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Patients with coagulation factor deficiencies were first treated with plasma products, but a wide variety of human-, animal-, and laboratory-derived products now exist for safer, more effective treatment. Each coagulation factor product differs in its composition, major indication, and dosage ( Table 41.1A–D ).
Product | Contains | Major Indications | Dosages | ||
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Factor VIII T 1/2 10–12 hours |
Recombinant human factor VIII Advate (T 1/2 12 hours) Helixate FS (T 1/2 14 hours) Kogenate FS (T 1/2 14 hours) Kovaltry (T 1/2 14 hours) Novoeight (T 1/2 11–12 hours) Nuwiq (T 1/2 17 hours) Recombinate (T 1/2 14 hours) Xyntha (T 1/2 11–12 hours) |
Hemophilia A Control and prevention of bleeding episodes Perioperative management |
Dose (IU) = body weight (kg) × Desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL) The dosage and duration depend on the severity of factor VIII deficiency, the location and extent of the bleeding, and the patient’s clinical condition Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes |
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Recombinant human factor VIII, long-acting Adynovate (T 1/2 14.7 hours) Afstyla (T 1/2 14.3 hours) Eloctate (T 1/2 19.7 hours) |
Target | Maintenance | |||
Minor bleed | 20–40 IU/dL | 10–20 IU/kg | |||
Mod. bleed | 30–60 IU/dL | 15–30 IU/kg | |||
Major bleed | 60–100 IU/dL | 30–50 IU/kg | |||
Minor surgery | 60–100 IU/dL | 30–50 IU/kg | |||
Major surgery | 80–120 IU/dL | 40–60 IU/kg | |||
Plasma-derived human factor VIII Hemofil M (T 1/2 14.8 hours) Koate-DVI (T 1/2 16.1 hours) Monoclate P (T 1/2 17.5 hours) |
Repeat infusions every 12–24 hours (8–24 hours for patients under the age of 6) for 3 days or more until the bleeding episode is resolved (as indicated by relief of pain) or healing is achieved | ||||
Recombinant human factor VIII (porcine sequence) Obizur (T 1/2 2–17 hours) |
Acquired hemophilia A Treatment of bleeding episodes in adults |
Initial dosing of 200 U/kg followed by additional dosing based on factor recovery levels and clinical response | |||
Factor IX T 1/2 20–24 hours |
Recombinant human factor XI BeneFIX (T 1/2 18.1 hours) Ixinity (T 1/2 24 hours) Rixubis (T 1/2 26.7 hours) |
Hemophilia B Control and prevention of bleeding episodes Perioperative management |
Dose (IU) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 1.0 (IU/kg per IU/dL) | ||
Recombinant human factor IX, long-acting Alprolix (T 1/2 86.5 hours) Idelvion (T 1/2 104 hours) |
Target | Maintenance | |||
Minor bleed | 20–30 IU/dL | 10–15 IU/kg | |||
Mod. bleed | 25–50 IU/dL | 15–30 IU/kg | |||
Major bleed/surgery | 50–100 IU/dL | 30–50 IU/kg | |||
Plasma-derived human factor XI AlphaNine SD (T 1/2 21 hours) Mononine (T 1/2 25.3 hours) |
Repeat infusions every 12–24 hours for: 1–2 days (minor); 2–7 days (moderate); 7–10 days (major) | ||||
Plasma-derived human PCC Profilnine; activity ratio factor II 150, factor VII 35, factor IX 100, factor X 100), no heparin in product
Bebulin VH; activity ratio factor II 120, factor VII 13, factor IX 100, factor X 139), small amounts of heparin (≤0.15 IU heparin per IU factor IX) |
Hemophilia B Prevention and control of bleeding Not indicated for use in the treatment of factor VII deficiency Hemophilia B Not indicated for use in the treatment of factor VII deficiency |
1.0 IU/kg × body weight (kg) × desired increase factor IX (% of normal); mild to moderate bleed may usually be treated with a dose sufficient to raise the plasma factor IX level to 20%–30%; major hemorrhage, factor IX level should be raised to 30%–50%.
