Indications for the Use of Therapeutic Plasma in Adult Patients

Abstract

Background

Different preparations for therapeutic plasma are available on the market. The German hemotherapy guideline has been completely updated in 2020 and, for this purpose, has reviewed the evidence for the most frequent clinical indications for the use of therapeutic plasma in adult patients.

Summary

The German hemotherapy guideline has reviewed the evidence for the following indications for the use of therapeutic plasma in the adult patient: massive transfusion and bleeding, severe chronic liver disease, disseminated intravascular coagulation, plasma exchange for TTP, and the rare hereditary FV and FXI deficiencies. The updated recommendations for each indication are discussed on the background of existing guidelines and new evidence. For most indications, the quality of evidence is low due to missing prospective randomized trials or rare diseases. However, due to the “balanced” content of coagulation factors and inhibitors therapeutic plasma remains an important pharmacological treatment option in clinical situations with an already activated coagulation system. Unfortunately, the “physiological” content of coagulation factors and inhibitors limits the efficacy in clinical scenarios with high blood losses.

Key Messages

The evidence for the use of therapeutic plasma for the replacement of coagulation factors due to massive bleeding is poor. Coagulation factor concentrates seem to be more appropriate for this indication, although the quality of evidence is also low. However, for diseases with an activated coagulation or endothelial system (e.g., disseminated intravascular coagulation, TTP) the balanced replacement of coagulation factors, inhibitors, and proteases may be of advantage.

Introduction

Human plasma belongs to the most frequently transfused labile blood products worldwide. About 630,000 U of plasma were transfused in Germany in 2020 [1] and 2,185,000 U in the USA in 2019 [2]. Although there are different plasma products approved worldwide differing by the production process or the method of virus inactivation, the majority of plasma consists of either fresh frozen, single-donor plasma (FFP) or pooled plasma from a certain number of donors, e.g., solvent/detergent (SD-)treated plasma.

Throughout the manuscript, the general term “therapeutic plasma” will be used for all different types of plasma as it was suggested by the German hemotherapy guideline to underscore the therapeutic character of the use of human donor plasma. Independent of the specific plasma product, therapeutic plasma was recommended and used [3, 4] to treat coagulation factor deficiencies associated with larger blood losses (e.g., by trauma or intraoperative bleeding) to prevent a coagulopathy caused by loss or consumption of coagulation factors [5]. Additionally, donor plasma is indicated in certain coagulation disorders, e.g., severe FV or FXI deficiency, or the plasma exchange in patients with thrombotic microangiopathic anemias, e.g., thrombotic thrombocytopenic purpura (TTP, Morbus Moschcowitz).

However, over time certain indications for the use of therapeutic plasma have changed due to implementation of new treatment protocols or recent pharmacologic developments. Therefore, the German guideline on the use of blood components and plasma derivatives (the “German hemotherapy guideline”) was completely revised in 2020 [6] (English language version pending) and published updated recommendations on the use of therapeutic plasma. The purpose of this publication is to present the updated recommendations for the use of donor plasma in the setting of the following:

The recommendations will be discussed in light of recent evidence and international guideline recommendations. To establish a common background for the readers, a short introductory chapter on the different types of human donor plasma, their product, and manufacturing characteristics as well as criteria for quality assurance will be placed at the beginning of the review.

Product Characteristics of Therapeutic Plasma

The different types of therapeutic plasma can be distinguished by different virus inactivation procedures. Single-donor plasma is manufactured from whole blood donations or plasmapheresis, deep frozen within 24 h after leucocyte depletion, and stored over a certain quarantine (Q) period (e.g., 4 months) without any pathogen reduction. This frozen plasma (Q or fresh frozen plasma, FFP) is distributed to the market only after donors were considered eligible for donation and have been tested negative for HIV, HAV, HBV, HCV, and Parvo B19 virus after the Q period [7].

Further types of single-donor plasmas use cell filtration and methylene blue plus monochromatic light or amotosalen plus UVA light radiation for pathogen reduction (plasma). Methylene blue and amotosalen are removed by absorption filtration prior to freezing.

