follows surgical interventions at sites without excessive local fibrinolysis, such as appendectomy, cholecystectomy, circumcision, and orthopedic surgery.277,303 This site-related bleeding tendency can now be understood in light of the demonstrated function of factor XI in preventing clot lysis (see above).
Spontaneous bleeding manifestations such as menorrhagia, gingival bleeding, ecchymoses, and epistaxis do occur in patients with severe factor XI deficiency but are uncommon.302,303 Postpartum hemorrhage can occur but is infrequent; only three episodes were observed following delivery of 28 children in 14 women.282
BLEEDING MANIFESTATIONS IN HETEROZYGOTES
Whether or not heterozygotes exhibit a bleeding tendency has been a matter of debate. In one extensive study, heterozygotes had almost no bleeding complications following a variety of surgical procedures, including operations at sites with enhanced local fibrinolysis.255 In another study, all heterozygotes who underwent urologic surgery did well, except for one patient, whose factor XI level was 25 percent of normal.304 Contrasting with these observations are studies that identified a bleeding tendency, particularly following injury in 33 percent,282 48 percent,302 and 20 percent303 of heterozygotes. Variable definitions of what constitutes a bleeding tendency305 can only partially explain this discrepancy. A more likely explanation for the variable manifestations in heterozygotes is the coexistence of additional hemostatic abnormalities in those patients who do bleed. Thus, heterozygotes who were defined as bleeders tended to have lower levels of factor VIII and von Willebrand factor, and possess blood group O, known to be associated with reduced von Willebrand factor levels. Moreover, in another study, most heterozygotes who presented with a bleeding tendency also had a platelet function abnormality.306 It can be concluded that heterozygotes for factor XI deficiency may display a risk of bleeding that is significantly lower than the risk of bleeding exhibited by homozygotes and compound heterozygotes. This statement is supported by a recent study that assessed the risk of bleeding in patients from 45 families.303 The odds ratio for bleeding was 13.0 in homozygotes and compound heterozygotes and only 2.6 in heterozygotes.
THROMBOSIS
Although factor XI plays an essential role in blood coagulation and fibrinolysis, a severe deficiency state does not protect patients from venous or arterial thrombosis. Patients with severe factor XI deficiency have been reported to have acute myocardial infarction307 and pulmonary embolism.308 Thrombotic events have also been described in patients following infusion of factor XI concentrates (see “Therapy,” below).
ASSOCIATION OF FACTOR XI DEFICIENCY WITH OTHER DISORDERS
Factor XI deficiency was described in patients with Gaucher disease.309,310 and 311 In view of the independent segregation of the two disorders,309 it seems that the coincidental occurrence of Gaucher disease and hereditary factor XI deficiency stems from the high frequency of the respective mutant genes in the Ashkenazi Jewish population. Patients with Noonan syndrome were reported to exhibit factor XI deficiency and a bleeding tendency.312 Recent studies, however, showed that, in addition to factor XI deficiency, patients with Noonan syndrome display several other abnormalities in coagulation factors and platelet function for which no explanation has been provided.313,314 A variety of other inherited disorders of hemostasis have been described in association with factor XI deficiency, including von Willebrand disease,315,316 factor VIII deficiency,282,317,318 and factor VII deficiency.319 Due to the high prevalence of factor XI deficiency in Jews, these associations are expected to be quite frequent.
ACQUIRED INHIBITORS
Inhibitors that neutralize factor XI activity have been described in patients with hereditary factor XI deficiency.320,321,322,323,324,325,326,327 and 328 Most patients had severe factor XI deficiency and received transfusions of plasma prior to the development of the inhibitor. The inhibitory activity was associated with polyclonal IgG antibodies in eight patients studied.321,323,325,326 The antibodies bound to various parts of factor XI, interfering with its activation, complex formation with HK, and catalytic activity. It is interesting to note that spontaneous bleeding manifestations did not seem to be aggravated by the development of the inhibitors, except for one patient, in whom the titer of the antibody was extremely high.321 Securing hemostasis during and after surgery in such cases is a serious problem (see “Therapy,” below).
LABORATORY FEATURES
Patients with factor XI deficiency have prolonged aPTT and normal PT (see Chap. 115). All homozygotes and compound heterozygotes have aPTTs that are longer than two standard deviations above the normal mean.329 However, aPTT values in heterozygotes substantially overlap the normal range.277,329 Consequently, screening of patients for a hemostatic abnormality prior to surgery (which is recommended for Jewish patients because of the high prevalence of factor XI deficiency) will identify all patients with a severe factor XI deficiency. The diagnosis is established by a clotting assay using a modified aPTT system and factor XI–deficient plasma.255 Factor XI antigen can be measured by radioimmunoassay.283 Analysis of DNA polymerase chain reaction and restriction enzyme digestion can identify the patients’ genotype.277,286,291,296 Mean factor XI levels and aPTT values in type II homozygotes are 1.2 percent of normal and 108 s, respectively; in compound heterozygotes for the type II and type III mutations the values are 3.3 percent of normal and 85 s, respectively; and in type III homozygotes the values are 9.7 percent of normal and 67 s, respectively.277,296 Although it has been reported that heterozygotes for the type II mutation have a significantly lower mean factor XI level than do heterozygotes for the type III mutation,277 in another study similar values were found in patients bearing these two genotypes.296
THERAPY
PATIENTS WITH A SEVERE DEFICIENCY
Patients with severe factor XI deficiency who have to undergo a surgical procedure should be carefully evaluated and meticulously prepared for the operation. A negative history of bleeding complications following previous procedures does not exclude the possibility of an increased bleeding tendency. Other hemostatic abnormalities and the presence of an inhibitor to factor XI should be excluded. Aspirin and other antiplatelet agents should be avoided for 1 week prior to surgery.
In choosing the treatment modality and the intensity of treatment, the following considerations should be taken into account:

