INTRODUCTION — A variety of inherited coagulation disorders are associated with clinical bleeding, including inherited deficiencies of factors XIII (13), XI (11), X (10), VII (7), V (5), and II (2, prothrombin), as well as some rare combined factor deficiencies. These conditions may be referred to as rare (or recessively) inherited coagulation disorders (RICDs); rare coagulation deficiencies (RCDs); rare bleeding disorders (RBDs); or rare congenital bleeding disorders.
This topic review discusses the genetics, diagnosis, and management of inherited deficiencies of factor XIII, X, VII, V, II, and combined deficiencies of factors V and VIII, and vitamin K-dependent factors.
The more common inherited coagulation disorders, such as von Willebrand disease (VWD), hemophilia A and B, factor XI (11) deficiency, and fibrinogen disorders, are discussed in detail in separate topic reviews:
●Hemophilia A and B – (See "Clinical manifestations and diagnosis of hemophilia" and "Treatment of bleeding and perioperative management in hemophilia A and B".)
●Von Willebrand disease – (See "Clinical presentation and diagnosis of von Willebrand disease".)
●Factor XI deficiency – (See "Factor XI (eleven) deficiency".)
●Fibrinogen disorders – (See "Disorders of fibrinogen".)
●Plasminogen activator inhibitor deficiency – (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1 deficiency'.)
Acquired coagulation disorders (eg, factor VIII depletion by inhibitory autoantibodies; factor X depletion by amyloid fibrils) are also discussed separately. (See "Acquired inhibitors of coagulation" and "Overview of amyloidosis", section on 'Hematologic abnormalities'.)
INHERITANCE — Most of the RICDs are autosomal recessive (figure 1), including deficiencies of factor XIII, X, VII, V, and II. In some cases of apparent autosomal dominant transmission, the unaffected parent has been discovered to be a carrier (ie, the transmission was actually autosomal recessive) [1].
●Individuals who inherit a disease variant from one parent (heterozygotes) are carriers and are relatively asymptomatic
●Individuals who inherit a disease variant from both parents (eg, homozygotes, compound heterozygotes) manifest the disease
However, for many of the RICDs, mild bleeding symptoms have been reported in heterozygotes, and heterozygotes may be susceptible to increased bleeding during surgery/invasive procedures and other hemostatic challenges such as pregnancy [2-4]. (See 'Bleeding in heterozygotes' below.)
Another exception is a disorder that creates a gain-of-function in a protein with anticoagulant activity, such as certain mutations in factor V, or a mutation that alters the localization of thrombomodulin from the endothelial cell to the circulation, as discussed below. (See 'Genetics' below.)
As with other autosomal recessive disorders, prevalence is higher in populations in which there is a high degree of consanguinity [2-4]. (See 'Epidemiology' below.)
GENETICS — In most cases, RICDs result from a pathogenic variant (mutation, deletion) in the DNA sequence encoding a coagulation factor gene. These variants commonly affect the protein's abundance by altering expression or stability; less commonly, normal amounts of a dysfunctional protein are produced [2-4]. Large gene deletions or nonsense mutations (which create premature stop codons) are more likely to cause complete absence of the coagulation factor protein, whereas missense mutations, which create amino acid substitutions, may have variable effects on protein function and stability [5-9].
By convention, variants that reduce the plasma level of a factor are referred to as type I deficiencies (quantitative deficiency), and those that alter protein function without reducing protein abundance are referred to as type II deficiencies (qualitative deficiency). The distinction between type I and type II generally does not affect management, but it may impact diagnostic testing in rare cases where an immunoassay reveals normal levels of the protein, and a functional assay is required to demonstrate that the protein is dysfunctional [2-4].
Numerous variants have been reported; many are unique to a single kindred. Large collections of variants can also be obtained from the Human Gene Mutation Database maintained at the Institute of Medical Genetics in Cardiff and from the International Society on Thrombosis and Haemostasis (ISTH) website [10].
●Factor XIII deficiency (F13D; OMIM 613225 or OMIM 613235) – The factor XIII enzyme is a heterotetramer consisting of two catalytic A subunits and two B subunits [11]. Most reported cases of factor XIII deficiency are due to variants affecting the A subunit; rare cases due to variants affecting the B subunit have been reported [12].
●Factor X deficiency (F10D; OMIM 227600) – Approximately three-fourths of patients have missense mutations that result in low but measurable levels of factor X activity [3,8,13-17].
●Factor VII deficiency (F7D; OMIM 227500) – More than two-thirds of factor VII pathogenic variants are missense mutations; the remainder are null mutations that decrease or abolish factor VII expression [3,18-20]. In general, patients who are homozygous or compound heterozygous for missense mutations have mild to moderate clinical phenotypes, whereas patients with deletions, nonsense mutations, and splicing and promoter mutations have more severe phenotypes.
●Factor V deficiency (F5D; OMIM 227400) – Pathogenic variants are almost invariably associated with severe reductions in factor V levels.
However, other types of pathogenic variants have been reported:
•Factor V Amsterdam (factor V with C2588G point mutation) and factor V East Texas (factor V with A2440G point mutation) both lead to production of truncated (shortened) forms of factor V protein that cause factor V gain-of-function, which in turn results in a prolongation of the half-life of tissue factor pathway inhibitor (TFPI) [21-23]. In these disorders, factor V levels (protein levels and activity) appear normal; there is mild prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT), with a bleeding phenotype [24]. These disorders show autosomal dominant inheritance.
•The in-trans association of the factor V Leiden mutation with variants causing type I factor V deficiency leads to the so-called "pseudohomozygous" activated protein C resistance phenotype, characterized by reduced factor V antigen levels, no bleeding symptoms, and a thrombotic tendency similar to that of factor V Leiden homozygotes [25,26]. (See "Factor V Leiden and activated protein C resistance" and "Factor V Leiden and activated protein C resistance", section on 'FVL genotypes'.)
●Factor II (prothrombin) deficiency (F2D; OMIM 613679) – Missense mutations in the prothrombin gene are the most frequent type of pathogenic variant in the relatively few patients evaluated [27]. Several cases of dysprothrombinemia, characterized by normal levels of a dysfunctional protein, have also been reported [28,29]. No case of completely absent prothrombin has been reported, suggesting that aprothrombinemia is incompatible with life.
●Thrombomodulin dysfunction – A pathogenic variant in the gene for thrombomodulin (TM) has been described (C1611A point mutation) that prevents TM from being sequestered on endothelial cells, leading to extremely high soluble TM levels in plasma and a bleeding disorder [30]. Inheritance is autosomal dominant.
Occasionally, a pathogenic variant in a regulatory gene (rather than the coagulation factor gene itself) can cause a RICD; in such cases, more than one coagulation factor is often affected. As examples:
●Factor V and VIII – An alteration in a gene encoding a transport protein can cause combined deficiency of factors V and VIII. Such patients have low but detectable levels of coagulant activity and protein level of both factors (eg, 5 to 20 percent of normal). Various genes encoding transport proteins have been implicated, including lectin mannose-binding protein (LMAN1, also called ERGIC-53) and multiple coagulation factor deficiency 2 (MCFD2), which encode proteins that form a complex involved in transport of factors V and VIII between endoplasmic reticulum and Golgi, which is important for their secretion [31-34]. (See 'Factor V and VIII combined deficiency (F5F8D)' below and "Genetics of hemophilia A and B", section on 'Combined factor VIII and V deficiency (LMAN1 and MCFD2 genes)'.)
●Vitamin K dependent factors – Abnormalities in factors involved in vitamin K metabolism may cause deficiency of multiple vitamin K dependent factors, both procoagulant and anticoagulant (factors II, VII, IX, X; protein S and protein C) [31,32,35,36]. Examples include a pathogenic variant in the gene encoding the vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum necessary for the carboxylase reaction; and pathogenic variants in the gamma-glutamyl carboxylase gene, which lead to the production of a dysfunctional enzyme [35,37,38]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid", section on 'Mutations' and 'Multiple vitamin K-dependent factor deficiencies' below.)
EPIDEMIOLOGY — Deficiencies of factors XIII, X, VII, V, and II account for only 2 to 5 percent of inherited coagulation factor defects in the general population; the remaining 95 percent of inherited coagulation factor defects are due to deficiencies of factors VIII (hemophilia A), factor IX (hemophilia B), or factor XI [2-4]. The most common RICDs include deficiencies of factor XI and factor VII, followed by factor V, factor X, fibrinogen, and factor XIII [39].
