TITLE: CLOTTING FACTOR DEFICIENCIES
AUTHORS: RACHID BAZ, MD -- Department of Hematology and Medical Oncology
   TAREK MEKHAIL, MD -- Department of Hematology and Medical Oncology
REVIEWED: JULY 15, 2004
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Figure 1 illustrates the current understanding of the coagulation cascade.
THE HEMOPHILIAS1,2-24
INHERITANCE AND INCIDENCE

Hemophilias are most commonly X-linked recessive diseases characterized by deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B, or Christmas disease).6,13 The clinical severity correlates well with factor levels, and they are clinically classified as mild (>5% of normal factor activity), moderate (1% to 5% factor activity), and severe (<1% factor activity). Coinheritance of the factor V Leiden mutation occurs in about 5% of patients and results in a decreased bleeding tendency.10 The incidence is 1 per 5,000 live births for hemophilia A and 1 per 30,000 live births for hemophilia B. In 30% of patients, hemophilia is the result of a de novo mutation, and no family history can be elicited. Males are most commonly affected; however, symptomatic females have been documented, and the proposed mechanisms include X chromosome inactivation or deletion, or the presence of a true homozygous offspring of an affected male and a carrier female.6,13
CLINICAL FEATURES
The most common bleeding sites are joints (80% of bleeding), muscles, and gastrointestinal mucosa. Ankles are the most commonly affected joints in children, whereas knees and elbows are more frequently involved in adults.6 Quadriceps and iliopsoas bleeding are the most common sites of muscle hematomas. Abdominal wall bleeding as well as gastrointestinal mucosal bleeding may occur. In most children, the hemophilia is already known at the time of first bleeding because of previous screening for a positive family history.17 In severe disease, bleeding occurs in the first 2 years of life, which contrasts with patients with milder disease, who may go undiagnosed for years.17 Late complications include hemarthroses and joint destruction, blood-borne infectious complications, and development of clotting factor inhibitors.
DIAGNOSIS
The diagnosis is suggested by an elevated aPTT in a male patient with a positive family history. This is frequently followed by a 1:1 mixing study with normal plasma, which corrects the aPTT level. Hemophilia B patients may have a normal aPTT.13,24 Factor VIII and XI levels will be decreased in Hemophilia A and B respectively. A two stage assay is recommended. It is however more technically demanding but also more accurate (especially so in patients with a mutation near the A domain of factor VIII, which makes the mutant factor less stable).13 Carrier detection often relies on DNA-based methods rather than finding 50% factor activity.7 Genetic testing can identify patients at risk of inhibitor development: patients with a missense mutation or small deletion are less likely to develop inhibitors than patients with nonsense mutations or large deletions.7
TREATMENT

Prevention
This includes avoidance of contact sports, good oral hygiene, careful immunization techniques, institution of timely replacement therapy after trauma, and treatment of acute bleeding episodes.3

Factor Replacement: Choices Include Recombinant Versus Plasma-derived Factor VIII Replacement
Plasma-derived concentrates vary in purity and undergo viral inactivation procedures, rendering them safer.11-13 First-generation recombinant products (Bioclate, Helixate, Kogenate, Recombinate) have demonstrated efficacy in clinical trials; however, they continue to carry a theoretic risk of viral transmission because of the added human albumin necessary for factor stabilization.5 Second-generation recombinant products (Kogenate FS and B-domain deleted recombinant factor VIII [BDDrFVIII]) do not require albumin stabilization.4,11,13 Factor IX replacement has traditionally been with prothrombin complex concentrates (PCCs) that contain factors II, VII, and X as well as IX, and were associated with thrombotic risk.12,13,22 Newer plasma-derived factor IX concentrates are currently available, effective, and undergo viral inactivation. Recombinant factor IX concentrates are also available and effective and have no added albumin, hence eliminating a theoretic risk of viral infection.22 The choice of replacement therapy depends on availability, safety, and cost, with the knowledge that plasma-derived products are becoming safer and recombinant products are less available and 2 to 3 times more costly.11-13 For patients with HIV, the use of recombinant products was associated with a slower decline in CD4 cell count, and many experts recommend using recombinant products in that setting. However, it is unknown if this advantages translates into improved clinical outcome.6,12,13 In some European countries, previously untreated patients uniformly receive recombinant products. The desired factor level depends on the site and severity of bleeding: 30% to 40% factor activity is required for early joint or muscle bleeding, 50% is required for dental surgery or more severe muscle bleeding, and 80% to 100% for life-threatening or serious bleeding (intracranial or intra-abdominal, or orthopedic surgeries).6,12,13 Because the half-life of factor VIII is about 12 hours and that of factor IX 16 hours, factor levels should be checked every 12 hours and 16 hours, respectively. When calculating the dose of replacement therapy, one should keep in mind that one unit of clotting factor is the amount of clotting factor contained in 1 milliliter of plasma.6,12,13 For example, if a patient with a plasma volume of about 3000cc and 1% factor level needs to undergo dental surgery (which requires correction to 50% of factor VIII level), 1500 units of factor VIII must be administered.

