Plasma components and other blood products

This chapter is relevant to Section Q4(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to demonstrate that they "understand the pharmacology of blood and its components, including individual factor replacement". To some extent, it also satisfies Section Q4(iii), which expects them to "understand the process of collection and production of blood and its components". As most CICM trainees and fellows are not ever expected to get involved in the industrial production of blood products, this particular area will be deprioritised to make room for more important material.

What is that important material? That was difficult to determine. The only two questions in the primary exam that touched on this were Question 3 from the first paper of 2019 and Question 2 from the second paper of 2022, which asked the candidates to compare FFP and prothrombinex. The pass rate was 10% in 2019. For the 90% who failed, the examiners' comments were useless - they were not particularly forthcoming with suggestions on how to improve the answer, other than to say that "useful headings included preparation and administration, dose, indications and adverse effect". This lack of guidance leans dangerously in the direction of learner autonomy,  leaving the scope of this topic up to the interpretation of the author. 

How to structure this response? At a minimum, some sort of pharmacological approach is probably called for, but the standard headings (eg. oral biavailability) should probably not be applied. Very basic headings taken from the college comments are used here as a means of organising the information. As an example, this summary box contains the facts necessary to answer Question 3:

  Fresh frozen plasma Prothrombinex
Description The liquid portion of the blood, separated and frozen within 8 hours of collection Lyophilised human clotting factor concentrate
Presentation 250-300ml bags, clearly labelled with the donor blood type. Glass vial with powdered concentrate inside, for reconstitution with sterile water. Each vial usually contains 500 units.
Preparation Separation (by centrifuge) from whole blood, either after donation or by apheresis. It must be prepared and frozen within 6-18 hours. Prepared by adsorption of coagulation factors from plasma onto an ion exchange medium followed by selective elution
Contents

Essentially all clotting factors 

  • Fibrinogen 400-900mg/unit
  • Factor VII of the extrinsic pathway (so it will correct the PT)
  • Factors XI and IX of the intrinsic pathway (so, it decreases your aPTT)
  • Factors X and II (Prothrombin) of the common pathway 
  • 200 IU of Factor VIII per adult dose
  • 500 units of Factor IX  
  • 500 units of Factor II (prothrombin)
  • 500 units of Factor X 
Storage

can be stored frozen for up to 12 months at -25ºC. 

Refrigerated, stored for 6 months
Indications

Coagulopathy

Plasma exchange

ACE-I angioedema

C1 esterase inhibitor deficiency

Suxamethonium apnoea

Warfarin reversal

Correction of coagulopathy from deficiency of specific factors

Dose 10–15 mL/kg per dose For the reversal of warfarin is 15–50 IU/kg
Precautions Large volume: may cause circulatory overload Small volume: not a resuscitation fluid
Group, crossmatch Needs to be ABO grouped, but does not require crossmatch Does not need to be ABO grouped or crossmatched
Adverse effects
  • Circulatory overload
  • Lung injury (TRALI)
  • Allergic reaction (from urticaria to anaphylaxis)
  • Acute or delayed haemolytic transfusion reaction
  • Non-haemolytic febrile transfusion reaction
  • Risk of bacterial or viral infection
  • Allergic or anaphylactic reaction
  • Thrombosis  in predisposed individuals 

The best single reference would have to be transfusion.com.au. If you ask a transfusion scientist where they would want you to get your information from before you start using blood products, that is where they would send you.  For some peer-reviewed resources, Benjamin & McLaughlin (2012) is the single best option for the plasma components. FFP specifically is covered in a short no-nonsense fashion by Khawar et al (2020), and cryoprecipitate, by (Wong & Curry, 2016).

Packed red blood cells

Description: Packed red blood cells is a plasma-depleted cell product for the replacement of haemoglobin.

Presentation: Usually, a bag of packed red blood cells will be a flattened flexible container with about 150-250ml of concentrated red cells. Essential elements of the packaging include the details of the crossmatch and some mechanism of tracing the donor.

Preparation of PRBCs involves adding citrate as an anticoagulant and then centrifuging the cells to remove the plasma. What remains is filtered though a leukodepletion filter to remove any white cells. As discussed elsewhere, leukodepleted red cells have become the standard in Australia, with noticeable improvement in the rate of transfusion-related lung injury. 