The so-called pool plasma originates from pooling of up to 1,500 blood group-compatible, single-donor plasma units that undergo a certain virus inactivation step (the SD procedure which uses tributyl phosphate as a SD Triton-X 100) to eliminate lipid-coated viruses before it is frozen to below −30°C. All frozen plasma types undergo routine microbiological and hematological testing (white blood cells <0.1 × 10⁹/L, thrombocytes <50 × 10⁹/L, and erythrocytes <6 × 10⁹/L) and have to fulfill the quality criterion of a FVIII activity >70% before distribution to the market. The storage time at below −30°C is about 3 years.

A completely different plasma preparation uses lyophilization of filtrated and frozen, single-donor plasma (lyophilized human plasma) that has been stored for a certain Q period. Lyophilized human plasma can be stored between 2 and 25°C for up to 15 months and is dissolved in injectable water before administration [6, 8].

All plasma types are to contain physiological levels of coagulation factors and inhibitors and do not contain activated coagulation factors [9]. The activity of coagulation factors may vary substantially according to variations in individual coagulation factor, to the pathogen inactivation steps and the type of thawing devices used [6, 9, 10].

Indications for Therapeutic Plasma

The following chapter will describe the different clinical indications for therapeutic plasma and recommendations that are based on scientific evidence as well as national and international guidelines.

Substitution of Coagulation Factors due to Bleeding or Large Blood Loss

For decades, therapeutic plasma was recommended to substitute coagulation factors in severe bleeding requiring massive transfusion [5] or clinical scenarios with large blood losses. The clinical dilemma, however, is that it remains unclear which level of coagulation factor activity is needed to secure hemostasis in the bleeding patient and probably the nonbleeding patient will manage with lower levels. Nevertheless, due to the donor-dependent, “physiological” activity of coagulation factors and inhibitors in therapeutic plasma [9], a clinical and significant increase of coagulation factor activities can be achieved by large volumes (>30 mL/kg) of plasma only. This recommendation is based on a small study in critically ill patients: 10 patients receiving 12.2 mL/kg versus 12 patients receiving 33.5 mL/kg. Only the latter group had significant increases in coagulation factor activity (about 25–35%), although with substantial differences for the individual factors and almost no increase for fibrinogen (factor I) even with 33.5 mL/kg [11]. These results have been confirmed in a newer study, showing an increase of coagulation factor activities by in average 10–12% after infusion of 15 mL/kg FFP [12]. In general, a close (possibly invasive) monitoring of the hemodynamic and volume status of the patients treated with large volumes of therapeutic plasma is recommended.

This influences the clinical applicability of therapeutic plasma as the larger volumes must be available for the health care giver. As an example, the recommended dose of 30 mL/kg in a 80 kg adult will require either 10 U of FFP (250 mL) or 12 U of SD plasma (200 mL). These products need to be thawed in a time-consuming process dependent on the thawing device used and have to be calculated in the emergency setting of severe bleeding and massive transfusion. Furthermore, the cardiopulmonary condition of the patient needs to be considered to avoid volume overload (transfusion-associated circulatory overload). Clinicians should also be aware that therapeutic plasma contains citrate which binds ionized calcium and may lead to a critical decrease in ionized calcium, which is as an essential cofactor for the activation of coagulation factors, so that calcium levels need to be closely monitored and substituted when necessary.

In contrast, coagulation factor concentrates (CFCs) seem to be more effective to compensate a severe deficiency of coagulation factors due to the higher concentration of coagulation factors per mL. Dependent on the amount of coagulation factor to be infused, concentrates are usually dissolved in volumes of 20–100 mL rarely causing volume overload. In a clinical scenario requiring volume restrictive therapy for the patient, the following simple example may demonstrate the differences in volume between CFC and therapeutic plasma: to transfuse 2,000 mg of fibrinogen either a volume of 100 mL to dissolve the concentrate (i.e., 20 mg/mL) or a volume of approximately 720 mL of FFP with each unit, therapeutic plasma containing, e.g., 275 mg/dL (i.e., 2.75 mg/mL) fibrinogen is needed. The perspective to substitute severe coagulation factor deficiencies originating from large blood losses with CFC has been adopted by the updated German hemotherapy guidelines similar to the recommendations regarding congenital coagulation factor deficiencies [6].

Given the limited efficacy of therapeutic plasma to substitute coagulation factors per mL transfused, massive transfusion protocols (MTPs) have been used for years with fixed ratios (either 1:1 or 2:1) of packed red blood cells (PRBCs) to therapeutic plasma. These MTPs aim at compensating the hemodynamic effects of large blood loss and concomitantly and the early substitution of coagulation factor and platelet concentrates (PCs) in a ratio of 1:1:1 or 1:1:2 for PRBC:FFP:PC [13]. This intends to prevent dilutional coagulopathy occurring if only PRBC is transfused initially, as it has been suggested with older transfusion protocols [14, 15].