Primary prophylactic therapy has been shown to reduce the incidence of arthropathy. However, considerable controversy surrounding factor use remains, especially with regard to the age of onset of such therapy and the cost.21

DDAVP
DDAVP is the treatment of choice in patients with mild hemophilia A and mild to moderate bleeding, but it has no role in hemophilia B.3

Antifibrinolytic Therapy
Antifibrinolytic therapy (in the form of tranexamic acid or EACA) is useful in controlling oral cavity bleeding and menorrhagia. For details on dosing, refer to the section in this chapter on its use in patients with vWD.3,6

Treatment of Long-Term Complications
Treatment of the long-term complications of hemophilia requires a multidisciplinary approach. Chronic hemarthrosis may be managed with short-term prophylaxis and at times requires synovectomy, which can be arthroscopic or via the use of radioactive phosphorous.3,6,18,19 The treatment of patients with inhibitors to factor VIII with life-threatening hemorrhage or in need of emergent surgery usually involves the use of recombinant factor VIIa when available.9,23 For patients with inhibitors presenting with hemarthrosis, the use of plasma-derived factor VIII bypassing products can be used.2,3,13 Finally, experimental treatments with gene-targeted therapies are currently undergoing testing.16
COAGULOPATHY OF LIVER DYSFUNCTION
Most clotting factors are synthesized by the liver (except for vWF and tissue plasminogen activator), and the liver reticuloendothelial system is responsible for metabolizing most clotting factors. The characteristics of the coagulopathy of liver disease are illustrated in Table 1. The treatment involves the correction of vitamin K deficiency when present and the judicious use of FFP.25
RARE FACTOR DEFICIENCIES
FACTOR XI DEFICIENCY
Factor XI deficiency is inherited in an autosomal fashion. The incidence in the general population is estimated to be 1 per 1 million, but about 10% of Ashkenazi Jews are heterozygous. The bleeding tendency does not correlate with factor levels, and bleeding is worse from areas with high intrinsic fibrinolytic activity, such as the oral cavity or the genitourinary tract. The propensity to bleed also seems to be increased in patients with a nonsense mutation compared with patients with a missense mutation. Treatment involves the use of FFP to achieve a factor XI level of 30% to 45% (despite the lack of clear consensus on the target factor XI activity). Factor XI concentrates are available in Europe and have the advantage of undergoing viral inactivation and having a smaller volume. However, they have been associated with DIC and increased thrombogenicity.1,26,27
FACTOR X DEFICIENCY
Factor X deficiency is a rare (1 per 1 million) autosomal recessive deficiency characterized by asymptomatic heterozygotes and by homozygotes with bleeding symptoms that correlate with factor activity. It can be acquired in association with amyloidosis, acute respiratory infections, and leukemias. The most common bleeding complications are hematomas, hemarthrosis, epistaxis, and menorrhagia. Treatment involves replacement with (10 to 15 mL/kg) or PCCs (that contain a variable concentration of factor X) to a target of 15% to 20% factor X activity.1
FACTOR VII DEFICIENCY
Factor VII deficiency is a rare (1 per 500,000) autosomal recessive deficiency that exhibits little correlation between the bleeding risk and the factor activity. In general, less than 1% activity produces severe bleeding that is similar to that seen in the hemophilias and more than 5% activity produces mild bleeding that is often localized to mucous membranes. Treatment involves the use of recombinant factor VIIa at a dose of 22 to 26 µg/kg (in contrast to a dose of 90 µg/kg in patients with hemophilia and inhibitors) to normalize the prothrombin time.1
FACTOR V DEFICIENCY
Factor V deficiency is a rare (1 per 1 million) autosomal recessive deficiency in which asymptomatic heterozygotes and homozygotes manifesting platelet-type bleeding (easy bruising, epistaxis, and oral bleeding). The patient may have an increased risk of thrombosis. Treatment involves replacement with FFP (an initial dose of 20 ml/kg followed by 5 ml/kg every 12 hours, with monitoring of factor V levels and bleeding) for a goal of 25% factor activity. The use of platelet transfusion may be required in severe bleeding, as platelets account for 20% of the total pool of factor V.1
FACTOR II DEFICIENCY
Factor II deficiency (prothrombin deficiency) is a rare (1 per 2 million) autosomal recessive disorder associated with mucosal and deep tissue bleeding. Treatment involves the use of PCCs, which contain variable concentrations of prothrombin. Factor survival analyses (measuring the effect of variable amounts of PCC) are required to ensure proper dosing.1
CONGENITAL AFIBRINOGENEMIA
Congenital afibrinogenemia is a rare (1 per 1 million) autosomal recessive bleeding disorder characterized by the absence of fibrinogen. A high rate of consanguinity is noted, and carriers often have decreased fibrinogen levels. Early symptoms include umbilical stump bleeding; bleeding later in life can be life-threatening and involve any organ system. Patients with hypofibrinogenemia have mild bleeding only. Low levels of fibrinogen are more commonly seen in clinical practice in liver disease, DIC, or after the use of thrombolytics. Treatment involves replacement with cryoprecipitate (250 mg fibrinogen per 5-7 kg loading dose followed by daily infusion of 250 mg/15 kg) to a target fibrinogen of 80 mg/L.1
FACTOR XIII DEFICIENCY
Factor XIII deficiency is a rare (1 per 1 million) autosomal recessive disorder. Acquired factor XIII deficiency has been noted in patients with Henoch-Schönlein purpura, erosive gastritis, and leukemia. Bleeding occurs early in life, with umbilical stump bleeding. Later in life, bleeding occurs in skin, muscles, and the oral cavity, and is often delayed after a hemostatic challenge. Intracerebral bleeding occurs in 30% of patients and is a major cause of mortality. Hemarthroses are rare, and female patients have recurrent abortions if they do not receive replacement therapy. Diagnosis is by noting clot solubility in both 5 M urea and 1% monochloracetic acid, and assaying factor XIII activity follows. Treatment involves the use of factor XIII concentrates (1,000 units). Some experts recommend primary prophylaxis with factor XIII concentrates (1,000 units every 6 weeks or every 3 weeks in pregnant patients). FFP can be used when the above-mentioned concentrates are not available (FFP contains varying concentrations of factor XIII).1,28
CLOTTING FACTOR INHIBITORS8,20,29,30
DEFINITION AND CHARACTERIZATION
Acquired inhibitors are antibodies that neutralize a specific clotting factor's function. They are called alloantibodies when they occur in patients with inherited factor deficiency, and autoantibodies when they arise in patients without an inherited factor deficiency. The most commonly inhibited factor in clinical practice is factor VIII, which is discussed here.30 (The management of inhibitors of other clotting factors follows the same general guidelines and will not be covered here).
FACTOR VIII INHIBITORS
INCIDENCE AND ETIOLOGIES