Estimated prevalences for the individual deficiencies are as follows [2-4]:
●Factor XIII – 1 in 2,000,000 (higher in southeastern Iran)
●Factor X – 1 in 1,000,000
●Factor VII – 1 in 500,000
●Factor V – 1 in 1,000,000
●Factor II (prothrombin) – 1 in 2,000,000
●Factor V and VIII combined – 1 in 2,000,000 (higher in Mediterranean countries, Middle Eastern Jews, and non-Jewish Iranians)
By comparison, the prevalence of the more common factor deficiencies is on the order of 1 in 5000 (factor VIII deficiency); 1 in 30,000 (factor IX deficiency); or 1 in 1,000,000 (factor XI deficiency).
Higher prevalences are found in countries/regions with populations in which consanguineous marriages are more common [40]. As an example, in a series of 168 patients diagnosed with an inherited coagulation factor deficiency in Jordan, RICDs constituted 14 percent of the disorders [41]. In a series of 294 individuals in a Rare Bleeding Disorders registry, nine had combined congenital factor deficiencies (3 percent) [42].
The following geographic variations in the prevalence of specific deficiencies have been observed [3,4,43]:
●Individuals of Ashkenazi Jew ancestry have a higher than average prevalence of factor XI deficiency.
●Individuals with ancestry from Asia have a higher than average prevalence of factor XII deficiency (which is not associated with bleeding).
●Individuals with ancestry from Iran have high prevalence of deficiencies of factor XIII, factor X, factor VII, and factor VIII and V combined.
●Individuals with ancestry from Turkey have a higher than average incidence of factor VII deficiency (one-third to one-quarter of RICDs) [44,45].
Equal numbers of males and females are affected by the RICDs, although females often have more bleeding manifestations because of the hemostatic challenges of menstruation and childbirth. This differs from hemophilia A and B, which are X-linked; severe hemophilia affects males almost exclusively.
CLINICAL MANIFESTATIONS — Bleeding is the predominant manifestation of RICDs. Impaired wound healing and early pregnancy loss are seen with some of the RICDs [2-4].
Bleeding onset; sites; severity — The age of bleeding onset in patients with RICDs can vary substantially. In a series of 294 patients in a Rare Bleeding Disorders registry, the median age at diagnosis was seven years (range, birth to 73 years) [42].
The sites and severity of bleeding with RICDs also can be variable. In general, bleeding in patients with RICDs is less severe than that in patients with hemophilia A or B for a comparable degree of factor deficiency [3,4]. However, deaths from intracranial hemorrhage (ICH) have been reported, especially in factor XIII deficiency [42]. (See 'Factor XIII deficiency (F13D)' below.)
In neonates, bleeding with umbilical cord separation is often a presenting finding. ICH can also occur. In older children and adults, common findings may include the following [2-4,42,46-51]:
●Excessive bleeding with trauma or invasive procedures such as circumcision or tooth extraction
●Heavy menstrual bleeding and/or postpartum bleeding
●Muscle and joint bleeding
●Mucosal tract bleeding such as epistaxis
Spontaneous bleeding generally occurs when factor levels are less than 20 percent of normal (table 1). Bleeding with trauma or invasive procedures can occur with higher factor levels. In a series of 294 patients in a Rare Bleeding Disorder registry, 10 to 20 percent of bleeds were severe enough to require transfusion [42].
Heterozygotes generally do not have severe bleeding manifestations, because the normal allele of the factor gene usually provides approximately 50 percent of normal factor level, which is sufficient for hemostasis (see 'Bleeding in heterozygotes' below). An exception is factor VII deficiency, for which bleeding symptoms correlate less well with factor activity levels (see 'Factor VII deficiency (F7D)' below). Other genetic changes may also modify bleeding severity (eg, coinheritance of a thrombophilic mutation such as factor V Leiden may reduce bleeding) [52].
Bleeding severity may be graded for the purposes of clinical trials or initiating therapy, although clinical judgment is required to determine if bleeding is clinically important for each patient [53]. The European Network of Rare Bleeding Disorders classifies bleeding as follows [53]:
●Asymptomatic: no bleeding
●Grade I: bleeding after trauma or antithrombotic therapy
●Grade II: spontaneous minor bleeding (eg, epistaxis, heavy menstrual bleeding)
●Grade III: spontaneous major bleeding (eg, umbilical, intramuscular, joint, central nervous system, gastrointestinal)
Frequent, severe, or chronic bleeding can lead to anemia and iron deficiency. Even seemingly minor bleeding, such as epistaxis, can cause iron deficiency if it occurs over longer periods of time. In a series of 294 patients in a Rare Bleeding Disorder registry, anemia occurred with up to half of bleeding episodes, most often in homozygotes with factor II, V, or X deficiency [42].
Chronic complications of joint bleeds, such as target joint development and muscle contracture, can also occur; these were reported in 7 to 23 percent of patients with musculoskeletal bleeding in a series of 294 patients from a Rare Bleeding Disorder registry [42]. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Hemophilic arthropathy'.)
In contrast to mucosal and deep tissue bleeding, individuals with RICDs generally do not have petechiae and bleeding at sites of minor cuts, which are characteristic of thrombocytopenia and platelet function defects (table 2).
Bleeding in heterozygotes — Individuals who are heterozygous for RICDs may also be at risk for bleeding, especially during surgical procedures or other hemostatic challenges such as pregnancy or trauma [54].
Features other than bleeding — Some RICDs are associated with other manifestations that may relate to their effects in pregnancy physiology, wound healing, or anticoagulant functions.
●Pregnancy loss – The relationship between coagulation factors and pregnancy physiology is complex. Cases of recurrent pregnancy loss associated with RICDs have been reported for factor XIII, factor X, and fibrinogen [55,56].
●Impaired wound healing – Fibrin crosslinking contributes to wound healing. Thus, impaired wound healing is a feature of some of the RICDs that interfere with fibrin crosslinking, including factor XIII deficiency and fibrinogen disorders. (See 'Factor XIII deficiency (F13D)' below and "Disorders of fibrinogen", section on 'Obstetric complications'.)
●Thrombosis – Paradoxically, some factor deficiencies are associated with thrombosis rather than bleeding, which is counterintuitive given the factors' importance in clot production [39,57]. The etiology of thrombosis is likely to be multifactorial. Major contributing factors may include the presence of a central venous catheter; use of coagulation factor replacement therapy, some of which may be prothrombotic; and coexisting inherited or acquired prothrombotic risk factors (eg, factor V Leiden mutation, immobility, oral contraceptives) [39].
Thrombosis has been reported with factor XI, factor VII, and factor V deficiencies, which can also be associated with bleeding; and factor XII deficiency, which is not associated with bleeding. (See "Factor XI (eleven) deficiency" and 'Factor VII deficiency (F7D)' below and 'Factor V deficiency (F5D)' below and "Overview of the causes of venous thrombosis", section on 'Factor XII deficiency'.)
In contrast, thrombotic events have not been reported with deficiencies of factor X or prothrombin (factor II).
RICDs do not appear to be protective against arterial thrombosis such as with acute coronary syndromes. This was illustrated in a series of 53 patients with RICDs who developed myocardial infarction or other acute coronary syndromes; these patients also had typical risk factors for coronary heart disease (eg, smoking, hypertension, hypercholesterolemia) [58].
●Bone cysts – Cases of bone cysts in patients with RICDs have been reported, but a causal relationship has not been established [59,60].
LABORATORY FINDINGS — The prothrombin time (PT), the activated partial thromboplastin time (aPTT), or both may be prolonged in patients with RICDs, depending on the factor affected and the severity of deficiency. The measurement(s) affected reflect the position of the clotting factor in the intrinsic, extrinsic, or common pathway as tested in the laboratory (figure 2). (See "Clinical use of coagulation tests".)
Patients with mild deficiency may have normal PT and aPTT because the factor activity level must be reduced substantially (eg, <20 percent) to affect the coagulation times in vitro. Patients with a more severe coagulation factor deficiency typically have the following laboratory findings (table 3).