The contents and properties of packed red blood cells are discussed elsewhere in much greater detail; it will suffice to say that this material does not resemble human blood. Each bag will be slightly different and will contain

  • 40-50g haemoglobin (i.e. a concentration of about 200g/L 
  • 25 mmol sodium  (i.e. a concentration of about 120 mmol/L)
  • 5 mmol potassium (i.e 25 mmol/L)
  • 5 mmol lactate (yes, the lactate of red cells is about 25mmol/L)
  • about 0.5mmol of citrate (i.e. about 2.5-3.0 mmol/L)
  • Water, with a pH of about 6.5

Storage is in the fridge, at 2-6º C. The cells have variable shelf lives depending on the local blood bank policy, but usually no longer than 42 days. They cannot be stored for much longer than that because of various metabolic and morphological changes which they undergo while in this cryostasis, broadly described as "storage lesions".

Indications for use for PRBCs should seem pretty straightforward, but in fact there is some controversy regarding the precise indications for blood transfusion in the ICU. One might summarise as follows:

  • To increase oxygen-carrying capacity where there is clinically significant anaemia
  • To decrease the myocardial workload
  • To replace ineffective red cells (i.e. exchange transfusion)

Dose is difficult to discuss, in the context of the above, and could be summarised as "enough to achieve the goals of the transfusion". A widely believed fact is that a single bag of PRBCs will increase the haemoglobin of an average-sized person by 10 g/L. 

Need for typing and crossmatching: yes, red cells need to be typed and matched as a necessary precondition before transfusion.

The adverse effects of blood transfusion, discussed elsewhere, in summary, are:

  • Circulatory overload
  • Lung injury (TRALI)
  • Allergic reaction (from urticaria to anaphylaxis)
  • Acute or delayed haemolytic transfusion reaction
  • Non-haemolytic febrile transfusion reaction
  • Iron overload
  • Transfusion-associated graft-versus-host-disease (TA-GVHD)
  • Post-transfusion purpura
  • Risk of bacterial or viral infection

Platelets

Description: concentrated human platelets

Presentation is usually as a very flat and transparent gas-permeable bag with concentrated human platelets, suspended in a nutrient solution. The total volume is usually 200-300ml. 

Preparation can go two ways:

  • Apheresis platelets are separated from donor blood by apheresis, i.e. the blood can be returned to the donor after the platelets are separated from it. This usually yields a large amount of platelets, as the apheresis can be continued until the desired platelet volume is extracted. Each apheresis donation can be used to make up to three platelet units. 
  • Pooled platelets are separated from whole blood donations, either from platelet-rich plasma or from the "buffy coat" of a whole blood donation, which is a thin layer of platelets and white cells that forms when anticoagulated blood is separated by centrifuge. This is less than 1% of each donated volume, which makes it a rather low-yield method of collecting platelets, and platelets from several donors must be combined to make a clinically useable platelet volume (usually, 4-6 donors contribute to each pooled bag)

Contents and chemical properties: after they are separated, platelets need to be suspended in a special "platelet additive solution". Some donor plasma remains (perhaps 30-40% by volume), and the rest is a crystalloid medium which is designed to increase their shelf life and decrease their immunogenicity. Usually this solution is not especially clever, consisting mainly of sodium chloride, sodium citrate, and sodium acetate. Small amounts of phosphate potassium and magnesium are included in the mixture. The total concentration of these electrolytes is too trivial to discuss, as platelets are rarely administered in such a massive volume that the electrolyte composition becomes troublesome. Each bag contains enough platelets to increase the platelet count of a normal size adult by 20–40 × 109/L.

Storage can be for up to seven days. Platelets have internal death clocks which limit their shelf life in storage; at the end of their life they will undergo apoptosis-like changes which label them for immediate destruction by the reticuloendothelial system. While in storage, they must remain at room temperature (20 - 24º C), and need to be rocked gently. The reason for this agitation has nothing to do with clumping or clotting - instead it is to allow gas exchange.  That is the reason the bag needs to be extremely flat, and the automated rockers blobble the bags of platelets to and fro in order to allow mixing, so each and every platelet has the opportunity to change gas (Van Der Meer et al, 2011)

Indications for use are basically confined to thrombocytopenia and correction of platelet dysfunction (for example, the reversal of antiplatelet agent effects)

Dose is related to what the patient plans to do with the platelets, but is usually one unit. This tends to increase the platelet count by enough points to allow whatever invasive procedure you were planning.

