Chapter 5

Concentrates for hemostatic disorders and hereditary angioedema

This chapter provides detailed information about concentrates for treatment of hemostatic disorders and hereditary angioedema in Canada. Clotting factor concentrates are highly effective treatments for patients with hemostatic disorders caused by missing or defective clotting factors. Clotting factor concentrates may be extracted from pooled donated plasma (plasma-derived) or manufactured using biotechnology (recombinant). Several protein concentrates are available for the treatment of thrombotic disorders and hereditary angioedema.

The factor concentrates available to Canadian patients, as either Health Canada-licensed or unlicensed products, are listed in Table 1a. Access to the unlicensed products and some licensed products that have not undergone Health Canada batch release can be obtained under the Health Canada Special Access Program (SAP) (see note in Table 1a). In addition, a bispecific monoclonal antibody, called emicizumab, that mimics the function of FVIII is now available in Canada. Emicizumab is indicated for hemophilia A patients (congenital factor VIII deficiency) with or without inhibitory antibodies against factor VIII as routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes (Table 1b).

Plasma-derived (pd)

The majority of clotting factor concentrates are manufactured from pooled donor plasma.

Recombinant (r)

Recombinant clotting factor concentrates are manufactured using biotechnology. Recombinant products are expressed in cultured cell lines transfected with vectors carrying the clotting factor gene. The recombinant proteins secreted into the culture medium are purified and formulated for therapeutic use. Tables 2 and 3 provide information about the cell lines and the human/animal proteins used during the recombinant product manufacturing process or in the formulation, and the associated allergy precaution required for each recombinant product.  

Factor concentrates available in Canada are listed in Table 1a. Table 1a is based on information available at the time of publication; however, this information is time-sensitive and will change regularly. Please refer to Canadian Blood Services’ Plasma Protein & Related Products Customer Table of Information (under the section on PPRP dosage, manufacturer and customer information) for the most recent updates. Note that some products may be licensed by Health Canada but not carried on the Canadian Blood Services and/or Héma-Québec formulary.

Pharmacokinetic data (IVR, t_1/2) may be rounded or generalised; consult product monograph for product-specific information.

Table 1a: Concentrates for hemostasis or hereditary angioedema

Ordering

For licensed products, contact Canadian Blood Services or Héma-Québec.

For all unlicensed and some licensed products not yet batch-released by Health Canada, contact the Health Canada Special Access Program (SAP). Regular business hours are weekdays from 8:30 am to 4:30 pm Eastern Standard Time (EST). Fax all requests to (613) 941-3194. For after hours and urgent requests requiring immediate attention please follow up with a call to the SAP at: (613) 941-2108 (available 24/7).

Notes on factor concentrates

Recovery or IVR (activity in IU/dL recovered in circulation after 1 IU/kg infused) and half-life (t_1/2) were established in patients with severe congenital deficiency, not in patients with acquired deficiency. For antithrombin and protein C products, recovery and t_1/2 are expected to be lower during acute thrombotic events. See Figure 1 for notes on dosing.

Recovery and t_1/2 indicated here are provided as rough guides only—the precise recovery and t_1/2 may be different from patient to patient and can be determined by pharmacokinetic studies to help with more precise dosing and dosing intervals (see Chapter 17 of this Guide). Recovery tends to be lower in children, who have higher plasma volumes.

Image

Emicizumab (Hemlibra®), bispecific monoclonal antibody to FIX/FIXa and FX/FXa is a non-clotting factor product manufactured by recombinant technology.

• produced in Chinese hamster ovary (CHO) cells (allergy precaution: trace hamster proteins)
• human-animal protein present in cell culturing but removed during manufacturing process (allergy precaution: trace bovine proteins)

Current criteria for access to Hemlibra® through Canadian Blood Services is:

1. Congenital hemophilia A with inhibitors to factor VIII
2. Severe congenital hemophilia A (intrinsic factor VIII level < 1%) without inhibitors

Table 1b: Non-clotting factor product for hemostasis available in Canada

Administration

Hemlibra® (emicizumab) is administered subcutaneously for bleeding prophylaxis in hemophilia A patients with or without inhibitors:

• Loading dose: 3 mg/kg weekly x 4 weeks
• Maintenance dose:
  • 1.5 mg/kg weekly, or
  • 3 mg/kg biweekly, or
  • 6 mg/kg every 4 weeks

Note: the maintenance dose of 6 mg/kg once every 4 weeks is not recommended for patients <40 kg body weight or patients <12 years of age.

The chromatographic process used during fractionation and purification of the clotting factors reduces the viral load.

Additionally, virus inactivation/partitioning procedures are incorporated into the manufacturing process for all plasma derived concentrates and most of the recombinant concentrates (see Tables 1a and 1b).