●Factor XIII – PT and aPTT normal; clot solubility in 5M urea or 1 percent monochloroacetic acid may be enhanced in patients with severe deficiency
●Factor XII – PT normal, aPTT prolonged (not associated with clinical bleeding)
●Factor XI (hemophilia C) – PT normal, aPTT prolonged
●Factor X – PT and aPTT both prolonged
●Factor IX (hemophilia B) – PT normal, aPTT prolonged
●Factor VIII (hemophilia A; some forms of VWD) – PT normal, aPTT prolonged
●Factor VII – PT prolonged; aPTT normal
●Factor V – PT and aPTT both prolonged
●Factor V and VIII combined – PT and aPTT both prolonged
●Factor II (prothrombin) – PT and aPTT both prolonged
●Fibrinogen – PT and aPTT both prolonged
●Combined vitamin K dependent factor deficiency – PT and aPTT both prolonged
The corresponding factor activity level, measured in international units/mL, will also be low; typically symptomatic patients will have levels in the range of 1 to 10 percent (0.01 to 0.10 international units/mL) and asymptomatic heterozygotes will have levels in the range of 20 to 70 percent (0.20 to 0.70 international units/mL).
In contrast to prolonged coagulation times and/or low coagulation factor levels, patients with RICDs do not have thrombocytopenia or morphologic abnormalities of platelets or other blood cells. These findings should prompt evaluation for other disorders in addition to, or instead of, an RICD. (See "Approach to the adult with a suspected bleeding disorder".)
DIAGNOSTIC EVALUATION — All patients should have a complete history of hemostatic challenges (eg, dental procedures, surgery, trauma, menstruation, childbirth) and bleeding manifestations, as well as other risk factors for bleeding such as antiplatelet medications (see "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding score'). Ethnic background and the possibility of consanguineous marriage may also be relevant.
The laboratory evaluation differs depending on whether the family history of a specific factor defect is known, because this information narrows the number of factor levels that need to be measured.
Genetic testing may be appropriate in some patients (eg, to facilitate preconception counseling) and for research purposes. However, genotyping is unavailable in many cases. In approximately 10 to 20 percent of patients with a factor deficiency, no mutation is found. These cases may be due to defects in noncoding regions, to large heterozygous deletions, or to large genomic rearrangements [61-63]. (See 'Inheritance' above.)
Known family history — For patients with a known family history of a factor deficiency, the pedigree is examined for the inheritance pattern. Screening tests of hemostasis and laboratory testing for the known deficiency is appropriate by measuring factor activity levels [2-4].
The timing of testing depends on the clinical setting. In vitro fertilization with preimplantation genetic diagnosis and selection of embryos lacking the variant (or heterozygous rather than homozygous) may be possible in some cases.
Neonates should be tested after birth, preferably on cord blood, and invasive procedures such as circumcision should be delayed until the diagnosis has been confirmed or excluded. It is important to use appropriate neonatal reference levels for coagulation factors. Additional neonatal management may be similar to infants with possible hemophilia A or B. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Obstetric considerations'.)
Rarely, a family presents with a bleeding disorder that appears to follow Mendelian inheritance, but a specific coagulation factor deficiency cannot be identified with standard laboratory evaluation. Referral to a center with expertise in RICDs may be appropriate in such cases.
New presentation — For patients with a new presentation of unexplained bleeding, laboratory testing is usually done in a stepwise fashion to determine the type of disorder (eg, coagulation factor versus platelet disorder; inherited factor deficiency versus acquired factor inhibitor). This approach is discussed in detail separately. (See "Approach to the adult with a suspected bleeding disorder" and "Approach to the child with bleeding symptoms".)
The possibility of an RICD may be considered in a patient with screening tests of coagulation (eg, PT, aPTT, factor level) that demonstrate a coagulation factor deficiency (eg, prolonged PT and/or prolonged aPTT and/or decreased factor activity level) that does correct with mixing studies, along with a normal platelet count and platelet morphology. (See 'Laboratory findings' above.)
For those with unexplained bleeding and a prolonged PT and/or aPTT, it is reasonable to test the factor(s) expected to be deficient based on which coagulation test is prolonged (table 3).
●Prolonged PT alone – Test factor VII activity
●Prolonged aPTT alone – Test factor VIII, factor IX, and factor XI activity
●Prolonged PT and aPTT – Test factor V, factor X, factor II (prothrombin), and fibrinogen
●Normal PT and aPTT – Test factor XIII activity
Although it is more cost effective to do this testing sequentially, it may be appropriate to order some or all of this testing simultaneously if the patient is experiencing active bleeding or requires an urgent invasive procedure. For neonates, it is important to use appropriate neonatal reference levels because normal values for some coagulation factors differ during the neonatal period. Genomic sequencing-based methods that could allow screening for a large number of possible mutations are under development [64,65].
Factor activity levels will also suggest whether the individual is likely to be a heterozygous carrier or homozygous for an RICD. The implications include the need for and amount of factor replacement needed prior to an invasive procedure or pregnancy, and the information conveyed during genetic counseling. (See 'Invasive procedure/surgery' below and 'Heavy menstrual bleeding and pregnancy' below and 'Education and counseling' below.)
Diagnostic criteria — Diagnosis of an RICD requires documentation of a specific factor deficiency (or rarely, combination of deficiencies) not caused by an inhibitor, in the proper clinical setting (eg, bleeding pattern, pedigree showing the expected inheritance pattern). Factor activity level below 50 percent of normal is generally considered to represent a deficiency; the European Network of Rare Bleeding Disorders does not specify an upper limit of factor activity level for diagnosis. Demonstration of a corresponding molecular defect is helpful but not required.
Rare exceptions include disorders in which the factor activity level is normal or even increased, but the protein has altered function (eg, certain factor V mutations, thrombomodulin mutation). (See 'Genetics' above.)
It may be important to specify whether an individual is heterozygous or homozygous for a defect, for purposes of genetic counseling; however, management is based on factor activity levels and clinical bleeding rather than on a specific genotype.
GENERAL ASPECTS OF MANAGEMENT — The optimal therapy for RICDs is often unknown due to the lack of high-quality evidence from randomized trials. Ideally, management should be guided with the input of a Hemophilia Treatment Center or a clinician with expertise in coagulation disorders, especially in preparation for an invasive procedure or pregnancy [54,66].
Recommendations presented here are based on our clinical experience gained with Iranian, Italian, and United States series of patients [2-4,42,46-51,67,68]. These are largely consistent with 2014 guidance from the British Committee for Standards in Haematology/United Kingdom Haemophilia Centre Doctors' Organization and 2011 guidance the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation in the United States [69,70].
Acute bleeding — Therapy for bleeding depends on bleeding severity, specific factor defect, and availability of factor replacement products. Each patient is managed individually with the early input from the consulting specialist.
A general approach to treatment of bleeding is as follows [2-4]:
●Factor replacement – Factor replacement is the mainstay of therapy for bleeding; the deficient factor should be replaced as rapidly as possible. Options in order of preference include plasma-derived or recombinant factor concentrate, prothrombin complex concentrate (PCC), and Fresh Frozen Plasma (FFP), depending on availability (table 4). All coagulation factors are proteins, so they are administered intravenously. The frequency of dosing and target for factor activity level depends on the half-life of the infused factor and activity level required for hemostasis (table 1).
•Factor XIII deficiency – Bleeding can be treated with recombinant factor XIII A subunit or a plasma-derived factor XIII concentrate. If one of these is not available, a plasma product such as Fresh Frozen Plasma (FFP; solvent/detergent [S/D] treated if available) or cryoprecipitate may be used. (See 'Factor XIII deficiency (F13D)' below and 'Recombinant and purified factors' below and 'PCCs' below and 'Plasma products' below.)
•Factor X deficiency – Bleeding can be treated with a plasma-derived factor concentrate (if available) or a 4 factor or 3 factor prothrombin complex concentrate (PCC) (table 5). Importantly, PCCs carry a prothrombotic risk, so they are not used for less severe bleeding. If a factor concentrate or PCC is not available, a plasma product such as FFP may be used. (See 'Factor X deficiency (F10D)' below and 'PCCs' below and 'Plasma products' below.)
•Factor VII deficiency – Factor VII deficiency can be treated with recombinant activated factor VII (rfVIIa). If this is not available, a 4 factor PCC (unactivated or activated) (table 5) or FFP (S/D treated if available) may be used. (See 'Factor VII deficiency (F7D)' below and 'Recombinant and purified factors' below and 'PCCs' below and 'Plasma products' below.)
