Approach Considerations
Factor XIII (FXIII) replacement is used to treat bleeding, to prevent perioperative bleeding during elective surgical procedures or, prophylactically, to prevent recurrent bleeding, as in central nervous system (CNS) or joint hemorrhages. Serial monitoring of achieved FXIII levels is essential to document the adequacy of any therapy.
Prompt and adequate therapy for acute bleeding is essential along with immobilization of the affected sites and pain relief. Most patients receive fresh frozen plasma (FFP) or cryoprecipitate to treat bleeding. Information regarding the amount of FXIII present in either of these products usually is not available; therefore, monitoring the adequacy of FXIII levels is essential.
Virus-inactivated FXIII concentrates made from human plasma or placenta are an improvement over traditional products. Human factor XIII concentrate (Corifact) is approved for prophylaxis in congenital FXIII deficiency by the US Food and Drug Administration (FDA). It is marketed under the brand name Fibrogammin P in Europe, South America, South Africa, and Japan. A second FXIII concentrate (Bio Products Laboratory, Elstree, Hertfordshire, UK) is available on a per-patient request.
Factor XIII A-subunit, recombinant (Tretten) was approved by the FDA in December 2013. [105] Approval was based on results from a clinical study that demonstrated the safety and efficacy of rFXIII A-subunit. The phase 3 trial included 41 patients and showed that preventive treatment with monthly 35 IU/kg rFXIII A-subunit injections significantly decreased the number of treatment-requiring bleeding episodes, compared with an historic control group of individuals who did not receive routine FXIII infusions, . [106]
The long half-life of FXIII of 6-19 days and the hemostatic efficacy of even small amounts of FXIII of approximately 5% allow replacement therapy to be administered every 4-6 weeks. An FFP dose of 2-3 mL/kg may be effective for up to 4 weeks. [107, 108] The dose of concentrate in adults with deficiency is 35 U/kg every 4 weeks. [109, 110, 111]
A paucity of data exists concerning the pediatric population. Hemostatic evaluation following a head trauma-induced large subcutaneous hematoma associated with recurrent postsurgical bleeding led to a diagnosis of severe FXIII deficiency in a 22-month-old boy. Following initial therapy, subsequent replacement with an FXIII concentrate dose of 50 U/kg every 5 weeks was sufficient to prevent rebleeding and allow healing. [112] Serial monitoring of actual levels achieved is important in children to determine adequacy of any therapy. For more information, see Pediatric Factor XIII Deficiency.
Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure, ice, and use of antifibrinolytic drugs. Avoidance of trauma and nonsteroidal anti-inflammatory drugs (NSAIDs) is helpful in reducing bleeding events.
Several reports exist of the use of FXIII in unusual circumstances. Note the following:
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Effectiveness of normalizing FXIII levels in the treatment of a cerebrospinal fluid leak, which started 2 weeks after removal of a meningioma, was reported in a Japanese patient. [113]
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The potential use of transglutaminases to mechanically stabilize and allow cultured epithelial autografts to take when used to repair extensive skin wounds supports a possible role of FXIII in the formation of de novo dermoepidermal junctions, thereby facilitating permanent skin replacement. [113]
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Improved stability of surgical wounds has been reported following infusion of FXIII concentrates.
Patients with acquired inhibitors to FXIII should be treated using well-established principles of therapy. Note the following:
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FXIII dose depends on the characteristics of the inhibitor. One patient was treated preoperatively using a 10-fold dose of FXIII concentrate (350 U/kg) followed by a similar postoperative dose resulting in adequate hemostasis after coronary bypass graft surgery. [111]
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In addition to administering an FXIII concentrate whenever available, treat the underlying disorder and, when appropriate, use immunosuppressive agents, including the newer B-cell-directed monoclonal antibodies.
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Note that spontaneous disappearance of acquired inhibitors is part of their natural history, and the use of milder less toxic immunomodulators, such as steroids, may suffice.
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The proper choice of agent is dictated by clinical circumstances. Simple immediate ancillary measures of ice, pressure, ace wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.