These older transfusion schemes were mainly based on clinical judgment and lack evidence showing improved hemostatic efficacy [16]. They suggested to initially stabilize the hemodynamic function with crystalloids and colloids and to correct low hemoglobin levels first (until approximately 70% of the circulating blood volume has been lost) before hemostatic blood products, e.g., 5–20 mL/kg of therapeutic plasma, were administered to increase coagulation factor levels [5, 15]. This approach, however, carries the risk of underestimating the dilutional effect of crystalloids and colloids and even PRBCs on the coagulation system. This has been shown in older cohort studies in patients undergoing surgical procedures with expected large blood losses, as the severity of blood loss is associated with a decrease of fibrinogen. It was calculated that if the blood loss would exceed 140% of the circulating blood volume a drop in fibrinogen below a “critical” margin of 100 mg/dL would be reached [17]. Of note, current guidelines designate the critical threshold for fibrinogen in severe bleeding at 1.5 g/L [6] or 1.5–2 g/L [18], although the (“critical”) level of fibrinogen that is significantly associated with a bleeding remains to be identified.

In addition to fibrinogen, a decrease by approximately 50% of the activity of factor V and IX was observed in 32 juvenile patients undergoing major scoliosis surgery; 17 (53%) showed clinical symptoms of abnormal hemostasis following loss of approximately 1.14 ± 0.27 times the circulating blood volume (without the substitution of hemostatic blood products). The fibrinogen levels decreased to a mean of 127 ± 47 mg/dL in the group with abnormal hemostasis, while the group with normal hemostasis had fibrinogen levels of 145 ± 39 mg/dL (nonsignificant in both groups) [15].

These data, together with international guidelines, suggest that early administration of hemostatic products seems reasonable to prevent a dilutional coagulopathy causing larger blood losses. This may be even more important in the traumatized patients with an unknown volume of blood loss on the scene and an additional consumption of fibrinogen due to the activation of fibrinolysis by the formation of activated protein C [19, 20, 21], whereas in the setting of elective surgery with expected blood loss the development of a coagulopathy may be monitored and followed by a goal-directed hemostatic protocol.

Prospective randomized clinical trials investigating the use of therapeutic plasma versus CFC in the setting of trauma-induced coagulopathy (TIC) or major surgery with high blood loss are sparse. The prospectively randomized Austrian RETIC study demonstrated no significant difference in the incidence of multiorgan failure (50% vs. 66%, p = 0.15) with the primary use of fibrinogen concentrate (50 IU/kg and/or 20 IU/kg prothrombin complex concentrate both guided by viscoelastic coagulation testing vs. 15 mL/kg of therapeutic plasma) in trauma patients with a plasmatic coagulopathy. However, significantly more patients in the plasma group required a second dose and a hemostatic rescue treatment (52% vs. 4%, p < 0.0001) and showed a higher need for massive transfusion (30% vs. 12%, p = 0.042). These results may be in part explained by the relatively small dose of therapeutic plasma (15 mL/kg) that was possibly not sufficient to adequately treat coagulopathy [22].

The PAMPer study investigated the effect of 2 pre-thawed units of FFP during prehospital air medical transport in patients at risk for hemorrhagic shock [23]. Control group patients received standard of care (crystalloid solution) and showed a higher 24-h mortality (22.1% vs. 13.9%, p = 0.02) and 30-day mortality (33.0 vs. 23.2%, p = 0.03) as well as a higher prothrombin-to-time ratio (1.3 vs. 1.2, p < 0.001), while other endpoints as multiorgan failure, acute lung injury, nosocomial infections, or transfusion-related reactions were not different between the study groups. However, the COMBAT trial (using 2 U of FFP) did not confirm a survival benefit for the prehospital administration of plasma [24], but a post hoc analysis of the PAMPer plus COMBAT trials found an increased survival for the plasma group if transport time was >20 min (HR 2.12; 95% CI, 1.05–4.30; p = 0.04) [25]. The PREHO-PLYO trial comparing 4 U (800 mL) of lyophilized plasma versus 1,000 mL saline yielded no benefit for the plasma group [26].