•Factor V deficiency – Specific recombinant or plasma-derived factor concentrates are not available for factor V replacement. FFP (S/D treated if available) must be used. (See 'Factor V deficiency (F5D)' below and 'Plasma products' below.)
•Factor II (prothrombin) deficiency – Bleeding can be treated with a 3 factor or 4 factor prothrombin complex concentrate (PCC) (table 5). Importantly, PCCs carry a prothrombotic risk, so they are not used for less severe bleeding. If a PCC is not available, FFP (S/D treated if available) may be used. (See 'Factor VII deficiency (F7D)' below and 'PCCs' below and 'Plasma products' below.)
●Antifibrinolytic agents – An antifibrinolytic agent, such as tranexamic acid or ε-aminocaproic acid, may also be useful in addition to coagulation factor replacement for severe bleeding and instead of replacement therapy for more minor bleeding, particularly in mucosal sites. (See 'Antifibrinolytic agents' below.)
●Other interventions – Other appropriate interventions for any clinically significant bleeding include rapid and continuous hemodynamic assessment; optimization of body temperature, blood pH, and electrolyte balance, especially calcium; and transfusions if required. (See "Use of blood products in the critically ill" and "Massive blood transfusion".)
Invasive procedure/surgery — Planning for invasive procedures and surgery should include an assessment of factor levels, the availability of appropriate replacement products and/or hemostatic agents, and the expertise to manage bleeding. Hemostatic levels of the deficient factor should be maintained for two to three days for minor surgery, and until healing is complete following major surgery. Case series of specific types of surgery have been published [71].
Heavy menstrual bleeding and pregnancy
●Heavy menstrual bleeding – In addition to the measures outlined above for acute bleeding, chronic therapy for heavy menstrual bleeding may include the use of estrogen-progestin contraceptives (see "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management"). Some patients may benefit from prophylactic factor replacement starting at the time of menstruation onset.
Attention to iron status and iron replacement if needed is also appropriate. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation' and "Treatment of iron deficiency anemia in adults".)
●Attempted conception and pregnancy – Cases of early and late recurrent pregnancy loss and premature labor have been reported with factor XIII deficiency and factor X deficiency. Management is individualized based on the clinical circumstances; in some cases prophylactic factor replacement therapy has been used [72,73]. (See 'Factor XIII deficiency (F13D)' below and "Disorders of fibrinogen", section on 'Conception and pregnancy'.)
Some coagulation factor levels rise during pregnancy, including fibrinogen, prothrombin, factor VII, VIII, X, XII, and XIII (table 6); this may contribute to a prothrombotic state. Pregnancy should be managed by a multidisciplinary team with expertise in the management of bleeding disorders and high-risk pregnancy. Planning for delivery, including possible need for surgery and/or neuraxial anesthesia, should include input from the consulting anesthesiologist, availability of an appropriate factor replacement product if needed, and expertise for the use of the replacement product.
●Delivery and postpartum – Delivery should occur at a center with experience in managing bleeding disorders. Management may be similar to that in individuals with hemophilia, although this approach has not been validated in clinical studies. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Obstetric considerations'.)
The risk of primary and secondary postpartum hemorrhage is increased in patients with RICDs, due to the hemostatic challenges of delivery and the return of factor activity to baseline levels. Testing of the newborn for the RICD is appropriate if both parents are known to carry the genetic defect. (See 'Known family history' above.)
Products for treating bleeding
Recombinant and purified factors
●Recombinant – Recombinant proteins are produced by expressing and purifying the factor in the laboratory so that exposure to human plasma is eliminated. Only the following recombinant coagulation factors are available:
•Factor XIII – Recombinant human factor XIII A subunit (Tretten) is used for the treatment of factor XIII deficiency; in which most cases are due to deficiency of the A subunit. (See 'Factor XIII deficiency (F13D)' below.)
•Factor VII – Recombinant human factor VII, in the activated form (rFVIIa; NovoSeven RT, Niastase, Niastase RT), is used for the treatment of factor VII deficiency. (See 'Factor VII deficiency (F7D)' below.)
The major advantage of recombinant products is avoidance of volume overload and elimination of exposure to potential pathogens from human plasma. The major disadvantages are cost and limited availability. There is a Boxed Warning for rFVIIa regarding the risks of arterial and venous thrombosis.
●Plasma-derived concentrates – Concentrates of individual coagulation factors can also be purified from human plasma, analogous to factor VIII and factor IX concentrates for hemophilia A and B. Concentrates for factors XIII, X, VII, and fibrinogen are available in some European countries, and factor XIII and factor X concentrates are available in the United States [2,74-76]. The main advantages of single factor concentrates include a smaller volume of infusion, fewer allergic reactions, and use of viral inactivation procedures during production. Limited availability and higher cost are the major disadvantages.
PCCs — Prothrombin complex concentrates (PCCs) are coagulation factor concentrates isolated from human plasma using a process that co-purifies vitamin K-dependent coagulation factors together. PCCs were originally developed for factor replacement in hemophilia B, but are no longer used in this condition due to the availability of purified plasma-derived and recombinant factor IX. Additional uses have included reversal of anticoagulation from a vitamin K antagonist such as warfarin, and occasionally severe bleeding of other etiologies. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'PCC products'.)
All PCCs contain factors II, IX, and X. The specific composition of 3 factor, 4 factor, and activated PCCs is as follows (table 5):
●4 factor PCCs contain factors II, VII, IX, and X
●3 factor PCC contain factors II, IX, and X (without appreciable factor VII)
●Activated PCC (aPCC; eg, factor eight inhibitor bypassing activity [FEIBA]) contains factors II, VIIa, IX, and X
Dosing depends on baseline factor levels and desired final factor concentration. Prescribing information for the specific product should be consulted prior to use. In order to reduce the risk of a prothrombotic effect, levels of vitamin K dependent factors should be monitored, and levels of the unaffected factors should be kept below 150 percent [2].
Advantages of PCCs include avoidance of volume overload and reduced pathogen exposure due to viral inactivation procedures. A disadvantage is their potential prothrombotic effect, which has been documented in a variety of small series and case reports. Some PCCs also contain protein S and protein C, as well as heparin added during purification. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Individual procoagulant factors'.)
Plasma products — Fresh Frozen Plasma (FFP) contains all of the coagulation factors. By definition, each mL of plasma contains one unit of each factor. Other plasma products include Thawed Plasma and Plasma Frozen Within 24 Hours After Phlebotomy (PF24). These are considered clinically interchangeable with FFP, with the exception that Thawed Plasma is not considered adequate as the sole source of factors V and VIII, and its use in neonates has not been evaluated. (See "Clinical use of plasma components", section on 'Plasma products'.)
Pathogen reduction/viral inactivation is done by treating plasma with a solvent and nonionic detergent prior to freezing to produce solvent/detergent plasma (S/D plasma). Several S/D plasma products are available in European countries, and an S/D plasma product was approved in the United States in 2013 (GAMMAGARD S/D) [77]. (See "Pathogen inactivation of blood products", section on 'Plasma/FFP'.)
Advantages of FFP and related plasma products are low cost and wide availability. Disadvantages include the risks of substantial volume overload, transfusion reactions, and potential exposure to pathogenic organisms. Liters of FFP may be required to raise factor levels to 50 percent, which are likely to cause significant volume overload, may take hours to days to administer, and is associated with a risk of several types of transfusion reactions. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)
Cryoprecipitate is the precipitate that forms when FFP is thawed at 4°C and then centrifuged. It contains factor VIII, fibrinogen, factor XIII, and von Willebrand factor in more concentrated form than FFP. Institutional guidelines should be followed regarding the number of units of FFP per "bag" of cryoprecipitate, as this may vary. (See "Clinical use of Cryoprecipitate".)
Antifibrinolytic agents — Antifibrinolytic agents are useful for treating severe and minor bleeding.
●For severe bleeding, an antifibrinolytic agent may be given in combination with specific factor replacement, or during administration of FFP.
●For minor bleeding, an antifibrinolytic agent may be sufficient to improve hemostasis. This is especially true for mucosal bleeding (eg, dental procedures, tonsil/adenoid procedures, epistaxis, heavy menstrual bleeding), in which fibrinolysis may make a large contribution to bleeding [78-80].
Available agents include tranexamic acid (TXA) and ε-aminocaproic acid (EACA). These disrupt the ability of plasmin to cleave fibrin; thus, they enhance clot stability. There are no large studies evaluating efficacy in RICDs; clinicians should use the agent with which they are most familiar. There is no benefit combining the two antifibrinolytic agents.