1.
The age of the patient and history of cardiovascular disease. Use of plasma may create volume overload, and use of a factor XI concentrate can induce thrombosis (see below).

2.
The baseline plasma level of factor XI. Homozygotes with levels of approximately 10 percent of normal have a low risk of bleeding (except for procedures at sites high in local fibrinolytic activity) compared to homozygotes or compound heterozygotes, who have lower levels.277

3.
Presence of an inhibitor to factor XI. In such patients, plasma or factor XI concentrate cannot be used.

4.
The site of surgery. In patients operated on at a site with high local fibrinolytic activity, as in dental surgery and urologic surgery, the risk of bleeding is high, and the use of an antifibrinolytic agent should be considered.

5.
Safety. Transmission of infectious agents and allergic reactions are more common following plasma transfusion than after infusion of factor XI concentrate; concentrates, however, can induce thrombosis.

6.
The half-life of factor XI. A mean half-life of 52 h was recorded following infusion of a factor XI concentrate330 and 45 h following plasma transfusion.331
Patients undergoing dental extractions do not need replacement therapy. Tranexamic acid (1 g q.i.d) from 12 h before surgery until 7 days after surgery is effective in preventing bleeding.278 Epsilon-aminocaproic acid (5–6 g q.i.d.) given similarly is expected to achieve the same results. For major surgery or surgery at sites with high levels of local fibrinolysis, transfusion of fresh-frozen plasma should be given for 10 to 14 days, aiming at trough factor XI levels of 45 percent of normal.332 For surgery at tissues not displaying high levels of local fibrinolysis, fresh-frozen plasma can be transfused for 5 to 7 days, targeting at trough factor XI levels of 30 percent of normal. Following prostatectomy and bladder operations, continuous flushing of the bladder with saline solution containing tranexamic acid 0.5 to 1 g/liter can be helpful for hemostasis. For nose surgery and tonsillectomy, apart from replacement therapy, tranexamic acid or e-aminocaproic acid, given as for dental extraction, should be considered.
Two viral-inactivated factor XI concentrates have been used for treatment of patients with factor XI deficiency.330,333,334 However, infusions of both concentrates give rise to laboratory signs of DIC.335,336 Pulmonary embolism and arterial thrombosis, including fatal cases, have also been reported in patients receiving the concentrates,337,338 albeit mostly in elderly patients who had preexisting cardiovascular disease and who were given a dose exceeding 30 units/kg. Consequently, at the present time these concentrates must be used with great caution.
PATIENTS WITH PARTIAL FACTOR XI DEFICIENCY
Heterozygotes who have a negative history of a bleeding tendency, who do not exhibit any additional hemostatic abnormality, and whose plasma factor XI level is more than 40 percent of normal probably do not need any treatment while undergoing surgery.304 If, however, a positive bleeding history is elicited in such patients, a detailed investigation of the hemostatic system should be performed. If an additional abnormality is found, adequate measures should be taken to correct it, in addition to the use of replacement therapy for 5 days, aiming at trough factor XI levels of 45 percent of normal. Desmopressin may be useful in the prevention of bleeding, but only a limited number of patients receiving this therapy have been reported.339,340 The beneficial effect of desmopressin may be related to the increase in the plasma levels of von Willebrand factor and factor VIII.
PATIENTS WITH AN INHIBITOR TO FACTOR XI
Most reported patients have not exhibited an aggravation of their bleeding tendency following the development of an inhibitor. Consequently, when such patients undergo dental extraction, use of tranexamic acid and fibrin glue may be sufficient,341 but limited evidence to support this contention is available. Uneventful surgery was described in a patient who underwent plasmapheresis and was given an antifibrinolytic agent.324 Another patient underwent uneventful tonsillectomy after receiving only an antifibrinolytic drug.342 Activated prothrombin complex321,328 and recombinant factor VIIa343 have also been successfully used for major surgical procedures.
FACTOR XIII DEFICIENCY
DEFINITION
Factor XIII (fibrin-stabilizing factor) is a transglutaminase that cross-links and thereby stabilizes fibrin monomers. Deficiency of factor XIII, first described by Duckert et al in 1960, results in a moderate to severe hemorrhagic disorder and sometimes in abnormal wound healing.344
BIOCHEMISTRY AND MOLECULAR FEATURES