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The complexity of required treatment is exemplified by a patient with an INH-induced inhibitor in whom INH was discontinued, cryoprecipitate and FXIII concentrate were administered, the patient underwent plasma exchanges and treatment with an immunoadsorption column to reduce the inhibitor's titer, and immunosuppressives were administered before hemostatic success was achieved. [94, 92, 96]
To date, prophylactic factor replacement has been undertaken mainly in patients with intracranial bleeding or recurrent miscarriages caused by severe FXIII deficiency. Successful prevention of recurrent joint bleeds also has been accomplished using periodic transfusions of FFP and cryoprecipitate. [5] FFP can be administered in a dose of 2-3 mL/kg every 4 weeks.
A literature review of bleeding risks and reproduction among patients with severe FXIII deficiency suggests that patients with clinically significant bleeding should start receiving factor replacement therapy in childhood to reduce early mortality from hemorrhages and to allow patients to reach adulthood. During pregnancy, monthly replacement was found to be effective in preventing miscarriages. [117] However, both short-term benefits and potential long-term adverse consequences of prophylactic use of these products must be discussed, with full patient participation in all decision making.
Advances in the types of available products improve care. Addition of Tween 20 makes a reduction of the generation of soluble and insoluble aggregates of rFXIII possible when rFXIII is subjected to freezing and thawing or agitation. [118] Another advance in the technology relates to solving problems faced during freeze-drying and storing the dry solid. Improvement in storage stability of therapeutic proteins has obvious advantages for both storage and transport. [119]
Pooled plasma treated with solvent-detergent (PLAS+SD) is available to treat any condition in which FFP typically is used and for which no factor concentrate is available. Viral inactivation using the solvent-detergent (SD) process has been used in preparation of coagulation factor concentrates in the past. In vitro treatment of donor plasma with 1% of the solvent tri(n- butyl) phosphate (TNBP) and 1% of the detergent Triton X-100 leads to significant inactivation of a broad spectrum of lipid-enveloped viruses. Note the following:
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Studies of viral inactivation using the SD process show significant inactivation of the human pathogenic viruses hepatitis B and C and HIV. Other lipid-enveloped viruses (eg, Sindbis virus, bovine viral diarrhea virus) also have been used to monitor inactivation.
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PLAS+SD is ABO blood type specific, and SD-treated plasma should be ABO compatible with the recipient's red cells.
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The frozen product is supplied in 200-mL bags. Each 200-mL bag has been demonstrated to raise factor levels by approximately 2-3%, with 4-6 bags raising the factor level of a 70-kg person by approximately 8-18%.
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Monitoring of specific factor levels before and after product infusion is important to ensure that hemostatically adequate levels are achieved and maintained to provide adequate hemostasis.
Antifibrinolytic agents are not used commonly to treat patients with FXIII deficiency but may be used as ancillary therapy. The hemostatic plug formed in the presence of adequate levels of FXIII at the time of surgical trauma (as with dental procedures or with mucosal bleeding) can be preserved by inhibiting fibrinolysis with ε-aminocaproic acid (EACA; Amicar) or trans-p- aminomethyl-cyclohexane carboxylic acid (AMCA; also termed tranexamic acid; Cyklokapron) administered orally or, if needed, intravenously.
EACA has been administered in a dose of 5 g orally or intravenously slowly prior to the surgical procedure, along with a dose of the appropriate FXIII replacement. This is followed by a maintenance dose of 1 g/h postoperatively until it is appropriate to start tapering the dose over the next several days.
AMCA is administered in a dose of 1.5 g intravenously every 6-8 hours and tapered, as needed. Hhowever, it is not available in the United States.
Antifibrinolytic agents also can be used as a mouthwash for oral bleeding and have been used to stop local intracavitary oozing.
Antifibrinolytic agents are contraindicated in patients with hematuria originating from above the bladder, because of the possible risk of development of a firm occluding clot in the ureters when administered simultaneously with factor replacement (however, many urologists routinely use EACA irrigations after prostatic and bladder surgery)
Antifibrinolytic agents are not useful in the treatment of joint bleeding (see Hemophilia A for more information).
In recent years, the use of NSAIDs to relieve pain has increased in patients with bleeding disorders. Although they provide relief from inflammatory pain, patients experience increased GI tract or other bleeding because of the impact of the drugs on primary hemostasis, and they require additional FXIII replacement to control bleeding. The problem is magnified by the availability of over-the-counter NSAID pain relievers. Non-NSAIDs, such as acetaminophen and codeine-type analgesics, are much less effective, and some are addictive.