●TXA can be administered orally or intravenously. A typical dose is 15 to 20 mg/kg or 1 to 1.5 grams every 8 to 12 hours, intravenously or orally, for the duration of bleeding. Intravenous doses are less well characterized; doses of 10 to 20 mg per kg as an intravenous bolus followed by 10 mg per kg intravenously every six to eight hours have been used in patients with major bleeding, hemophilic bleeding, or after major trauma. TXA excretion is highly dependent on renal function; the interval between doses is substantively increased in patients with renal insufficiency. Nausea and diarrhea are the most common adverse events [81].
●EACA can be administered orally or intravenously. A typical starting dose is 2 grams intravenously every six hours; as much as 1 gram intravenously every hour can be given. EACA can also be administered orally at a dose of 3 grams three to four times per day.
Oral rinses containing TXA (5 percent) or EACA (1.25 g/5 mL) can also be used for dental procedures associated with bleeding.
Advantages of antifibrinolytic agents include wide availability, low cost, and safety; thrombotic risk is not increased with these agents. Disadvantages include insufficient hemostatic effect when used as a single agent in major surgery or major bleeding.
Anemia/iron deficiency — Attention to the possibility of iron deficiency, and iron replacement if needed, are important components of therapy for patients with chronic or frequent bleeding episodes. Diagnosis and management of iron deficiency are discussed in detail separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron deficiency in infants and children <12 years: Treatment" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)
Complications of therapy — Potential complications of factor replacement include the development of an antibody to the foreign protein (ie, inhibitor), transfusion reactions, and exposure to infectious organisms with products derived from human plasma. Complications related to central venous catheters used for administering replacement products can also be seen. (See "Overview of complications of central venous catheters and their prevention in adults".)
●Inhibitors – The likelihood of inhibitor development in RICDs is generally on the order of a few percent; this is much lower than the rate of 30 to 35 percent in hemophilia A. Inhibitors in RICDs may be more likely in patients with undetectable factor levels, in whom the infused factor may be seen as foreign.
•Two patients in a Rare Bleeding Disorder registry developed inhibitors following treatment (3 percent) [42]. One was a patient with factor V deficiency treated with FFP, and the other was a patient with factor XIII deficiency treated with a factor XIII concentrate.
•Inhibitors were reported in 3 of 72 patients with factor XIII deficiency (4 percent), although only one was clearly therapy-related [82].
•Inhibitors were reported in 2 of 101 patients with factor VII deficiency after receiving factor VII replacement products (one receiving rFVIIa and one receiving factor VII concentrate) [83].
Additional discussion of inhibitors in patients with deficiencies of factors VIII, IX, or XI (hemophilia A, B, or C) is presented separately; the applicability of this information to inhibitors in patients with RICDs is unknown. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication" and "Factor XI (eleven) deficiency", section on 'Inhibitor development'.)
●Transfusion reactions – Exposure to plasma products can result in transfusion reactions including allergy, anaphylaxis, or transfusion related acute lung injury (TRALI). In a series of 294 patients from a Rare Bleeding Disorder registry, allergic reactions occurred in 2 to 26 percent and anaphylaxis in 2 to 5 percent of patients who received plasma products [42]. The evaluation and management of these reactions are discussed in details separately. (See "Approach to the patient with a suspected acute transfusion reaction" and "Immunologic transfusion reactions" and "Transfusion-related acute lung injury (TRALI)".)
●Infections – Bloodborne viral infections are a potential complication of any plasma exposure. The risk of bloodborne infections with factor concentrates is substantially lower due to additional steps during manufacture (eg, heat treatment, solvent/detergent treatment, 20 nm filtration); however, some non-enveloped viruses, such as parvovirus, may be present in factor concentrates. In patients with RICDs, seropositivity for hepatitis viruses is in the range of 15 percent for hepatitis B and 25 to 50 percent for hepatitis C [42,50,51]. HIV seropositivity was seen 1 percent of patients in the Rare Bleeding Disorder registry; none of the patients in a series of 93 patients in Iran were HIV seropositive [42,51].
Education and counseling — RICDs are relatively neglected diseases. Patients and their families usually have less extensive information on their condition than those with hemophilia. Prevention of RICDs relies on genetic counseling and preimplantation genetic diagnosis, which may not be possible for the majority of patients. (See "Genetic testing" and "Preimplantation genetic testing".)
For patients who have inherited a RICD, prevention of bleeding focuses on avoiding or minimizing trauma (eg, avoiding high bleeding risk activities), and avoiding the use of medications that impair hemostasis, such as aspirin, nonsteroidal antiinflammatory drugs, or certain herbal preparations. (See "Overview of herbal medicine and dietary supplements", section on 'Surgical patients'.)
Vaccinations — Appropriate vaccination is important for individuals with RICDs [54]. Vaccinations should follow the appropriate schedule for the age and expected exposures for the patient (eg, from travel). (See "Standard immunizations for nonpregnant adults" and "Immunizations for travel" and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)
The route of vaccination (intramuscular versus subcutaneous) depends on the specific vaccination. For vaccinations that are thought to have comparable efficacy regardless of administration route, subcutaneous administration has a theoretical advantage in reducing the risk of intramuscular hematomas. Examples include pneumococcal polysaccharide, inactivated polio, hepatitis A, and hepatitis B vaccines [84].
All vaccinations should be administered using a fine gauge needle (eg, 23 gauge or smaller caliber), and firm pressure should be held without rubbing.
MANAGEMENT OF SPECIFIC DEFICIENCIES
Factor XIII deficiency (F13D) — Factor XIII deficiency is characterized by spontaneous and provoked bleeding in homozygotes (including umbilical cord, surgical, joint, and intracranial hemorrhage) and heavy menstrual bleeding; patients may also have recurrent pregnancy loss and impaired wound healing [51,85-88].
Most patients with factor XIII activity level <5 percent are symptomatic from bleeding, and the severity of bleeding correlates relatively well with plasma factor XIII levels. In a 2017 series involving 64 patients with factor XIII deficiency from the Prospective Rare Bleeding Disorders Database, a value of 15 percent (15 international units/dL) was found to be the level below which the risk of spontaneous major bleeding increases [89]. Most of the patients with undetectable factor XIII levels presented with bleeding in the neonatal period. Individuals with B subunit deficiency may have milder bleeding than those with A subunit deficiency [90]. Data from an international registry of 104 patients with factor XIII deficiency reported the following frequencies [90]:
●Subcutaneous bleeding – 59 patients (57 percent)
●Delayed umbilical cord bleeding – 58 patients (56 percent)
●Muscle hematoma – 51 patients (49 percent)
●Postoperative bleeding – 42 patients (40 percent)
●Hemarthrosis – 37 patients (36 percent)
●Intracerebral bleeding – 35 patients (34 percent)
●Gastrointestinal bleeding – 6 patients (6 percent)
The high frequency of intracranial bleeding has been confirmed in other series [91].
In addition to bleeding, reports have suggested that patients with severe factor XIII A subunit deficiency are unlikely to have a successful term pregnancy without replacement therapy [92-95]. This may be due to a role of the factor XIII A subunit in anchoring the cytotrophoblast [96-99].
Several factor XIII replacement products are available for the treatment and prophylaxis of bleeding in patients with factor XIII deficiency. These include recombinant factor XIII A subunit (Tretten; produced in yeast cells; approved by the US Food and Drug Administration [FDA] in December 2013), and factor XIII purified from human plasma (Fibrogammin and Fibrogammin-P in Europe, South America, and Asia; Corifact in the United States) [92,100-106]. Factor XIII replacement is facilitated by the long half-life of factor XIII (11 to 14 days), allowing infusion as infrequently as once per month [107]. Further, effective hemostasis can be achieved with factor XIII levels as low as 2 to 5 percent [107]. For patients who do not have access to these products, Fresh Frozen Plasma (FFP; solvent/detergent treated if available) or cryoprecipitate can also be used to supply factor XIII.
The following dosing strategies are used:
●Bleeding – Patients with acute bleeding should receive factor XIII replacement as rapidly as possible, with a goal of raising the factor XIII level to >5 percent, which is often sufficient for hemostasis (table 4). In some major or life-threatening bleeding, higher doses may be used. Typically a single dose of the replacement product is sufficient because the half-life of factor XIII is long.
