Chapter 5 -Concentrates for hemostatic disorders

Question 1

How are clotting factor concentrates sourced?

Answer 1

They can be extracted from pooled donated plasma (plasma-derived) or manufactured using biotechnology (recombinant).

Question 2

What is the Health Canada Special Access Program (SAP)?

Answer 2

** It allows access to unlicensed or certain licensed clotting factor products that have not undergone Health Canada batch release.**

Question 3

What is Emicizumab?

Answer 3

Emicizumab is a bispecific monoclonal antibody that mimics the function of factor VIII and is indicated for routine prophylaxis in hemophilia A patients with or without inhibitory antibodies against factor VIII.

Question 4

What is the main indication for Emicizumab in hemophilia A patients?

Answer 4

Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Question 5

What are recombinant clotting factor concentrates (r)?

Answer 5

These are clotting factor concentrates produced using biotechnology, where clotting factor genes are transfected into cultured cell lines to express the factor.

Question 6

How are recombinant clotting factor concentrates made?

Answer 6

Clotting factor genes are inserted into vectors, **transfected into **cell lines, and the recombinant proteins are purified for therapeutic use.

Question 7

Non-clotting factor product

1-What is Emicizumab (Hemlibra®)
2- How is Emicizumab produced?

Answer 7

1. A bispecific monoclonal antibody to FIX/FIXa and FX/FXa, used as a non-clotting factor product for hemostasis.
2. It is manufactured using recombinant technology in Chinese hamster ovary (CHO) cells.

Question 8

What allergy precautions should be considered with Emicizumab?

Answer 8

Trace hamster proteins (from CHO cells)
Trace bovine proteins (human-animal protein used in cell culturing but removed during the manufacturing process)

Question 9

What are the criteria for access to Emicizumab through Canadian Blood Services?

Answer 9

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

Question 10

What is the function of Emicizumab?

Answer 10

It mimics the function of factor VIII in the coagulation cascade to prevent or reduce bleeding episodes in hemophilia A patients.

Question 11

How does the chromatographic process affect viral load in clotting factor concentrates?

Answer 11

It reduces the viral load during fractionation and purification.

Question 12

What virus inactivation/partitioning procedures are used in plasma-derived and recombinant concentrates?

Answer 12

Procedures are incorporated to inactivate/partition viruses during manufacturing for plasma-derived and most recombinant concentrates.

Question 13

What pathogens are effectively targeted by virus inactivation procedures?

Answer 13

Effective against HIV, hepatitis C (HCV), and hepatitis B (HBV).

Question 14

Since when have virus-inactivated factor concentrates been used in Canada, and what has been the impact?

Answer 14

Introduced in 1985
No cases of HIV or HCV transmission due to concentrates since 1987 and 1988, respectively.v

Question 15

Are all viruses inactivated by these procedures?

Answer 15

No, non-enveloped viruses such as parvovirus B19 and hepatitis A can be resistant to inactivation processes.

Question 16

: What vaccines **should be **administered to patients with congenital coagulation deficiency receiving blood products?

Answer 16

Hepatitis B virus (HBV)
Hepatitis A virus (HAV)

Question 17

What is the theoretical risk associated with plasma-derived concentrates?

Answer 17

The transmission of Creutzfeldt-Jakob disease (CJD) and variant CJD.

Question 18

Effects and side effects

How do clotting factor concentrates affect hemostasis?

Answer 18

Correct the underlying clotting defect, which may lead to thrombotic complications in patients with clotting factor deficiency and coexisting risk factors for thrombosis or disseminated intravascular coagulation (DIC).

Question 19

What clotting factor products should be used with caution in patients at risk for thrombosis or DIC?

Answer 19

• FEIBA (Factor VIII Inhibitor Bypass Activity)
• Factor XI (FXI) concentrate
• Recombinant Factor VIIa (rFVIIa)

Question 20

What are the precautions for using Prothrombin Complex Concentrate (PCC) and Activated Prothrombin Complex Concentrate (aPCC)?

Answer 20

Not indicated for liver disease, DIC, or patients with active arterial/venous thromboembolism or thrombotic risks.
Can cause myocardial infarction or intracardiac thrombus.
Contraindicated in those with a history of heparin-induced thrombocytopenia (HIT) due to heparin presence.

Question 21

What is the maximum dosage for FEIBA?

Answer 21

Should not exceed 200 IU/kg/day.

Question 22

What are the risks associated with Hemlibra® (emicizumab) prophylaxis in combination with PCC or aPCC?