Routine dental care is of the utmost importance in maintaining dental hygiene. Other routine care, such as mammography in women older than 50 years or colonoscopy for patients older than 50 years, must be provided as in nonbleeding patients.
Gene therapy has not been used as a treatment modality in patients with FXIII deficiency thus far. However, the reader is referred to a review of gene therapy in the hemophilias and other blood diseases. [120]
Surgical Care
All elective procedures require proper perioperative management. Note the following:
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Patients with severe FXIII deficiency require FXIII replacement both preoperatively and postoperatively. Levels of as little as 3-5% may be sufficient to provide adequate hemostasis, and a single dose is sufficient to last several weeks unless excessive blood loss occurs. Serial factor levels must be performed to ensure adequacy of FXIII levels.
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Procedures such as endoscopies, although considered routine for unaffected individuals, require preprocedural product replacement so that patients do not bleed during or following a needed biopsy. Postbiopsy replacement must continue until the biopsy site has healed.
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Dental extractions or mucosal procedures can be handled using a single preprocedure dose of FXIII along with Amicar or AMCA. A standardized approach to dental extractions, as has been proposed for patients with hemophilia, may be used in patients with FXIII deficiency. Continuing antifibrinolytics on an outpatient basis for several days after a dental extraction is routine practice, with gradual tapering of dosage.
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Avoidance of NSAIDs and other platelet-inhibiting drugs perioperatively is essential to minimize bleeding risk. Ice packs and pressure are always useful when feasible.
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Application of fibrin glue as an ancillary measure is useful in helping control bleeding at surgical sites. Fibrin glue consists of a mixture of fibrinogen, thrombin, and FXIII used to cross-link freshly formed fibrin. Cryoprecipitate also has been used as a source of fibrinogen and FXIII, with the use of bovine thrombin to clot fibrinogen. Some preparations also incorporate antifibrinolytic agents to prevent clot lysis. In particular, fibrin glue has been useful in orthopedic surgery and with surgical procedures in patients with FXIII inhibitors. Bovine thrombin may elicit antibodies.
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Bleeding from suture holes is a complication in a variety of invasive vascular procedures (surgery, radiologic procedure, coronary angiography). In an experimental porcine vascular graft model, fibrin sealant containing FXIII effectively reduced blood loss and reduced the time to achieve adequate hemostasis more than fibrin alone or thrombin-coated gelatin sponges. [121]
Consultations
A hematologist, orthopedist, physical therapist, dentist, social worker, psychologist, infectious disease specialist, gastroenterologist/hepatologist, geneticist, and an appropriately equipped special laboratory all play important roles in providing optimal care for patients with FXIII deficiency and their families.
The efforts of the National Hemophilia Foundation and its regional chapters must be recognized in helping to educate patients, assist service providers, foster dialog regarding problems and solutions among patients with bleeding disorders, and improve conditions for the entire community through support of legislation.
Diet
A healthy and nutritional diet should be encouraged.
Activity
Appropriate physical activity and physical therapy must be encouraged to maintain and preserve muscle function.
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Coagulation reactions leading to thrombin generation and activation of factor XIII.
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Final steps in clot formation (from article: Factor XIII).
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Activation of factor XIII and generation of insoluble cross-linked fibrin. Adapted from Lorand L. Ann N Y Acad Sci. 2001;936:291-311.
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Postulated interaction between factor XIII and thrombin-activatable fibrinolytic inhibitor.
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Cell surfaced–directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing (TF-bearing) cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation (from article: Factor XIII). Adapted from Hoffman and Monroe. Thromb Haemost. 2001;85(6):958-65.
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Gene, messenger RNA, and protein for subunit A of factor XIII. Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III, Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.
Tables
Properties |
A Chain |
B Chain |
Plasma FXIII |
Has 2 A chains |
Has 2 B chains |
Plasma level |
Approximately 15 mg/mL |
Approximately 21 mg/mL |
Chains are free in plasma |
No. All bound to B chain and present as an A2 B2 tetramer |
Yes. Excess B chain present in plasma as a B2 dimer |
Chain contains the catalytic site |
Yes |
No |
Chain is the carrier protein |
No |
Yes |
Chain acts as a brake on FXIII activation |
No |
Yes |
Cellular FXIII |
Has 2 A chains (A2 dimer) |
Has no B chains |
Mutations can lead to decreased FXIII activity |
Yes |
Yes |