•Recombinant factor XIII A subunit (Tretten; NovoThirteen) – 35 international units/kg
•Plasma-derived factor XIII concentrate: Corifact – 40 international units/kg; Fibrogammin, Fibrogammin P – 10 to 20 international units/kg
•FFP (solvent/detergent [S/D] treated if available) – 2 to 3 mL/kg
•Cryoprecipitate – 1 bag/10 kg
The concentration of the recombinant and plasma-derived factor XIII products depends on the reconstitution volume and should be checked closely. For the recombinant product, the concentration is approximately 833 international units/mL (range, 667 to 1042 depending on the vial).
●Perioperative – Dosing is similar to dosing to treat bleeding. If a routine prophylaxis dose was given within the previous seven days, additional doses may not be needed. If the last prophylactic dose was given more than seven days ago, additional full doses or partial doses may be needed. In a series of six patients undergoing surgical procedures, factor XIII concentrate was given preoperatively to all of the patients (25 to 40 international units/kg); in three cases additional doses were given intraoperatively or postoperatively [108]. Repeat doses were required in two patients with excessive bleeding (one wisdom teeth extraction, one cardiopulmonary bypass); their factor XIII levels at the time of bleeding were approximately 40 percent.
●Pregnancy – Administration of factor XIII must begin by five weeks gestational age to prevent miscarriage [96]. Factor activity levels are generally raised to at least 2 to 3 percent, and preferably above 10 percent [109]. A proposed dosing regimen uses factor XIII concentrate at a dose of 250 international units once weekly through week 22, followed by 500 international units once weekly from week 23 onward, and 1000 international units at the onset of labor to achieve a factor activity level >30 percent for delivery [109]. Other groups have administered factor XIII concentrate at 10 international units/kg every two weeks throughout pregnancy [110].
●Prophylaxis – For patients who have frequent bleeding or a factor XIII activity level ≤5 percent, we recommend regular prophylactic therapy with recombinant factor XIII A subunit or a plasma-derived factor XIII concentrate, at doses specified above for bleeding [42,51,87,111]. Individuals with B subunit deficiency should use the plasma-derived concentrate, which contains both A and B subunits. For patients who do not have access to a recombinant product or factor XIII concentrate, FFP (S/D treated if available) or cryoprecipitate may be used. The dosing interval is approximately every 20 to 30 days (every three weeks to monthly); dose and/or dosing interval may be adjusted for breakthrough bleeding and/or to maintain trough factor XIII activity levels ≥5 percent.
The efficacy of factor XIII replacement in the treatment of bleeding and in routine prophylaxis is illustrated in the following studies; differences in study populations preclude direct comparison between the recombinant product and plasma-derived concentrates:
●Recombinant factor XIII A subunit – In a 2012 prospective study in the prophylactic setting, the recombinant product (designated rFXIII-A2) was administered as 35 international units/kg intravenously in a single dose, once per month for one year, to 41 patients with inherited factor XIII deficiency [107]. Patient ages ranged from 7 to 60 years (mean age, 26 years). Annualized bleeding rates (ABRs) were lower with recombinant factor XIII than with historical controls receiving prophylaxis or on-demand therapy with other factor XIII preparations (ABR 0.048, versus 0.33 for other prophylactic therapy or 2.91 for on-demand therapy). Of the 41 patients, 37 had no bleeding that required therapy (90 percent). There were five bleeds in four patients, all trauma-related, that required therapy; and 48 bleeds that did not require therapy. There were no intracranial bleeds and no severe internal bleeding. Therapy was generally well tolerated, and there were no thromboembolic events. Transient, low-titer, non-neutralizing antibodies to factor XIII developed in four patients (10 percent), three of whom discontinued therapy. Mean peak levels of factor XIII activity were 0.77 ± 0.20 international units/mL, and mean trough (pre-dose) levels were 0.19 ± 0.05 international units/mL, confirming the long half-life of factor XIII and the appropriateness of monthly dosing. A 2018 report including updated results, additional patients, and the use of rFXIII-A2 or plasma-derived factor XIII in trauma-induced bleeding and surgery also showed excellent hemostatic efficacy and no additional safety concerns [112].
A pharmacokinetic study in 23 patients receiving monthly recombinant factor XIII-A subunit (35 international units/kg once per month) reported no bleeding episodes; factor XIII activity levels were consistently greater than 1 percent [113].
●Plasma-derived factor XIII concentrate – A prospective study evaluated the efficacy and safety of a plasma-derived concentrate, administered at 40 international units/kg once every four weeks, adjusted to maintain a trough factor XIII activity level of 5 to 20 percent for one year in 41 patients with inherited factor XIII deficiency [114]. Patient ages ranged from 1 to 42 years (median, 19 years). There were nine episodes of minor bleeding induced by trauma or surgery, and no spontaneous bleeding episodes. There was one minor infusion reaction, and no serious adverse events related to therapy.
Another study prospectively evaluated the efficacy and safety of a factor XIII concentrate in 19 patients with inherited factor XIII deficiency [104]. Patient ages ranged from 18 days to 47 years (median, 13 years). Prophylactic therapy was used in 16, at doses ranging from 2.5 to 15.6 international units/kg per week, given as a single injection once every four or six weeks. Ten of the 16 patients (63 percent) had no bleeding. For the remaining six patients, bleeding was most common in those receiving the lowest weekly dose (<5 international units/kg). Six patients in the original cohort of 19 were initially treated with on-demand therapy, of which five had bleeding, including one intracranial hemorrhage; three of these patients were switched to prophylactic therapy, after which no further bleeding occurred. There were no serious adverse events or thromboses.
A retrospective review of prophylactic therapy with factor XIII concentrate in seven patients compared bleeding rates before and after initiation of prophylactic therapy [111]. The mean annualized bleeding rate decreased to 0.2 events with prophylaxis, versus 2.5 events before prophylaxis. There were no severe bleeds once prophylaxis was initiated.
Factor XIII replacement products are generally well tolerated. The major disadvantages are limited availability and high cost. Potential complications include complications of the central venous catheter, development of an inhibitor, and adverse events from exposure to a plasma-derived product. (See "Overview of complications of central venous catheters and their prevention in adults" and 'Complications of therapy' above.)
FFP and cryoprecipitate are widely available, but their major disadvantages are the volume of administration required to raise factor XIII levels, transfusion reactions, and infectious complications.
Factor X deficiency (F10D) — Factor X deficiency is associated with bleeding in individuals who have a factor X activity level <10 percent (0.10 international units/mL). This includes excessive bleeding after invasive procedures, intracranial, umbilical cord, joint and muscle bleeding [55,115]. Life-threatening bleeding may occur. The risk of bleeding correlates relatively well with factor X activity levels in plasma.
Plasma-derived factor X concentrates for treating bleeding are available in some European countries and became available in the United States in October 2015 (table 4). Dosing is 25 international units/kg, repeated daily until bleeding stops [76]. In a series of 10 individuals with severe factor X deficiency, this product provided excellent hemostasis and was well-tolerated; the median half-life of the product was 27 hours [116].
In institutions where a factor X concentrate is not available, bleeding can be treated with a 3 factor or 4 factor prothrombin complex concentrate (PCC; dose: 20 to 30 international units/kg) (table 5) or a plasma product such as Fresh Frozen Plasma (FFP; solvent/detergent treated if available; dose: 15 to 20 mL/kg). The short half-life of factor X (40 to 60 hours) necessitates administration of the replacement product on a daily basis or as a continuous infusion [117]. The target factor X level is >20 percent of normal. Patients receiving PCC should be closely monitored to avoid allowing the levels of the other factors (eg, II, VII, IX) to exceed 150 percent of normal.
Decisions regarding the use of prophylactic therapy and management during pregnancy are made on a case-by-case basis, ideally in consultation with a hemophilia treatment center.
Factor VII deficiency (F7D) — Factor VII deficiency presents with a wide spectrum of clinical severity that correlates poorly with plasma factor VII levels [42,47,118-122]. Bleeding is unlikely with factor VII activity levels >10 percent, but some patients with undetectable levels are asymptomatic [122]. The most common symptoms are excessive bleeding after invasive procedures; heavy menstrual bleeding; and mucosal tract, joint, and muscle bleeding [123]. Intracranial bleeding, reported to be frequent and severe after birth in one series of factor VII-deficient patients, was rare in Iranian, Italian, and American cohorts; the overall incidence of intracranial bleeding is approximately 20 percent [42,47,124].