Though designed with almost identical inclusion criteria, 30-day mortality in the PAMPer control group was three times higher than that in the COMBAT study (33% vs. 10%). In fact, the control group of COMBAT with a median injury severity score of 27 received only saline but had 2-fold lower mortality than the intervention group of PAMPer with an injury severity score of 22, who then received plasma and RBCs (10% vs. 23.2%). Based on the volume of plasma infused in PAMPer, COMBAT, and PREHO-PLYO, the increase in factor levels would be between 7 and 20% in a 75-kg adult patient. If there is a benefit for prehospital plasma, it may be argued that this is probably not due to the clotting factors in the product [27]. Therefore, the existing evidence, so far, does not unequivocally support the assumption that prehospital lyophilized plasma is effective for patients at risk of hemorrhage with a minimum transfer time of 30 min to prevent TIC and reduce mortality.

A randomized clinical pilot trial (VIPER-OCTA trial) investigated the effect of an SD-treated plasma preparation (OCTAPLAS LG®) versus standard FFP on shock-induced endotheliopathy, coagulopathy, massive bleeding, transfusion requirements, cost of blood products, morbidity, and mortality in patients with acute dissections of the thoracic aorta [28]. In this pilot trial of 23 versus 21 patients (SD-treated plasma vs. FFP), all endpoints showed significantly better results in the SD plasma than in the FFP group, except of length of stay in the ICU and in hospital, morbidity, and mortality. Although this pilot study proved the concept that endotheliopathy, volume of bleeding, and requirements for blood and hemostatic product transfusions are reduced by using SD-treated plasma as compared to single-donor FFP, these effects so far did not translate into a clinical benefit in terms of reduced morbidity or mortality in patients with volume-depleted shock [29].

Unfortunately, these studies are not comparable regarding patient populations, study designs, and hemostatic interventions so that the determination of the value of therapeutic plasma as compared to CFC in the setting of trauma coagulopathy and severe bleedings remains difficult. Therefore, the German hemotherapy guideline recommends using therapeutic plasma “if plasma volume needs to be replaced” [6]. For the prevention of a coagulopathy by uncompensated loss of coagulation factors, the early use of MTPs with either fixed ratio of PRBC to therapeutic plasma (1:1 or 2:1) is recommended (grade of recommendation 1C). Apart from the early substitution of coagulation factors, this recommendation also aims at stabilizing the circulating blood volume and prevents secondary organ failure due to hemorrhagic shock. For acute and severe blood losses, however, CFC is suggested to be used in addition to therapeutic plasma to be more effective regarding replenishment of coagulation factor deficiency [6].

These recommendations are similar to current guidelines on the treatment of perioperative bleeding [18] or TIC [30] recommending therapeutic plasma to be given in bleeding patients only [18], to prevent a dilutional coagulopathy and to maintain prothrombin time (PT) and activated partial thromboplastin time (aPTT) below 1.5 times of the upper reference value [30]. However, in the clinical setting of bleeding laboratory measurements of the coagulation system are of limited value to determine the effectivity of the substitution of coagulation factors, so that the clinical assessment of the progress of bleeding is still mandatory and might be assisted by viscoelastic testing or other point of care monitoring.

Of note, for the first time, the working group did not designate definite laboratory values for PT or aPTT and suggests using CFC in addition to therapeutic plasma for the substitution of severe coagulation factor deficiencies, for which therapeutic plasma is not effective enough. Furthermore, it is not recommended to use plasma for bleeding prophylaxis after surgery involving cardiopulmonary bypass (recommendation 1A) [6, 31] or correction of preprocedural of abnormal coagulation parameters (compare chapter 3.2). Of note, after the bleeding has stopped, the substitution of coagulation factors by therapeutic plasma or CFCs is not justified.

Severe Chronic Liver Disease

The disturbances of the coagulation system by severe liver disease are complex. While it is widely assumed that patients with liver failure have a primary and high risk to bleed due to reduced activities of coagulation factors, thrombocytopenia, and decreased inhibitors of fibrinolysis, evidence from laboratory measurements has shown a concomitant decrease in the activity of inhibitors of the coagulation system [32] that correlate with clinical observations of a normal bleeding tendency and no transfusion requirements even during liver transplantation [33, 34]. Moreover, it was shown that the capacity of thrombin generation was maintained [35], the levels of FVIII and von Willebrand factor antigen increased [31], and the activity of the von Willebrand factor cleaving protease ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) reduced [36]. All factors contribute to the thrombotic risk of patients with severe liver disease.