Answer 22

Increased risk of thromboembolism and thrombotic microangiopathy (TMA).
aPCC should not exceed 50 IU/kg/dose or 100 IU/kg/day with TMA monitoring.
PCC/aPCC should not be used for 6 months after Hemlibra® has been stopped due to Hemlibra’s long half-life (~4 weeks).

Question 23

What is the maximum dosage for Factor XI concentrate?

Answer 23

Should not exceed 30 IU/kg per dose.

Question 24

What has been reported in patients with von Willebrand disease (VWD) treated to raise FVIII levels during surgery?

Answer 24

Thrombosis has been reported when FVIII levels exceed 200 IU/dL (2 IU/ml).

Question 25

What should be avoided when using PCC and aPCC (including FEIBA)?

Answer 25

Antifibrinolytic therapy should be avoided.

Question 26

What concentrates contain heparin and should be avoided in patients with a history of HIT? A:

Answer 26

Factor VII concentrate (Takeda), FX®P (CSL-Behring), FXI concentrate (BPL), FIX Immunine® VH (Takeda), PCC Beriplex® P/N (CSL Behring), PCC Octaplex® (Octapharma), Antithrombin III NF (Takeda).

Question 27

1- How can minor allergic reactions to protein products be prevented? 2- What should patients on home therapy have on hand to manage serious allergic reactions or anaphylaxis?

Answer 27

1- By pre-medicating with antihistamines. 2- Epinephrine (e.g., Epipen®).

Question 28

What can be done if an allergic reaction occurs during treatment with a protein product?

Answer 28

A similar concentrate from a different manufacturer can be used for subsequent treatment, which may not cause an allergic response.

Question 29

Why should caution be exercised with some recombinant concentrates or products?

Answer 29

They may contain trace amounts o**f non-human proteins.** Manufacturers suggest caution in patients with known allergies to these proteins.

Question 30

What is unique about recombinant porcine FVIII?

Answer 30

It contains porcine protein.

Question 31

What severe allergic responses may occur in hemophilia B patients?

Answer 31

****Severe allergic reactions, including anaphylaxis, can occur when patients develop inhibitors to factor IX (FIX) concentrates.

Question 32

When are hemophilia B patients most likely to develop inhibitors and allergic responses?

Answer 32

Usually early on during treatment with FIX concentrate in severe hemophilia B patients.

Question 33

Where should newly diagnosed severe hemophilia B patients be treated during their initial treatments?

Answer 33

In a setting equipped to manage severe allergic reactions, especially during the first 10-20 treatments.

Question 34

# Storage What is required for long-distance transportation of clotting factor concentrates stored at 2–8°C?

Answer 34

Transport in validated containers cooled with cold packs. ## Footnote They are stable until the printed expiration date when stored at the specified temperature.

Question 35

Can clotting factor concentrates be stored at room temperature (RT)?

Answer 35

Some concentrates can be stored at RT (usually ≤25°C or ≤30°C) for a specified period after removal from refrigeration.

Question 36

What must be done when clotting factor concentrates are removed from refrigeration for storage at RT?

Answer 36

The date of removal from refrigeration must be clearly marked on the box.

Question 37

Can RT-stored concentrates be returned to refrigeration?

Answer 37

No, manufacturers do not recommend returning RT-stored concentrates to refrigeration.

Question 38

Should clotting factor concentrates be stored at freezing temperatures?

Answer 38

No, storage at freezing temperatures should be avoided.

Question 39

How are clotting factor concentrates packaged for Canadian patients?

Answer 39

**Supplied with a kit for reconstitution and infusion, usually with the appropriate diluent.** ## Footnote 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.

Question 40

What proprietary devices do many manufacturers provide for reconstitution?

Answer 40

Devices for **transferring diluent into the vial with the lyophilized** concentrate and for withdrawing the dissolved concentrate to syringes for infusion.

Question 41

What should be followed during reconstitution of clotting factor concentrates?

Answer 41

The reconstitution instructions in the product insert and aseptic techniques.

Question 42

What is the ideal temperature for vials of diluent and concentrate before mixing?

Answer 42

They should be at room temperature or pre-warmed to 20–37°C for refrigerated products.

Question 43

How should the diluent be added to the vial containing the concentrate?

Answer 43

t should flow down the side of the vial wall, and the mixture should be swirled gently to allow dissolution.

Question 44

Why should shaking be avoided during reconstitution?

Answer 44

Shaking may create bubbles/foam, which can lead to denaturation of proteins.