Need for typing and crossmatching: preferably platelets should be ABO-typed. It is not essential but is highly desirable as platelet may also have ABO antigens of their surface and the small dilute remnant of donor plasma in the donated sample may contain anti-ABO antibodies. Crossmatching is not necessary

Adverse effects are similar to the transfusion of red cells, but realistically one is never going to be giving enough platelt bags to see TACO or TRALI. A much more likely complication is infection. Because platelets are kept at room temperature, they are much more likely to develop bacterial or fungal contamination.

FFP: fresh frozen plasma

Description: The liquid portion of the blood, separated and frozen within 8 hours of collection

Presentation is 250-300ml bags, clearly labelled with the donor blood type.

Preparation is by separation from whole blood, either after donation or by apheresis. It must be prepared and frozen within 6-18 hours.

Contents and chemical properties:  FFP contains essentially all of the clotting factors, including even fibrinogen:

  • Fibrinogen content is 400-900mg/unit, so approximately the same as 2-3 units of cryoprecipitate - unless the FFP is specifically cryodepleted. The concentration of fibrinogen in cryoprecipitate is higher: FFP may have 1.3-3.0g/L of fibrinogen, whereas cryoprecipitate contains about 7-8g/L.
  • Factor VII of the extrinsic pathway (so it will correct the PT)
  • Factors XI and IX of the intrinsic pathway (so, it decreases your aPTT)
  • Factors X and II (Prothrombin) of the common pathway (so, it decreases TT, PT and aPTT)

Unfortunately, there isn't much factor VIII. Its solubility is too low at low temperatures, and FFP (once thawed) doesn't contain enough of it. Stil, the Australian Red Cross claims theirs has  200 IU of Factor VIII per adult dose.

Storage, as frozen plasma, can be for up to 12 months at -25ºC. 

Indications for use are numerous:

  • To correct coagulopathy where the coagulopathy can't be corrected with a specific factor concentrate
  • To replace plasma extracted in the course of therapeutic plasma exchange, where albumin would not be an appropriate replacement fluid, for example in TTP/HUS
  • To replace a circulating protein which is missing of dysfunctional, eg. where it is given for C1 esterase inhibitor deficiency, or to supplement lacking plasma esterases in cases of suxamethonium apnoea

Dose is usually said to be 10–15 mL/kg per dose, but realistically the dose is "however much is required to achieve whatever the desired effect is".

Need for typing and crossmatching: preferably FFP should be ABO-typed, as donor plasma in the donated sample may contain anti-ABO antibodies. Crossmatching is not necessary, nor is matching for RhD type

Adverse effects: The side effects of transfusing FFP are essentially the same as those of transfusing red cells, as you can still end up with antibody-antigen reactions, and the possibility of giving massive quantities of FFP to cause TACO and TRALI is totally legitimate. 

Cryoprecipitate

Description: The fraction of plasma that loses its solubility at cold temperatures

Presentation: small flat plastic container bags with 30-50ml of factor concentrate

Preparation: As the name suggests, this material is extracted from plasma as it is thawing. At a temperature of around 1-6ºC (i.e normal refrigerator), some of the plasma proteins remain water-soluble, whereas others become insoluble and precipitate. This cold precipitate is collected and refrozen for storage. 

Contents and chemical properties: This is a concentrate, meaning to say it is a hyperoncotic solution. Each unit of which contains:

  • 160 IU of Factor VIII
  • 260 IU of Von Willebrand factor
  • 380mg of Fibrinogen 
  • Fibronectin, platelet microparticles, and a small amount of immunoglobulin.