• The virus inactivation procedures are all effective against important human pathogens such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV). In Canada, virus-inactivated factor concentrates were introduced in 1985. No case of HIV or HCV transmission due to concentrate use has occurred since 1987 and 1988, respectively.
• However, no virus inactivation procedure is expected to inactivate all viruses. In particular, non-enveloped viruses such as parvovirus B19, a pathogen in immunosuppressed patients, can be resistant to viral inactivation processes.

Patients with congenital coagulation deficiency who are expected to receive any blood product(s) should be immunized against HBV and hepatitis A virus (HAV).

Transmission of Creutzfeld-Jakob disease (CJD) and variant CJD is considered a theoretical risk for plasma derived concentrates.

Clotting factor concentrates affect hemostasis by correcting the underlying clotting defect.

Patients with clotting factor deficiency and with coexisting risk factors for thrombosis or disseminated intravascular coagulation (DIC) may develop thrombotic complications when the hemostatic mechanism is corrected.

Factor eight inhibitor bypass activity (FEIBA), factor XI (FXI) concentrate and recombinant factor VIIa (rFVIIa) should be used with caution and under the guidance of a hematologist/thrombosis or transfusion specialist physician in patients with risk factors for thrombosis or DIC.

Prothrombin complex concentrate (PCC) and activated prothrombin complex concentrate (aPCC) should be administered as directed on the package insert to prevent thrombotic complications. It is not indicated for liver disease, DIC, or patients with active arterial or venous thromboembolism or with underlying thrombotic risks. Use of PCC and aPCC has been reported to result in myocardial infarction and intracardiac thrombus.^1-3 Due to presence of heparin, it is contraindicated in those with a history of heparin-induced thrombocytopenia (HIT).

The dosage for FEIBA should not exceed 200 IU/kg/day.

• Patients on Hemlibra® (emicizumab) prophylaxis
  • should avoid using aPCC or PCC because of the risk of thromboembolism and thrombotic microangiopathy (TMA).
  • If aPCC must be used, the dose should NOT exceed 50 IU/kg/dose or 100 IU/kg/day with TMA monitoring
  • Hemlibra® has a half-life of ~4 weeks and remains in circulations for months after discontinuation. aPCC and PCC should not be used for 6 months after Hemlibra® has been stopped
• The dosage for FXI concentrate should not exceed 30 IU/kg per dose.
• Thrombosis has been reported in patients with von Willebrand disease (VWD), treated to raise factor VIII (FVIII) level in excess of 200 IU/dL (2 IU/ml) in the surgical setting.
• Antifibrinolytic therapy should be avoided when using PCC and aPCC (including FEIBA).

Several plasma-derived concentrates contain heparin (Factor VII concentrate [Takeda], FX®P [CSL-Behring], FXI Factor XI concentrate [BPL], FIX Immunine^® VH [Takeda], PCC Beriplex^® P/N [CSL Behring], PCC Octaplex^® [Octapharma], Antithrombin III NF [Takeda]; see Table 1a). These concentrates should be avoided in patients with a history of heparin-induced thrombocytopenia.

As with infusion of any protein products, allergic reactions may occur.

• Minor allergic reactions may be prevented by pre-medication with antihistamines.
• When an allergic reaction occurs, a similar concentrate from a different manufacturer can be used for subsequent treatment and may not result in an allergic response.
• Patients on home-therapy should have epinephrine (e.g., Epipen^®) on hand to deal with serious allergic reactions or anaphylaxis.
• Some recombinant concentrates or products may contain trace amount of non-human proteins (see Tables 2 and 3). The manufacturers suggest caution in the use of their respective products in patients with known allergy to these proteins. Recombinant porcine FVIII is of porcine protein in nature.

Hemophilia B patients may have severe allergic responses (including anaphylaxis) to concentrates containing factor IX (FIX) (including prothrombin complex concentrates and FEIBA) at the time inhibitors are developing.

• In susceptible severe hemophilia B patients, inhibitors develop usually early on with FIX concentrate treatment.
• It is advisable to treat newly diagnosed severe hemophilia B patients in a setting equipped for management of severe allergic reactions during at least the initial 10-20 treatments.⁴

Table 2: Cell lines used for the manufacturing of various recombinant factor concentrate

Table 3: Human/animal proteins that may be present during the manufacturing process (cell culturing or purification) or in formulation in recombinant factor concentrates

Clotting factor concentrates are stable until the printed expiration date on the vials (or boxes) when stored at the specified temperature.

• For products that are to be refrigerated at 2–8°C (see Tables 1a, 1b), long distance transportation must occur in validated transport containers cooled with cold packs.
• Some, but not all, of these concentrates can be stored at RT (usually ≤25°C or ≤ 30°C) for a specified period after removing from the refrigerated temperature (see Table 1).
• When it is necessary to store these products at RT, the date when the box is removed from refrigeration must be clearly marked on the box, and the manufacturers do not recommend returning these RT stored concentrates to refrigeration.
• Storage of concentrates at freezing temperature should be avoided.

