FDP: The Forgotten Dried Product

In the shocked trauma patient - successful resuscitation with blood products relies not just on restoring circulating volume, but on restoring the body's haemostatic ability. It's all very well to fill up the tank, but it's equally important to stop the tank from leaking further.

We routinely use fresh frozen plasma (FFP) as part of our standard balanced component transfusion strategy. In addition to all the other logistical and practical issues inherent in storing, transporting, and transfusing blood products, FFP in particular has the additional disadvantage of taking time to thaw.

Discovery and early use of freeze dried plasma

While the first human-to-human blood transfusion was undertaken by British obstetrician James Blundell in 1818, it was not until 1918 – one hundred years later – that Oswald Hope Robertson published his account of the first blood bank utilised in World War I – where type O donors were screened for disease, their whole blood frozen, mixed with citrate, and then transported to the front to be transfused (often by Robertson himself).

Jump forward twenty years to 1938, and plasma was freeze dried ("lyophilised") by an Italian doctor, Max Strumia, just two years after the American Dr John Elliot first isolated fresh plasma for use in traumatic shock [1,2].

A case report detailing the use of FDP published in the Annals of Surgery (1940) [1]

By 1941 the war in Europe was underway. Both the Allies and the International Committee of the Red Cross began to fund the industrial production of FDP to treat casualties. Due to its longer shelf life, it was favoured as an adjunct to walking blood banks in areas where supply chains were disrupted by isolation or there was a lack of air superiority.

An example of FDP reported as an adjunct in far-forward resuscitation [3].

Its use was short-lived, however, as FDP processing from large human pools also preserved viral hepatitis, as adequate sterilisation was not yet possible. Rates of hepatitis after plasma transfusion reached 21% during the Korean War, and so widespread FDP production ceased and it was replaced with colloids like as albumin and dextran [4]. The French kept producing FDP in limited amounts, though by 1985 the growing fear surrounding HIV transmission put the final nail in the coffin.

Modern day use of freeze dried plasma

After the Gulf War, the French military saw a potential need for FDP and re-established production in 1994 with new control measures in place, such as smaller donor pools, donor screening, post production testing, and ultraviolet pathogen reduction during the processing phase. The German Red Cross then followed suit, opting for single donor production in 1996 [5].

Unlike most high-income countries, South Africa has a high incidence of penetrating trauma. In fact, penetrating injuries account for the more than half the major trauma seen in emergency departments, about a third of which involve firearms. The national burden of trauma necessitated the South African National Bioproducts Institute to begin the production of Bioplasma FDP in 1996. They opted for a screened donor pool, and use a solvent detergent process that specifically inactivates viruses like HIV, HBV, and HCV [5].

Bioplasma FDP is indicated whenever plasma and/or coagulation factors are felt to be required, and contraindicated in patients with severe protein S deficiency. Each unit is reconstituted with a 200mL pack of sterile water, and can be prepared in less than 10 minutes. It is then infused over 15-20 minutes. Unlike FFP, it has a shelf life of 2 years, only needs to be stored below 25°C, and costs around $65 USD per unit, compared to $85 USD for a unit of FFP.

Pictured: sterile water for reconstitution (left) and reconstituted FDP ready for use (right).

Current best evidence and future use

There's now some evidence to support a position that early administration of plasma is associated with better outcomes. The PAMPer trial (n=501) [6] showed that early transfusion of 2 units of FFP was associated with an absolute risk reduction in 30-day mortality of 9.8% (95% CI 1.0-18.6%; p=0.03) when compared to crystalloids. That's a NNT of 10, which is phenomenal, if true. The similarly designed, albeit smaller, COMBAT trial (n=125) [7] did not show the same benefit however (and actually showed a non-significant increase in mortality in the plasma group).