Hence, the hemostatic function in severe liver disease is complex and vulnerable. Levels of procoagulant and inhibitory factors of the coagulation system may be decreased to a similar extend [37] supporting the concept of a “re-balanced hemostasis” on a lower activity level in these patients. The complex pathophysiology is not sufficiently reflected by the standard parameters of the coagulation laboratory (PT, aPTT) that often seem stronger prolonged than the clinical bleeding tendency. This may be confusing [38, 39] as the interpretation of the prolonged laboratory values in conjunction with a low platelet count suggests the use of hemostatic products before interventional procedures or operations, although these will probably not be needed.

Based on the described pathophysiological background and in agreement with a recent British guideline, the German hemotherapy guideline, in general, supports a restrictive approach to substitute therapeutic plasma or other hemostatic agents in patients with stable, i.e., nonbleeding, liver failure. So, the prophylactic administration of therapeutic plasma before diagnostic interventions or minor surgery (central venous catheter, thoracocentesis, or paracentesis) is not recommended [40, 41, 42, 43]. The only exception from this may be the placement of an external ventricular drainage for intracranial pressure monitoring as it was recommended by European Association for the Study of the Liver (EASL) for patients with acute liver failure [44]. This restrictive approach toward a prophylactic correction of coagulation defects applies to the use of PCs for thrombocytopenia and prothrombin complex for an elevated INR as well [41]. Recent ex vivo research point to the fact that substitution of 4 U of prophylactic FFP and 1 U PC increases the thrombin generation potential as measured by an increase of 92% and 38% in thrombin-antithrombin complex and prothrombin fragment 1 + 2 levels, respectively, that may be associated with an increase in the risk of thrombosis [44].

However, patients with severe chronic liver disease undergoing major surgery or having a severe bleeding may be transfused with therapeutic plasma (recommendation grade 2C) to stop the bleeding but not to correct abnormal coagulation tests. It should be noted that the evidence for this recommendation is weak and requires further research.

Disseminated Intravascular Coagulation

DIC is a pathological process which is characterized by an unspecific activation of thrombocytes and the plasmatic coagulation system resulting in fibrin deposition in the microvasculature of all organs [45]. Acute DIC or DIC-like states are associated with a variety of conditions ranging from severe trauma, shock, sepsis, placental disruption, amniotic fluid embolism to endovascular treatment of aortic aneurysms, while chronic DIC may develop with chronic liver disease, malignant diseases like promyelocytic leukemia, prostate or pancreatic cancer. One of the most frequent causes of DIC is sepsis or septic shock which affects more than 200,000 hospitalized patients each year in Germany [46]. For this reason, the following paragraphs describe the current recommendations for the use of therapeutic plasma in sepsis or septic shock. However, it should be noted that successful treatment of septic DIC firstly requires treatment of the underlying cause of sepsis (e.g., antibiotics, surgery). Without successful treatment of the source of sepsis, hemostatic treatment of septic DIC will not benefit the patient's outcome.

In sepsis or septic shock, the thrombotic phenotype may potentially lead to organ failure due to hypoperfusion, bowel infarction, and necrosis of extremities, and a hemorrhagic phenotype associated with disseminated microvascular bleeding may occur [47]. While the first step of the treatment of the more thrombotic state of septic DIC consists of the use of anticoagulants in order to interrupt the activation of the plasmatic coagulation system [47], the patient with an overt bleeding tendency may require the substitution of hemostatic products ranging from therapeutic plasma to PCs or CFCs [48]. The physiological “nature” of therapeutic plasma is that it both contains coagulation activators and inhibitors. On the one hand, this may be of advantage in a state of activated coagulation since antithrombin and protein C and S may balance thrombin activation and coagulation factor activation (FV and FVIII). On the other hand, the physiological content of coagulation factors and the administration of coagulation inhibitors will probably be not sufficient to restore decreased coagulation factor levels or sufficiently enhance thrombin generation [11, 12]. A statement from the Scientific and Standardization Committee on DIC of the International Society of Thrombosis and Hemostasis (ISTH) that harmonized three different national guidelines on the treatment of DIC recommended that therapeutic plasma may be given in patients with active bleeding with prolonged PT/aPTT (>1.5 times normal) or decreased fibrinogen levels (<1.5 g/L). Therapeutic plasma may be administered to patients before invasive procedure with similarly deranged coagulation parameters. However, based on the existing literature, this was a low-quality recommendation [49]. Since then, no new evidence or guideline recommendations regarding the administration of therapeutic plasma in patients with DIC have been published. Therefore, the German hemotherapy guideline underscores that therapeutic plasma (as well as other hemostatic products) shall be given to patients with septic DIC who show signs of active bleeding only [48]. A prophylactic use of therapeutic plasma, however, is not recommended.