Plasma factor XIII is a heterotetramer with a Mr of aproximately 340,000 composed of two a chains and two b chains linked together through noncovalent bonds. The a chain (Mr »82,000) contains the catalytic site of factor XIII, an activation peptide, and a calcium-binding site.345 The factor XIII a chain is structurally homologous with the a chain of tissue transglutaminase,346 the a chain of keratinocyte transglutaminase,347 and band 4.2 of erythrocytes,348 although the latter lacks tansglutaminase activity. At the N terminus of the factor XIII a chain is an activation peptide that is removed by thrombin cleavage during thrombin-catalyzed activation.349,350 An active-site sulfhydryl residue, which is characteristic for this class of enzymes, is located at Cys298. Two calcium-binding domains flank the active-site cysteine.
The two b chains of factor XIII function as carrier proteins for the a chains,351,352 stabilizing the a chains in the circulation and regulating the calcium-dependent activation of factor XIII. The b chain, Mr approximately 76,500, is composed of ten homologous consensus, or “sushi,” repeats.353 Each repeat is approximately 60 amino acids in length and contains four disulfide bonds, with Cys1 linked to Cys3 and Cys2 linked to Cys4. The function of these repeats is unknown.
The gene for the factor XIII a chain is located on chromosome 6p24-p25.354,355 The gene spans 142 kb and is composed of 15 exons ranging in size from 63 to 1688 bp. In general, there is conservation among genes of the transglutaminase family. For example, the sequences encompassing the active site thiol is encoded by exon VII; the calcium-binding sequences are encoded by exons VI and XI; and the fibrin-binding sequences are encoded by exons III and V. Where the transglutaminases diverge is at the N terminus in the sequences encoded by exon II; in factor XIII a chain, exon II encodes the activation domain, and, in keratinocyte transglutaminase, exon II encodes sequences that localize the protein intracellularly.
The b chain has been localized to chromosome 1q31–q32.1.356 It is interesting to note that a number of other genes encoding for proteins with sushi repeats are also located on chromosome 1. The gene for the b chain spans 28 kb and is composed of 12 exons.353 The first exon encodes the leader sequence, while exons II through XI each encode a single sushi repeat. Exon XII encodes the C terminus of the b chain.
The site of synthesis of the a chain is uncertain. The protein has been identified in monocytes and platelets357,358 and 359 and, variably, in the liver. 358,360,361 The b chain is synthesized in the liver.357,361 The assembly of the factor XIII tetramer probably occurs in the circulation.
Factor XIII circulates in plasma as an inactive precursor that is activated by thrombin. Thrombin cleaves an Arg37-Gly38 bond at the N terminus of the a chain, releasing a 4500-kDa activation peptide.349 Following thrombin-mediated removal of the activation peptide and binding of calcium, the active-site sulfhydryl residue becomes exposed and factor XIII becomes proteolytically active.350 The b-chain dimer subsequently dissociates from the complex to produce the fully active a-chain dimer.
Factor XIIIa catalyzes the formation of peptide bonds between adjacent molecules of fibrin monomer and thus imparts chemical and mechanical stability to a clot. The peptide bond that is formed consists of an amide bond between the g-carbonyl group of glutamine and the e-amino group of lysine. In fibrin, this amide bond is between a-chain sequences and between g-chain sequences. The g-chain links occur between Glu398 on the g chain of one fibrin molecule and Lys406 on the g chain of another fibrin molecule.362 Cross-linking sites in the a chain have been identified as Glu328, Glu366, Lys508, Lys556, and Lys562, but the linking residues are not certain.363 Factor XIIIa also cross-links a2-antiplasmin to the a chain of fibrin,364 thereby increasing the resistance of fibrin to plasmin degradation, and cross-links fibronectin to the a chain of fibrin,365 thereby affecting the mechanical properties of the clot and increasing cell adhesion. A number of other proteins are also substrates for factor XIIIa, including collagen, thrombospondin, von Willebrand factor, vinculin, vitronectin, actin, myosin, and lipoprotein(a),365,366,367,368,369,370,371,372,373 and 374 but the physiologic significance of these reactions is less clear.
Tissue transglutaminase consisting only of two a chains is present in the soluble fraction of a variety of cells, particularly platelets and monocytes.375,376,377 and 378 Upon activation by thrombin, tissue transglutaminase cross-links fibrin in a manner that is similar to the effect of activated factor XIII.
GENETICS
Inherited factor XIII deficiency is transmitted in an autosomal recessive manner. Parents of affected individuals are typically asymptomatic, and consanguinity is common. Deficiency of the factor XIII a chain is the predominant abnormality and occurs at a frequency of approximately 1 in 2 million. Approximately 200 unrelated cases have been described. The molecular defects responsible for the a chain deficiency are presented in Table 122-3,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393 and 394 and an updated listing is available on the internet.83 Missense mutations are the most common mutations of the a chain gene. Deficiency of the b chain as a cause of factor XIII deficiency has been reported in only three cases.395,396,397 and 398