1.2 IU/kg × body weight (kg) × desired increase factor IX (% of normal) |
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Target | Initial Dose | ||||
Minor bleed | 20 IU/dL | 25–35 IU/kg, 1 day | |||
Mod. bleed | 40 IU/dL | 40–55 IU/kg, 2 days | |||
Major bleed | >60 IU/dL | 60–70 IU/kg, 2–3 days | |||
Minor surgery | 40–60 IU/dL | 50–60 IU/kg | |||
Major surgery | >60 IU/dL | 70–95 IU/kg |
Product | Contains | Major Indications | Dosages |
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Factor VII T 1/2 5 hours |
Recombinant human factor VII, activated NovoSeven RT (T 1/2 2.3–3.9 hours) |
Hemophilia A or B with inhibitors, acquired hemophilia, congenital factor VII deficiency Treatment of bleeding episodes Prevention of bleeding in surgical interventions or invasive procedures |
Hemophilia A or B with inhibitors: 90 mcg/kg given every 2 hours by bolus infusion until hemostasis is achieved, or until the treatment has been judged to be inadequate; for severe bleeds, dosing should continue at 3–6 hour intervals after hemostasis is achieved, to maintain the hemostatic plug Doses between 35 and 120 mcg/kg have been used successfully in clinical trials, and both the dose and administration interval may be adjusted based on the severity of the bleeding and degree of hemostasis achieved Acquired hemophilia: 70–90 mcg/kg repeated every 2–3 hours until hemostasis is achieved 90 mcg/kg body weight given immediately before surgery and repeated at 2-hour intervals for the duration of the surgery
Factor VII deficiency |
Activated prothrombin complex concentrate (aPCC) | Plasma-derived human PCC, activated FEIBA NF; contains human factors II, VIIa, IX, X, and VIII; 1 bypass activity unit (arbitrary) shortens aPTT of high titer to 50% of blank value |
Hemophilia A or B with inhibitors Indicated for the control of spontaneous bleeding episodes or to cover surgical interventions (>5 Bethesda units) |
50 to 100 units of aPCC, per kg of body weight every 6–12 hours with a maximum daily dose of 200 units/kg |
von Willebrand factor (VWF) T 1/2 11–12 hours |
Plasma-derived human VWF Humate-P; 2.4:1 VWF/FVIII Alphanate; 0.6:1 VWF/FVIII Wilate; 1:1 VWF/FVIII |
von Willebrand disease (vWD) Treatment of spontaneous and trauma-induced bleeding episodes; it is not indicated for the prophylaxis of spontaneous bleeding episodes Prevention of excessive bleeding during and after surgery. This applies to patients with severe vWD as well as patients with mild to moderate vWD where the use of desmopressin is known or suspected to be inadequate |
Treatment of bleeding episodes—administer 40–80 IU VWF:ristocetin cofactor (RCo) per kg body weight every 8–12 hours
Emergency surgery, administer a dose of 50–60 IU VWF:RCo/kg body weight; maintenance doses are half of loading dose every 8–12 hours |
Recombinant human VWF Vonvendi; VWF only, may need to supplement with rhFVIII if FVIII <40%; administer in ratio of 1.3:1 VWF/FVIII |
Product | Contains | Major Indications | Dosages | |||
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Prothrombin complex concentrate (PCC) | Plasma-derived human PCC KCentra; dose based on FIX content Activity ratio: factor II 76–160, factor VII 40–100, factor IX 80–124, factor X 100–204, protein C 84–164, protein S 48–136, antithrombin III 0.8–6; all human derived; product contains heparin |
Acquired deficiency of the prothrombin complex coagulation factors (e.g., vitamin K antagonist) Treatment of bleeding and perioperative prophylaxis of bleeding No adequate study in subjects with congenital deficiency is available PCC can be used for the treatment of bleeding and perioperative prophylaxis of bleeding in congenital deficiency of any of the vitamin K–dependent coagulation factors only if purified specific coagulation factor product is not available |
Initial INR | 2.0–3.9 | 4.0–6.0 | >6.0 |
Dose IU FIX/kg | 25 | 35 | 50 | |||
Max Dose IU (FIX) | 2500 | 3500 | 5000 | |||