Heterozygotes for a factor VII defect may also be symptomatic. This was demonstrated in a review of 717 patients in the Greifswald Registry of Factor VII Deficiency who were homozygous, compound heterozygous, or heterozygous for factor VII deficiency [123]. One-fifth of heterozygotes had spontaneous bleeding symptoms, although none had spontaneous intracranial bleeding; the mean factor VII level in this group was 39 percent.
Thrombosis (deep veins, arterial) has been reported in approximately 3 to 4 percent of patients with factor VII deficiency, including individuals with severe deficiency, in the setting of factor replacement or spontaneously [39].
Bleeding can be managed with recombinant human factor VII in the activated form (rFVIIa; NovoSeven RT, Niastase, Niastase RT), which became available in 1999; or plasma-derived factor VII concentrates, which are available in some European countries (table 4).
Recommended dosing of rFVIIa is 15 to 30 mcg/kg every 12 hours, and dosing of factor VII concentrates is 30 to 40 international units/kg, repeated every 6 to 12 hours, with the goal of maintaining factor VII activity levels above 15 to 20 percent. Higher doses may be required in severe or life-threatening bleeding.
Evidence for the efficacy of rFVIIa and plasma-derived factor VII concentrates in inherited factor VII deficiency comes from small series and case reports. As examples:
●A retrospective series of administration of rFVIIa for 39 bleeding episodes in 30 patients reported marked reduction in bleeding or cessation of bleeding [125]. Indications included elective surgery, emergency surgery, spontaneous hemorrhage, childbirth, heavy menstrual bleeding, and hematuria. Dose and schedule of administration varied, with a median dose of 13.3 mcg/kg and median of three doses per patient.
●The Seven Treatment Evaluation Registry (STER) has evaluated the use of rFVIIa in surgical patients; spontaneous bleeding; and prophylactic therapy. A series of 41 elective surgeries in 34 patients estimated a minimally effective dose for hemostasis with rFVIIa was ≥13 mcg/kg, with at least two additional doses administered [126]. A series of 101 spontaneous or traumatic bleeding events reported favorable outcomes using rFVIIa for one day in muscle bleeding or hemarthroses, and multiple dose schedules for heavy menstrual bleeding [83]. A series of 38 patients found that frequent bleeding episodes could be controlled effectively with administration of prophylactic rFVIIa three times per week (total weekly dose 90 mcg/kg) [127].
●Additional case reports describe successful use of rFVIIa or plasma-derived factor VII concentrates during a variety of surgical procedures including cesarean delivery, hysterectomy, coronary artery bypass grafting, thoracic surgery, and intracerebral hematoma surgery [128-132].
The major advantage of rFVIIa and factor VII concentrates is avoidance of volume overload. The major disadvantage of the recombinant product is cost and the risk of arterial and venous thrombosis, for which there is Boxed Warning in the product information [133]. However, this issue may apply more to individuals with underlying risk factors for thrombosis, as discussed in more detail separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Adverse events'.)
For individuals who do not have access to rFVIIa or a factor VII concentrate, bleeding can be managed using a 4 factor PCC (unactivated or activated) (table 5) or a plasma product such as FFP (solvent/detergent treated if available). Compared with FFP, PCCs have the advantage of less volume overload, avoidance of potential transfusion reactions and infectious risks, but PCCs carry a thrombotic risk. Patients treated with PCCs should be monitored for the levels of other coagulation factors.
The very short half-life of factor VII (two to eight hours) makes it difficult to use FFP without causing volume overload. FFP also carries risks of transfusion reactions and infections, and there may be a substantial delay in achieving hemostatic levels of factor VII due to the volume of FFP required. Because of these risks, it may be preferable to treat patients with minor bleeding or those who require minor surgery and do not have access to rFVIIa or a FVII concentrate with an antifibrinolytic agent rather than PCC or FFP.
Decisions regarding the use of prophylactic therapy and management during pregnancy are made on a case-by-case basis, ideally in consultation with a hemophilia treatment center [127,134].
Factor V deficiency (F5D) — Severe factor V deficiency is associated with a mild to severe bleeding diathesis, but many patients with factor V levels <1 percent bleed less than anticipated [135]. The explanation for this observation is unknown, although residual platelet factor V activity may be involved [136,137]. Of interest, a case report described a patient with factor V deficiency who was treated with FFP; the patient had endocytosis of FFP-derived factor V by megakaryocytes, which restored platelet thrombin generation for many more days than after plasma infusion and decline of plasma factor V to undetectable levels [138]. The most common clinical symptoms are excessive bleeding after invasive procedures and mucosal tract bleeding. Intracranial hemorrhage has been reported [139-142]. Inhibitors to factor V develop in some patients, making management more challenging [143,144].
A procoagulant state with thrombosis rather than bleeding has been reported in factor V deficiency [145]. Potential mechanisms include the coinheritance of a mutation causing factor V deficiency with the factor V Leiden mutation, resulting in pseudo-homozygosity. (See "Factor V Leiden and activated protein C resistance", section on 'FVL genotypes'.)
No recombinant factor V or plasma-derived factor V concentrate is available, and PCCs do not contain factor V. Thus, bleeding must be treated using FFP (solvent/detergent [S/D] treated when available) (table 4). Concern has been raised that S/D treatment (see 'Plasma products' above) may reduce the level of factor V; however, S/D plasma has been used successfully in factor V deficiency, and the use of S/D plasma may reduce risks of viral infection [146]. In contrast, Thawed Plasma is not an adequate source of factor V [147]. The recommended starting dosage for FFP is 15 to 20 mL/kg. The half-life of factor V (16 to 36 hours) usually requires daily infusion to keep factor V at hemostatic levels (ie, >20 percent of normal). In some instances this schedule may cause volume overload; monitoring for this complication must be done, and diuretics are sometimes needed. Some experts have also advocated the use of platelet transfusions, because normal platelets contain factor V that should concentrate at the site of bleeding [148]. Additional information about available products and their administration is presented separately. (See "Clinical use of plasma components" and "Platelet transfusion: Indications, ordering, and associated risks".)
Decisions regarding the use of prophylactic therapy and management during pregnancy are made on a case-by-case basis, ideally in consultation with a hemophilia treatment center. Successful pregnancy and surgical interventions have been reported in patients with factor V deficiency managed with various interventions including FFP, recombinant activated human factor VII (rFVIIa), and platelet transfusions [143,149,150]
Factor V and VIII combined deficiency (F5F8D) — Patients with combined factor V and VIII deficiency generally have higher baseline factor levels than those with isolated factor V or VIII deficiencies, so that the bleeding disorder is typically mild to moderate, with a weak correlation between factor activity levels and bleeding severity [69]. Typical bleeding sites include surgical, traumatic, and mucocutaneous bleeding (epistaxis, heavy menstrual bleeding) [48,151]. Spontaneous joint, muscle, umbilical and intracranial bleeding are rare [152].
Treatment of bleeding in combined factor V and VIII deficiency is generally reserved for traumatic, surgical, or obstetrical bleeding [69]. The only product that can replace both factor V and factor VIII is FFP (solvent/detergent treated if available) (table 4). The recommended starting dosage of FFP is 15 to 20 mL/kg IV, repeated daily to keep factor V at hemostatic levels (>20 percent). Subsequent dosing is based on factor activity levels and the clinical course. In some instances this schedule may cause volume overload, so that surveillance is mandatory and diuretics are sometimes needed.
FFP will replete factor VIII less efficiently than factor V because factor VIII has a shorter half-life than factor V (10 to 14 versus 16 to 36 hours) and factor VIII requires higher plasma levels for hemostasis (50 versus 15 to 20 percent). Therefore, a separate source of factor VIII is recommended by some experts [69]. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Factor VIII products for hemophilia A' and "Treatment of bleeding and perioperative management in hemophilia A and B".)
An alternative to providing a separate source of factor VIII is the administration of FFP more frequently than needed for factor V replacement; the interval is determined based on plasma factor activity levels. As another alternative, we and others have sometimes successfully used desmopressin (DDAVP) to further raise factor VIII levels when the post-FFP trough levels of this factor were thought to be inadequate for hemostasis [153-155]. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP'.)
Decisions regarding the use of prophylactic therapy and management during pregnancy are made on a case-by-case basis, ideally in consultation with a hemophilia treatment center.