Almost all clotting factor concentrates available to Canadian patients are supplied in packages containing a kit for reconstitution and infusion, usually with the appropriate diluent.

Many manufacturers also provide proprietary devices for transferring diluent into the vial containing the lyophilized concentrate and for withdrawing the dissolved concentrate to syringes for infusion. The reconstitution instructions in the product insert must be followed and aseptic techniques observed. 

In general, the vials of diluent and concentrate should be at room temperature (or pre-warmed to 20–37^oC for refrigerated products) before mixing. The diluent should, if possible, be allowed to flow down the side of the vial wall and the mixture should then be swirled gently to allow dissolution of the concentrate. Shaking must be avoided as it may create bubbles/foam and result in denaturation of the proteins.

Table 4 below provides indications, monitoring, contraindications/precautions and available alternatives for different classes of factor concentrates (Table 1a) and nonfactor product (Table 1b). For specific product information refer to the package insert provided by the manufacturer of each concentrate.

Table 4: Use of clotting factor concentrates and nonfactor product

Prothrombin complex concentrates for acquired bleeding disorders (Table 4, items 21-22)

• For rapid reversal of warfarin anticoagulant (or severe Vitamin K deficiency) in patients with severe bleeding or requiring emergency surgery (see also Chapter 17 of this Guide): for dosage at different INR, please consult National Advisory Committee on Blood and Blood Products (NAC) 2022 recommendations on use of prothrombin complex concentrates,  as well as the Thrombosis Canada clinical guides.
• For reversal of DOAC (anti-Xa) in patients with severe bleeding or requiring emergency surgery (see also Chapter 17 of this Guide) and when specific antidote (Andexanet alfa [AndexXa^®]) is not available. Dosage: 25-50 IU/kg, maximum 3000 IU

For treatment of dilutional coagulopathy with acquired clotting factors deficiency. A Canadian pilot study suggested 4-factor PCC may be a suitable alternative to fresh plasma for management of bleeding following cardiac surgery.⁵

Activated prothrombin complex concentrate for acquired bleeding disorders (Table 4, item 23)

• For reversal of DOAC (anti-IIa, Dabigatran^®) in patients with severe bleeding or requiring emergency surgery (see also Chapter 17 of this Guide) and when specific antidote (idarucizumab [Praxbind^®) is not available. Dosage 50 IU/kg, maximum 2000 IU. For more information, please consult the Thrombosis Canada clinical guides and the 2022 NAC recommendations on use of prothrombin complex concentrates.

Fibrinogen concentrates for acquired fibrinogen deficiency (Table 4, items 24-25)

Fibrinogen concentrates are safe and effective alternatives to cryoprecipitates and plasma in severe bleeding with hypofibrinogenemia following surgery/trauma and in association with dilutional and consumptive coagulopathies (e.g., massive transfusion, see Chapter 11 of this Guide).⁶ The Canadian FIBRES randomized clinical trial showed that 4 g fibrinogen concentrate was non-inferior to 10 units cryoprecipitates for patients with significant bleeding and hypofibrinogenemia following cardiac bypass surgery.⁷

The product monographs/package inserts should be consulted for further information about the various products discussed in this chapter. See Chapter 17 of this Guide for more information on hemostatic disorders.

The information presented in this chapter was obtained from the individual manufacturers, usually vetted through their medical/scientific and regulatory departments, and from product monographs available online. Where possible, data from different sources were compared to each other and to the literature. It should be noted that parameters such as average IVR and t_1/2 are approximate and may differ slightly from different sources including those from different studies and different phases of clinical trials.

Fellows and health-care professionals who participate in the Canadian Royal College's Maintenance of Certification (MOC) program can claim the reading of the Clinical Guide to Transfusion as a continuing professional development (CPD) activity under Section 2: Individual learning. Learners can claim 0.5 credits per hour of reading to a maximum of 30 credits per year.

Medical laboratory technologists who participate in the Canadian Society for Medical Laboratory Science’s Professional Enhancement Program  (PEP) can claim the reading of the Clinical Guide to Transfusion as a non-verified activity. 

The authors acknowledge Kathryn Webert, MD, MSc, FRCPC; Aditi Khandelwal, MDCM, FRCPC; and Caitlin Jones, BScPhm, RPh, PharmD, MScHQ, for their review of this chapter.

Poon M, Goodyear D, Rydz N, Lee A. Concentrates for hemostatic disorders and hereditary angioedema. In: Clarke G, Abe T, editors. Clinical Guide to Transfusion [Internet]. Ottawa: Canadian Blood Services, 2022 [cited YYYY MM DD]. Chapter 5. Available from: https://professionaleducation.blood.ca

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