People unfamiliar with unit measurements and factor quantities may find themselves asking, "is that a lot"? Reader, it's not. For example, for the fibrinogen: consider that the total blood volume of a 70kg person with a serious haemorrhagic situation might be containing 1.0 g/L of fibrinogen. That total 5g of circulating fibrinogen inside the patient corresponds to approximately 13 banked units of fibrinogen. Thus, a normal person has between 25 to 50 units of cryoprecipitate circulating around. 

Storage is frozen, in the fridge next to the FFP (i.e. at a similar temperature).

Indications for use are essentially limited to :

  • Haemorrhage and its control, eg. as a part of a massive transfusion
  • Maintentance therapy of hypofibrinogenemia
  • Management of haemophilia, von Willebrand’s disease or Factor XIII deficiency (and only where you are unable to get a hold of the specific factor concentrate)

Originally, this stuff was actually invented for the purpose of replacing Factor VIII in haemophilia (Wong & Curry, 2016) but we now have specific products for that purpose. 

Dose for haemorrhagic shock, as recommended by the Red Cross, is 10 units (or 3-4g of fibrinogen), which would push the abovementioned haemorrhage patient into the territory where their fibrinogen level is ~ 1.7-1.8g/L

Need for typing and crossmatching: preferably FFP should be ABO-typed, as donor plasma in the donated sample may contain anti-ABO antibodies. Crossmatching is not necessary, nor is matching for RhD type

Adverse effects are related to the fact that it is a) not your own blood protein, and b) not completely without immunoglobulin. Thus, various febrile reactions are still possible. Moreover, the risk of viral transmission is still there, as it is not heat-pasteurised.  However, there are very few adverse reactions in the literature which can be clearly attributed to the cryoprecipitate. According to British data, only 1 in 43 acute transfusion reactions are due to this product.

Prothrombinex

Description: lyophilised human clotting factor concentrate. To be entirely clear, Australian Prothrombinex®-VF is a registered trade name.

Presentation is as a glass vial with powdered concentrate inside, for reconstitution with sterile water. Each vial usually contains 500 units.

Preparation is prepared by adsorption of coagulation factors from plasma onto an ion exchange medium followed by selective elution.

Contents and chemical properties: Each 500 unit vial contains:

  • 500 units of Factor IX  
  • 500 units of Factor II (prothrombin, hence the name)
  • 500 units of Factor X (prothrombinex, get it)

When reconstituted, each unit occupies a very small volume (500 units = 50ml), which is a major benefit if you do not wish to infuse vast volumes of hyperoncotic protein-rich fluid into your hemodynamically fragile patient.

Storage is in a regular refrigerator, for up to 6 months. It should not be frozen.

Indications for use are rather limited, and warfarin reversal is usually the only indication one will encounter in routine practice. The use of prothrombinex in massive transfusion is less clearly established, as often enough other factors are also deficient, and one is rarely concerned about the absolute fluid volume.

Dose for the reversal of warfarin is 15–50 IU/kg

Adverse effects: One can never rile out the possibility that an allergic or anaphylactic reaction could occur, but they are rare. More common and threatening is probably thrombosis, which it can cause in predisposed individuals - for example those with liver disease (Anderson et al, 1990)

References

Benjamin, Richard John, and Lisa Swinton McLaughlin. "Plasma components: properties, differences, and uses." Transfusion 52 (2012): 9S-19S.

Khawar, Hina, et al. "Fresh frozen plasma (FFP)." StatPearls [Internet] (2020).

R. Sümpelmann , T. Schürholz , E. Thorns , J. Hausdörfer Acid–base, electrolyte and metabolite concentrations in packed red blood cells for major transfusion in infants Pediatric Anesthesia Volume 11, Issue 2, pages 169–173, March 2001

Van Der Meer, Pieter F., and Dirk de Korte. "Platelet preservation: agitation and containers." Transfusion and apheresis Science 44.3 (2011): 297-304.

Wong, Henna, and Nicola Curry. "Cryoprecipitate transfusion: current perspectives." International Journal of Clinical Transfusion Medicine 4 (2016): 89-97.

Anderson, Brian J., Steven R. Keeley, and Neil D. Johnson. "Prothrombinex‐induced thrombosis and its management with regional plasminogen activator in hepatic failure." Medical journal of Australia 153.6 (1990): 352-356.