Plasma-based Transfusion Therapy

Dr. Erin Long heads the hospital’s small animal emergency and critical care service.

Plasma is the liquid, non-cellular portion of blood constituting approximately 55% of whole blood in health. Over 90% of plasma is water, but the remainder contains vital proteins, hormones, electrolytes, and other nutrients. These important compounds are distributed to tissues via flowing blood.

When plasma or its constituents are prepared for use in transfusion, whole blood is fractionated into plasma by centrifugation. Alternatively, plasma can be removed from a donor via apheresis.

The plasma yielded at this stage of processing would then be considered liquid (never frozen) plasma, or LP. When stored at refrigerated temperature, this type of form of plasma is as stable as fresh frozen plasma (FFP) (perhaps even hemostatically superior) for up to 5 days after the expiration of the whole blood from which it was derived (so 26+ days).

Plasma has played a key role in transfusion therapy for decades. Through the administration of FFP or LP, one can deliver all the benefits (and risks) of plasma therapy to the recipient: all coagulation proteins (both procoagulant and anticoagulant), vWF, fibrinogen, albumin, immunoglobulins, and procoagulant microparticles, all in the largest fluid volume.

There are several conditions that are perfectly suited for transfusion of the entire unit of plasma. However, use of further processed products allows the provider to transfuse fewer unnecessary plasma constituents.

Rationale for Transfusion of Plasma

The classic indication for FFP transfusion is the management of hemorrhage caused by hemostatic protein deficiency (e.g., anticoagulant rodenticide toxicity, hemophilia, vWF deficiency, synthetic liver failure). This is true for these cases both when spontaneously bleeding and to preempt uncontrolled bleeding when invasive diagnostics or surgical procedures are planned. In the case of severe spontaneous hemorrhage, it is ideal to pair plasma transfusion with physiologic ratios of cell-based components (pRBC, platelets) or, where available, whole blood. For prevention of hemorrhage in coagulopathy, plasma transfusion alone may be sufficient.

FFP, LP, or thawed plasma (TP) can also be transfused to provide colloidal volume support. A 2001 manuscript indicated that albumin replacement was the reason for plasma transfusion in 63% of cases. However, it is generally accepted that, on a mg/kg basis, a substantial volume of plasma would be needed to truly raise serum albumin and this is particularly true in cases of ongoing loss or physiologic derangements. Rather than considering plasma as an albumin repletion product, it might be best to think of plasma as an albumin support product with the goal of maintaining serum protein concentrations rather than truly raising them. Certainly, plasma is superior to clear fluids when it comes to accomplishing this goal.

Plasma transfusion (whether as FFP, LP, TP or as a constituent of whole blood) is highly important in trauma resuscitation. The past 20 years of trauma research have affirmed that early death from exsanguination can be reduced when higher ratios of plasma (or plasma-containing products) to pRBC are used for resuscitation. Superiority over clear fluid resuscitation (crystalloid or synthetic colloid) is also apparent as the latter may worsen coagulopathy, may promote organ edema and ARDS, and fails to restore endothelial health compared to plasma.

Compared to crystalloid therapy, plasma resuscitation in trauma not only repletes volume with minimal redistribution, but it also restores fibrinogen and other coagulation factors lost in shed blood, provides additional cofactors V and VIII which may be degraded via the activated protein C pathway in cases of acute traumatic coagulopathy, provides albumin support which is critical for wound healing, and, above all, eliminates the dilutional effect of crystalloid resuscitation.

The benefit from plasma seems to extend beyond its hemostatic effects to include protection to the endothelium, which we now know is injured under conditions of shock.

Endothelial Glycocalyx

The endothelial glycocalyx is a protein and carbohydrate-rich barrier on the luminal surface of vascular endothelial cells that participates in circulatory homeostasis. It protects the endothelial cell from access to blood cells and other constituents, regulates vascular permeability, maintains an anticoagulant surface, and participates in mechanotransduction and control of vascular tone. This protective layer can be damaged by conditions other than tissue injury (wherein the transition into a procoagulant surface designed to support clot formation would be welcomed).