The correction of the vitamin K antagonist-induced impairment of hemostasis is reached at the latest 30 minutes after the injection and will persist for approximately 6–8 hours. However, the effect of vitamin K, if administered simultaneously, is usually achieved within 4–6 hours. Thus, repeated treatment with human prothrombin complex is not usually required when vitamin K has been administered. For patients weighing more than 100 kg the dose calculations have to be based on 100 kg b.w. | ||||||
Factor X T 1/2 40–60 hours |
Plasma-derived human factor X Coagadex (T 1/2 30.0 hours) |
Congenital factor X deficiency | For treatment of bleeding episodes: 25 IU per kg body weight, repeated at intervals of 24 hours until the bleeding stops | |||
On-demand treatment and control of bleeding episodes | ||||||
Perioperative management of bleeding in patients with mild hereditary factor X deficiency (not studied in moderate/severe deficiencies) | Presurgery, raise plasma FX levels to 70–90 IU/dL | |||||
Postsurgery, maintain plasma FX levels at a minimum of 50 IU/dL until the patient is no longer at risk of bleeding due to surgery | ||||||
Required dose (IU) = Body weight (kg) × desired dactor X rise (IU/dL or % of normal) × 0.5 | ||||||
Plasma (FFP, FP24, thawed plasma) | ∼1 IU/mL each of human factors I, II, V, VII, VIII, IX, X, XI, XII, XIII, ATIII, PC, PS, VWF, and others | Coagulation factor deficiencies | 10–20 mL/kg loading dose with the T 1/2 of the factor being replaced guiding the frequency of subsequent doses 30 IU/dL coagulation factor levels are typically sufficient to achieve hemostasis; however, this can be difficult to achieve with plasma alone due to the large volumes required |
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Treatment of patients with documented coagulation factor deficiencies (congenital or acquired) and active bleeding, or who are about to undergo an invasive procedure Use when factor concentrate does not exist or it is unavailable (e.g., factor V, factor XI, protein S, plasminogen activator inhibitor-1, α 2 -antiplasmin) |
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Cryopreciptated antihemophiliac factor (cryoprecipitate) | Plasma-derived human factors I (≥10 mg/mL), VIII (≥5.3 IU/mL), XIII (2.7–4 IU/mL), VWF (5.3–8 IU/mL), and fibronectin | Hypofibrinogenemia, factor XIII deficiency | 8–10 bag pool (120–150 mL); postinfusion fibrinogen level should be measured to guide further therapy | |||
Treatment of patients for bleeding or immediately before an invasive procedure in patients with significant hypofibrinogenemia (<100 mg/dL) | ||||||
Factor XIII deficiency if factor concentrate not available | ||||||
Fibrinogen (factor I) T 1/2 100–150 hours |
Plasma-derived human factor I RiaSTAP (T 1/2 78.7 hours) |
Congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia |
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Treatment of acute bleeding episodes Not indicated for dysfibrinogenemia |
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or if baseline unknown, 70 mg/kg | ||||||
In Europe, this product has been used as fibrinogen replacement in postpartum hemorrhage and trauma settings | Target fibrinogen level of 100 mg/dL should be maintained until hemostasis is obtained | |||||
Factor XIII T 1/2 7–12 days |
Plasma-derived human factor XIII | Congenital factor XIII deficiency Prophylactic treatment |
40 IU per kg body weight, loading dose; dosing should be guided by the most recent trough Factor XIII activity level, with dosing every 28 days (4 weeks) to maintain a trough level of approximately 5%–20%. Recommended dosing adjustments of ±5 units per kg should be based on trough FXIII activity levels of <5% or >20%, and the patient’s clinical condition. | |||
Corifact (T 1/2 6.6 days) | Perioperative management of surgical bleeding | |||||
Recombinant human factor XIII | ||||||
Tretten (A-subunit, T 1/2 5.1 days) | ||||||
Not for B-subunit deficiency |
Product | Contains | Major Indications | Dosages |
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Antithrombin III (ATIII) T 1/2 2.8–4.8 days |