This was all in FFP however - is FDP equivalent? Studies looking at surrogate outcomes would suggest it may be better. The TRAUCC trial (n=48) [8] demonstrated that FDP achieved higher serum concentrations of Factors II, V, and fibrinogen compared to FFP, and produced a greater improvement in INR. These differences also persisted out to 6 hours after transfusion. Does FDP actually change clinically important outcomes though? The PREHO-PLYO trial (n=135) [9] attempted to answer this question, which, like PAMPer and COMBAT, compared plasma against crystalloids. It did not find any significant difference in 30-day mortality, transfusion requirement ... or even INR values. The RePHILL trial [10] demonstrated no difference in mortality for pre-hospital transfusion of both FDP and PRBC when compared to crystalloids. This caused quite a stir, as it contradicted the long held belief in the superiority of blood products. There are many issues and a lot of discussion that could be had around the subject of pre-hospital blood transfusion more generally - much of which exceeds the scope of this article. Some critics have pointed out that this study was underpowered to detect the 10% difference in mortality that had been determined a priori, as they failed to recruit a sufficient number of participants. It is also relevant to note that 79% of patients in this trial had blunt trauma, so this result may not be generalisable to the penetrating trauma we so commonly see in South Africa, and the pre-hospital transport times were likely short (this was a UK-based study), so the effect size of any benefit is likely to be underestimated, as patients are never too far away from blood products regardless of their treatment arm in the trial. Don't even get me started on why they chose to include "lactate clearance" as part of their composite primary outcome, as this is potentially the least patient-oriented outcome of all.

Meta-analyses of the available evidence [11] suggest there is no difference in outcomes between FFP and FDP, but given the paucity of the research and the heterogeneity of the outcomes, this probably doesn't tell us much. There is, however, no suggestion of any outsized risk to patients associated with FDP use.

So what?

Overall, it seems that freeze dried plasma is safe and feasible. It is probably comparable to FFP for use in trauma patients with haemorrhagic shock, though the jury is probably still out on how, when, and where plasma gets used in a more general sense. Its benefits over FFP probably lie largely in its logistical and practical advantages, specifically its lack of refrigeration requirement, shelf-life, and its shorter preparation time, though there is some suggestion it provides better and more sustained correction of coagulopathy than FFP. Thus far, however, it has failed to demonstrate any clear benefit when assessing patient oriented outcomes, when compared against FFP or even just crystalloids. The utility of FDP in the pre-hospital and military contexts is certainly an attractive prospect for future research however.

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Dr Pete Havell is a junior emergency medicine registrar from New Zealand. He has recently finished his Masters in Traumatology through the University of Newcastle and also has interests in pre-hospital and military medicine.

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References:

1. Strumia MM, Wagner JA, Monaghan JF. The intravenous use of serum and plasma, fresh and preserved. Ann Surg. 1940;111(4):623-9.

2. Schmidt PJ. The plasma wars: a history. Transfusion. 2012;52 Suppl 1:2S-4S.

3. 'Live-blood' banks save soldiers' lives in Sicily when plasma proves inadequate [Internet]. The New York Times. 1943. Available at: https://www.nytimes.com/1943/08/27/archives/liveblood-banks-save-soldiers-lives-in-sicily-when-plasma-proves-in.html.

4. The blood, plasma, and related programs in the Korean War [Internet]. The Office of the Surgeon General Department of the Army, Washington D.C. 1964. Available at: https://achh.army.mil/history/book-wwii-blood-chapter20 

5. Pusateri AE, Given MH, Schreiber MA, et al. Dried plasma: state of the science and recent developments. Transfusion. 2016;56: S128-S139.

6. Sperry JL, Guyette FX, Brown JB, et al. Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock. N Engl J Med. 2018; 379(4): 315-26.

7. Moore HB, Moore EE, Chapman MP, et al. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet. 2018;293(10144):283-91.

8. Garrigue D, Godier A, Glacet A, et al. French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy: a randomized open-label trial. J Thromb Haemost. 2018;16(3):481-489.

9. Jost D, Lemoine S, Lemoine F, et al. Prehospital Lyophilized Plasma Transfusion for Trauma-Induced Coagulopathy in Patients at Risk for Hemorrhagic Shock: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(7):e2223619.

10. Crombie N, Doughty JA, Bishop JRB, et al. Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2022;9(4):e250-e261.

11. Mok G, Hoang R, Wajid Khan M, et al. Freeze-dried plasma for major trauma - systematic review and meta-analysis. J Trauma Acute Care Surg. 2021;90(3):589-602.