Examples of pathologic causes of glycocalyx injury include severe inflammatory states (e.g., sepsis), trauma, shock, ischemia/reperfusion injury, and neoplasia.

Exposure and activation of the endothelial cell result in a cascade of changes, including release of vWF, platelet activation, exposure of tissue factor, and leakage of protein and fluid through post-capillary venules. This ultimately results in large-scale thrombin generation and clot formation, increased inflammation, altered vascular tone, and edema.

Many experiments have shown that albumin, plasma, and (more recently) cryoprecipitate are capable of reducing or attenuating glycocalyx damage in sepsis, hemorrhagic shock, and traumatic brain injury.

Plasma Derivatives: Cryoprecipitate

Cryoprecipitate is an excellent plasma derivative option for transfusion of vWF, fibrinogen, or factor VIII in dogs with hereditary coagulopathy associated with those factors.

In people, factor concentrates have largely supplanted the use of cryoprecipitate for this indication in favor of more targeted therapy. However, cryoprecipitate is used in many massive transfusion protocols, especially in the UK. Retrospective studies suggest that, in both children and adults, early use of cryoprecipitate is independently associated with survival, but prospective studies have yet to demonstrate a benefit beyond maintenance of higher fibrinogen concentrations in recipients. More clinical trials are forthcoming.

Failed synthesis of fibrinogen as a result of liver failure may result in excessive bleeding, particularly if provoked (e.g., in aspirate or biopsy procedures). In this circumstance, global hemostasis should be evaluated through viscoelastic testing if possible.

If clot reaction time is altered along with other parameters, plasma might be the optimal therapeutic choice. However, if hypofibrinogenemia appears to be the main contributor to coagulopathy (as evidenced by normal reaction time and prolonged alpha angle and clot kinetics), then perhaps cryoprecipitate would be a suitable product. Little is known in veterinary medicine about using cryoprecipitate for acquired coagulopathy.

Plasma Derivatives: Cryosupernant

Cryosupernatant (aka cryopoor plasma) can be used for the treatment of hereditary or acquired factor deficiencies not involving factor VIII or fibrinogen. This is especially useful for replenishing vitamin K-dependent factors II, VII, IX, and X (and appears equivalent to FFP in its capacity to do so).

This product can also be used as an “albumin support” fluid as suggested above. These units are reduced in volume compared to a unit of plasma, but also in cost per mL, offering an advantage over FFP where fibrinogen, factor VIII, and vWF are not required. Globulins are also retained in this product but are not highly concentrated, even with removal of the cryoprecipitate component. Despite its advantages, this product is not widely available commercially.

Frozen Plasma

FFP is renamed frozen plasma (FP) after its one-year life at -18°C has passed. The product is still highly useful for colloid oncotic support and does contain all coagulation factors, albeit with lower factor activity (particularly labile factors V and VIII). Unlike cryosupernatant, this product is an accessible option for most hospitals that maintain fresh frozen plasma in such a quantity that it occasionally “expires”—the product is usable as FP for four additional years (5 years from the time of collection).

The immunoglobulins present in plasma have also been exploited for neutralization of viral antigen—a highly contemporary topic given the recent use of this therapy during the COVID-19 pandemic. This use of plasma relied on high-titer individuals to donate plasma for transfusion to early infected high-risk patients in hopes of reducing risk of severe inflammatory response.

Convalescent plasma’s greatest advantage is that it is immediately available once someone recovers from the disease. Veterinarians have also used plasma for this indication in management of parvoviral enteritis.

More recently, a plasma product became available that originates from dogs that are hyperimmunized against canine parvovirus as well as E. coli bacterin. A clinical trial revealed that dogs treated with hyperimmune plasma had evidence of less shock when compared to the placebo group, but did not detect a survival advantage (but was underpowered to do so).

By Erin Long, DVM, DACVECC

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