Factor II (prothrombin) deficiency (F2D) — Severe factor II (prothrombin) deficiency is characterized by excessive bleeding after invasive procedures, and umbilical cord, joint, muscle, and mucosal bleeding [27]. Life-threatening bleeding may also occur. According to our experience and that of others, the minimal coagulation factor levels necessary for hemostasis are somewhat higher for prothrombin (20 to 30 percent) than for most other RICDs (table 1) [87].
No recombinant or plasma-derived factor II concentrates are available to treat bleeding. However, factor II is present in 3 factor and 4 factor PCCs (table 5) and in FFP. PCCs are dosed at 20 to 30 units/kg, with a target factor II level >30 percent (table 4). The plasma half-life of factor II is three to four days (table 1); thus, dosing interval may be less frequent than for some other RICDs, guided by clinical bleeding and factor activity levels. Laboratory monitoring of other factors is advisable when prolonged administration of PCCs is used, in order to avoid levels of the non-deficient factors in excess of 150 percent (factors IX and X for 3 factor PCC; factors VII, IX, X for 4 factor PCC). FFP (solvent/detergent treated if available) is dosed at 15 to 20 mL/kg.
Prophylaxis is generally not used in individuals with factor II deficiency. However, successful prophylactic use of PCC to prevent recurrent bleeding events has been reported for two individuals [156,157]. Decisions regarding the use of prophylactic therapy and management during pregnancy are made on a case-by-case basis, ideally in consultation with a hemophilia treatment center.
Multiple vitamin K-dependent factor deficiencies — Individuals with a genetic defect that affects production of the vitamin K-dependent coagulation factors are deficient in both procoagulant (II, VII, IX, X) and anticoagulant (protein S, protein C) factors, as well as vitamin K-dependent proteins involved in bone formation [35,158,159]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid".)
Plasma factor activities range from less than 1 percent to 30 percent; clinical manifestations occur early in life and may be fatal, and include umbilical cord and central nervous system bleeding [35,158].
In most families, bleeding can be treated with oral or parenteral vitamin K supplementation, which normalizes or partially corrects the activity of the vitamin K-dependent coagulation factors [87,158-162]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid", section on 'Mutations'.)
In the rare circumstance when vitamin K is ineffective, treatment with FFP has been successful in a limited number of patients [163-165]. Since such experience is limited, it would appear most prudent to correct factor levels to 20 to 30 percent, similar to that recommended for prothrombin deficiency.
Decisions regarding the use of prophylactic therapy and management during pregnancy are made on a case-by-case basis, ideally in consultation with a hemophilia treatment center.
REGISTRIES AND OTHER RESOURCES — Several large RICD registries provide information about clinical manifestations and treatment:
●The European Network of Rare Bleeding Disorders (EN-RBD) and the associated Rare Bleeding Disorders Database (RBDD) registry (www.rbdd.org/014/) provides information on more than 3230 patients from 66 centers around the world.
●The World Federation of Hemophilia (www.wfh.org) provides information about RICDs for patients and clinicians [166,167].
●A registry of rare bleeding disorders has been kept since the early 1970s in Iran, where marriages among first cousins are common and RICDs are seen more frequently than in other countries. A cohort of over 750 patients is being prospectively followed.
●A North American registry has been established and has provided information about RICDs in the United States and Canada [42].
Additional information concerning blood coagulation proteins (eg, sequence, structure, mutations, function, associated diseases, related literature) is available on ClotBase (http://www.clotbase.bicnirrh.res.in) and a web-based resource developed by the RBDD registry, the National Hemophilia Foundation, and the Indiana Hemophilia and Thrombosis Center (http://www.rarecoagulationdisorders.org) [168,169]. Country-specific registries and resources also have been developed [170].
Overviews of hemostasis, coagulation testing, and evaluation of a patient with abnormal bleeding are also presented separately. (See "Overview of hemostasis" and "Clinical use of coagulation tests" and "Approach to the adult with a suspected bleeding disorder".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rare inherited bleeding disorders".)
SUMMARY AND RECOMMENDATIONS
●Background – Inherited deficiencies of factors XIII, X, VII, V, and II are autosomal recessive genetic disorders referred to as rare inherited coagulation disorders (RICDs). They affect 1 in 500,000 to 1 in 2,000,000 individuals and are found more frequently in populations with a high degree of consanguinity. Rare autosomal dominant disorders affecting factor V or thrombomodulin have been reported. (See 'Inheritance' above and 'Genetics' above and 'Epidemiology' above.)
●Clinical features – The predominant manifestation is bleeding, with umbilical cord separation, trauma, invasive procedures, postpartum, menstrual bleeding, muscle and joint bleeding, or epistaxis. Bleeding typically begins in childhood but can vary substantially. Bleeding can also be seen in heterozygotes, especially with greater hemostatic challenges (table 1). Other findings include impaired wound healing (factor XIII deficiency), early pregnancy loss (factor XIII, X deficiencies), and thrombosis (factor VII, V deficiencies). (See 'Clinical manifestations' above.)
●Laboratory – A factor activity level <20 percent may cause prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), or both (table 3), depending on the position of the factor in the coagulation cascade (figure 2). Factor XIII deficiency does not prolong the PT or aPTT. (See 'Laboratory findings' above.)
●Evaluation – All patients with a suspected RICD should have a complete history of hemostatic challenges and bleeding manifestations. Ethnic background and the possibility of consanguineous marriage may be relevant. Screening tests of hemostasis are done and factor activity levels are measured in the appropriate clinical setting. Neonates are tested after birth, with invasive procedures delayed until diagnosis is established. Genetic testing is appropriate for some individuals. Diagnosis is confirmed by low factor activity (typically, ≤50 percent) not caused by an inhibitor. (See 'Diagnostic evaluation' above.)
●Treatment of bleeding – Therapy depends on bleeding severity and available factor replacement products. Early input from the consulting specialist is important. (See 'General aspects of management' above.)
•The mainstay for severe bleeding is rapid factor replacement (table 4). Access to specific factor products varies by institution. Options in order of preference include recombinant or plasma-derived factor concentrate, prothrombin complex concentrate (PCC) if it contains the deficient factor (table 5), and Fresh Frozen Plasma (FFP; solvent/detergent [S/D] treated if available). (See 'Acute bleeding' above and 'Invasive procedure/surgery' above.)
•Antifibrinolytic agents may be used in conjunction with factor replacement for severe bleeding or alone for less severe bleeding, particularly mucosal bleeding. (See 'Heavy menstrual bleeding and pregnancy' above and 'Antifibrinolytic agents' above.)
●Prophylaxis – Factor XIII deficiency confers a risk of severe bleeding and early pregnancy loss. For factor XIII deficient patients with frequent bleeding or activity level ≤5 percent, we recommend monthly prophylaxis with recombinant factor XIII A subunit or factor XIII concentrate (Grade 1B). Individuals with B subunit deficiency (which is extremely rare) should receive the plasma-derived concentrate. Alternatives for those without access to these concentrates include FFP (S/D treated if available) or cryoprecipitate. More intensive dosing may be used during attempted conception and early pregnancy. (See 'Factor XIII deficiency (F13D)' above.)
Prophylaxis for other RICDs depends on factor activity levels and bleeding symptoms, with input from a hemophilia treatment center. (See 'Factor X deficiency (F10D)' above and 'Factor VII deficiency (F7D)' above and 'Factor V deficiency (F5D)' above and 'Factor V and VIII combined deficiency (F5F8D)' above and 'Factor II (prothrombin) deficiency (F2D)' above and 'Multiple vitamin K-dependent factor deficiencies' above.)
●Other interventions – Additional interventions may include treatment of iron deficiency, patient education, and reproductive counseling. Appropriate vaccinations should not be withheld. (See 'Anemia/iron deficiency' above and 'Education and counseling' above and 'Vaccinations' above.)
●Resources – Informative resources are available. (See 'Registries and other resources' above.)
●Other coagulation disorders – (See "Clinical manifestations and diagnosis of hemophilia" and "Treatment of bleeding and perioperative management in hemophilia A and B" and "Clinical presentation and diagnosis of von Willebrand disease" and "Factor XI (eleven) deficiency" and "Disorders of fibrinogen" and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1 deficiency'.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Flora Peyvandi, MD, who contributed to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Stefano Duga, PhD (deceased), who contributed to an earlier version of this topic.