TABLE 122-3 INHERITED FACTOR XIII DEFICIENCIES*

CLINICAL MANIFESTATIONS
Factor XIII deficiency causes formation of blood clots that are less stable and more susceptible to fibrinolytic degradation by plasmin. As a result, affected individuals have an increased tendency to bleed. Bleeding from the umbilical cord in the first few days of life is common. Patients with factor XIII deficiency have a higher incidence of intracranial hemorrhage than do patients with other inherited bleeding disorders. This is the basis for recommending prophylaxis against intracranial hemorrhage by regular replacement therapy. Ecchymoses, hematomas, and prolonged bleeding following trauma are also characteristic. Hemarthroses and bleeding into the muscles are less common, however, than in the hemophilias. In some patients, bleeding following trauma may be delayed for 12 to 36 h, while in other patients immediate bleeding occurs. Habitual abortions and poor wound healing have also been described.
DIFFERENTIAL DIAGNOSIS
The PT, aPTT, and thrombin time are normal in factor XIII deficiency (see Chap. 115). Because of increased fibrin breakdown, levels of fibrin degradation products may be increased and result in a minimally prolonged thrombin time. This may be the only clue to the diagnosis based on simple coagulation screening tests. The diagnosis of factor XIII deficiency is established by the demonstration of increased clot solubility in 5 M urea, dilute monochloroacetic acid, or acetic acid. Factor XIIIa may also be determined quantitatively by measuring its ability to catalyze the incorporation of fluorescent or radioactive amines into proteins such as casein.
The disorder is easily differentiated from other deficiencies of plasma coagulation factors by the demonstration of normal screening coagulation test results and the demonstration of increased fibrin solubility. Deficiency of a2-antiplasmin may also cause an increased tendency to bleed, normal screening test results, and increased clot solubility. A specific assay for a2-antiplasmin is required to distinguish between the two disorders. Patients with a2-antiplasmin deficiency, however, appear to have a milder bleeding disorder and do not manifest umbilical cord and intracranial hemorrhages. Acquired factor XIII deficiency may occur during DIC, during primary fibrinolysis, or in the presence of an inhibitor against factor XIII. Disseminated intravascular coagulation and fibrinolysis are usually easy to distinguish from inherited factor XIII deficiency because of the reduced fibrinogen levels and other abnormalities (see Chap. 126). A family history and a lifelong history of bleeding help to distinguish inherited factor XIII deficiency from an acquired inhibitor or other causes for the deficiency.
THERAPY
Replacement therapy for factor XIII deficiency is highly satisfactory because of the small quantities of factor XIII needed for effective hemostasis and the long half-life of factor XIII, which is approximately 19 days. Plasma-derived, virus-inactivated concentrates of factor XIII are available399 and are the treatment of choice. Fresh-frozen plasma can also be used where the concentrates are unavailable. Transfusion of only 2 to 3 ml of plasma per kilogram of body weight will produce hemostasis for periods of up to 4 weeks. Prophylactic therapy using infusions of plasma every 3 to 4 weeks has been successful in achieving normal hemostasis and preventing habitual abortions.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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2 comments on “CHAPTER 122 INHERITED DEFICIENCIES OF COAGULATION FACTORS II, V, VII, XI, AND XIII AND THE COMBINED DEFICIENCIES OF FACTORS V AND VIII AND OF THE VITAMIN K-DEPENDENT FACTORS

  1. Association Between Genetic Defect and Heart Malformation…

    Mutations in SHP-2 gene disrupts the shape of cardiac muscle cells and thereby result in heart malformation, shows research. The study also shows that treatment with a drug that regulates cell shape rescues the cardiac defect, pointing to the……

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