Autoantibodies to VIII:C are characteristically oligoclonal non-complement-fixing IgG. Patients with lymphoproliferative disorders or multiple myeloma may have IgM or IgA antibodies. The incidence is 0.2 to 1 per million person-years with a higher incidence in older age groups. There is an equal gender distribution.8,30

Causes include connective tissue disorders (rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, temporal arteritis, and pemphigus); drugs (penicillins, sulfa, alpha-interferon); malignancy (lymphoproliferative disorders, graft-versus-host disease, or prostate, renal, lung, and colon cancer); pregnancy (usually within 3 months of an uncomplicated primipara delivery); and idiopathic (especially in the elderly).8,30
CLINICAL PRESENTATION
Soft-tissue bleeding, gross hematuria, and postsurgical hemorrhage can occur; however, fatal bleeds may take place in 15% of patients. Hemarthroses are rare. Laboratory tests disclose a prolonged aPTT, which is not corrected by a 1:1 mixing study with normal plasma. Quantification is done with a Bethesda inhibitor assay (1 Bethesda unit [BU] is the amount of antibody in the patient's plasma that permits detection of 50% residual factor activity when mixed with normal plasma).8,30
TREATMENT

It depends in part on the cause of the inhibitor. For drug-induced inhibitors, discontinuing the culprit drug will result in recovery within several months; most postpartum inhibitors will resolve within 2 to 3 months. For symptomatic patients, the treatment is aimed at managing the bleed and reducing the antibody titer. The latter involves immunosuppression (with steroids, Cyclophosphamide, or Azathioprine), biologic response modifiers (DDAVP), IVIG, or plasmapheresis.8,29,30 Prednisone at 1 mg/kg/day for 3 to 6 weeks is the treatment of choice and results in about a 30% response rate. For nonresponders to steroids, cyclophosphamide at 2 mg/kg/day for 6 weeks results in an added 30% response.8,29,30 Azathioprine has also been used as an immune suppressant. IVIG at 0.4 g/kg/day for 5 days results in a 25% to 30% response rate.8,29,30 It is used for patients with contraindications to immune suppression. Plasmapheresis can lower high-titer antibodies. It can be coupled with a staphylococcal protein A column (which attaches to the Fc portion of the antibody) and results in a 50% to 90% decrease in circulating antibodies. Disadvantages include cost, difficulty of performing it in unstable patients, the need for central venous access, and the potential for circulatory collapse with the use of staphylococcal protein A.8,29,30 The management of the bleeding patient includes factor replacement to overwhelm the antibody for low-titer antibody (<5 BU/mL), or the use of porcine factor VIII, activated thrombin complexes, or recombinant factor VIIa for patients with high-titer antibodies (as these patients would not respond to factor replacement in the form of VIII concentrates, FFP, or cryoprecipitate).8,29,30
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  21. van den Berg HM, Fischer K, Mauser-Bunschoten EP, Beek FJ, Roosendaal G, van der Bom JG, Nieuwenhuis HK. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. British Journal of Haematology. 2001;112:561-565.

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  24. White GC, 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, Factor V, Factor IXS. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thrombosis & Haemostasis. 2001;85:560.

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  26. Bolton-Maggs PH. Factor XI deficiency and its management. Haemophilia. 2000;6 Suppl 1:100-109.

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