Plasma-derived human ATIII Thrombate III (T 1/2 2.5 days) |
ATIII deficiency Treatment of patient with congenital ATIII deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism Can be useful in cases of heparin resistance but no clinical trial data supports this usage |
Loading dose and 60% loading every 24 hours for maintenance; Target levels of 80–120 IU/dL; to be maintained 2–8 days |
Recombinant human ATIII ATryn (T 1/2 11.6–17.7 hours) |
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Protein C T 1/2 6–10 hours |
Plasma-derived human Protein C Ceprotin (T 1/2 9.9 hours) |
Protein C deficiency Prevention and treatment of venous thrombosis and purpura fulminans Replacement therapy |
100–120 IU/kg, followed with subsequent dosing of 60–80 IU/kg every 6 hours and maintenance dosing of 45–60 IU/kg every 6 or 12 hours |
Thrombin (topical) | Recombinant human factor II, activated Recothrom |
To aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical; may be used in conjunction with an absorbable gelatin sponge | For TOPICAL USE only, DO NOT INJECT, DO NOT use for the treatment of massive or brisk arterial bleeding Reconstituted solution can be applied on the surface of bleeding tissue; the amount of topical thrombin required depends on the area of tissue to be treated and method of application |
Plasma-derived human factor II, activated Evitrhom |
Historically, the major source of coagulation factors for treatment of congenital deficiencies was donated human plasma or its derivative cryoprecipitated antihemophilic factor (cryoprecipitate). Next, the development of plasma fractionation and factor purification became available. In the 1980s, HIV, hepatitis B, and hepatitis C were discovered and resulted in a large proportion of transfusion infection transmission in patients with congenital coagulation factor deficiencies. This led to improved testing, processing, and the development of recombinant products with no human proteins.
(1) Plasma is collected either through apheresis as source plasma or whole blood as recovered plasma from donors who have undergone a rigorous donor health questionnaire and infectious disease screening similar to which is performed for allogeneic blood donation. (2) Large numbers of individual donor plasma units are pooled, concentrated, and purified to various levels with several processes, which include protein precipitation, chromatographic separation methods, and antibody-antigen capture columns. (3) The concentrated coagulation factors are treated to substantially reduce pathogen-infectious risk with methods such as heat inactivation, organic solvent treatment, in addition to nanofiltration.
Additionally, the pooled, concentrated, and virally inactivated product is tested with nucleic acid amplification tests to many pathogens including HIV, hepatitis C, hepatitis A, hepatitis B, HTLV-I/II, WNV, and parvovirus. While a substantially safer product than those previously offered has resulted, with no case of transfusion-transmitted disease being reported since the mid-1990s, patients still exhibit a high level of apprehension with receiving human-derived factor concentrates, which has led to the development of recombinant products without human proteins.
With the advent of genetic and cellular engineering technologies, it is possible to isolate the genes of specific coagulation factors, such as factor VIII, and to artificially produce properly functioning protein from cell culture, thereby eliminating the infection transmission risk. Another potential benefit of artificially producing coagulation factors was the freedom from reliance on blood donation, thereby ensuring a more predictable supply. While the safety is perceived to be much higher, the trade-off of laboratory-derived products is a substantially higher price. Enhanced purity has also contributed to an increased ability to characterize the biological effect and make it a more uniform product with less lot-to-lot variability than with human-derived factors.
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