Plasma Exchange for TTP

The thrombotic-TTP together with the adult hemolytic uremic syndrome belongs to the microangiopathic-hemolytic anemias. A congenital and immune-mediated, acquired form of TTP can be distinguished. The congenital form of TTP is caused by an absolute deficiency of ADAMTS 13, the cleaving protease of von Willebrand multimers. In contrast, the pathophysiology of the immune-mediated, acquired sub-type of TTP is determined by the development of an autoantibody against ADAMTS 13. Immediate diagnosis, distinction from other conditions presenting with thrombocytopenia and anemia (e.g., DIC due to sepsis), and disease-specific treatment are imperative as mortality is 90% without treatment [50]. Clinical symptoms of immune-mediated TTP consist of neurological signs (stroke, transient ischemic attacks, seizures, etc.), renal impairment, abdominal pain, and cardiac complaints. The diagnosis of the TTP is confirmed by a deficiency in ADAMTS 13 with activities<10% being highly indicative for immune-mediated TTP. The treatment of choice is plasma exchange that will remove antibodies against ADAMTS 13 and substitute the metalloproteinase ADAMTS 13, which is different from sole plasma infusions that substitute the protease only, which can be used if plasma exchange is not available. Plasma exchange has reduced mortality to approximately 10% (8 of 78 patients) in an early landmark study involving patients with complicated, immune-mediated TTP [51]. For this reason, the German hemotherapy guideline – in conjunction with international guidelines – strongly recommends the use of plasma exchange at a volume of 40–60 mL/kg per day in acute TTP until the platelet count remains stable >100,000/µL (recommendation 1A). Furthermore, for patients with congenital TTP the infusion of therapeutic plasma at a dose of 5–10 mL/kg every 2–3 weeks is recommended. The rather long-time interval between plasma transfusions is explained by the long half-life of ADAMTS 13 of 50–80 h [52, 53].

Recently, the bivalent, single-domain antibody caplacizumab has been introduced to the market. This nanobody consists of an immunoglobulin fragment that binds to the von Willebrand factor and prevents microvascular thrombosis by inhibiting the adhesion of von Willebrand factor to the platelet glycoprotein Ib-IX-V receptor. Caplacizumab as an adjunct therapy to plasma exchange was investigated in a double-blind, controlled trial against placebo [54]. The primary endpoint was the time to normalization of the platelet count and discontinuation of plasma exchange within 5 days thereafter. Secondary outcomes included a composite of TTP-related mortality, recurrence of TTP, or thromboembolic events. In the caplacizumab group, the platelet count normalized with 2.69 days (95% CI: 1.89–2.83) versus 2.88 days (95% CI: 2.68–3.56), a result that was statistically significant (p < 0.01). The occurrence of the composite outcome was significantly lower with caplacizumab than with placebo (12% vs. 49%, p = 0.001), and also the recurrence rate of TTP was significantly lower with caplacizumab (12% vs. 38%, p < 0.001). 1 patient in the caplacizumab and 3 patients in the placebo group died. It is expected that caplacizumab will influence the treatment of TTP using exchange therapeutic plasma in the future. However, so far it is unclear how the concept of removal of the antibody by plasma exchange and substitution of ADAMTS 13 by therapeutic plasma will be affected by the new pharmacological treatment option.

Congenital FV and FXI Deficiency

Both congenital FV and FXI deficiencies belong to the rare bleeding disorders with an estimated prevalence of approximately 1:1,000,000 patients [55]. FV is synthesized in liver cells and circulates in about 80% in plasma and in 20% in alpha-granula of platelets. FV is a nonenzymatic cofactor that binds to FX in the prothrombinase complex to activate prothrombin to thrombin. The deficiency results in mucocutaneous, soft-tissue, surgical, and heavy menstrual bleeding, and the severity of bleeding seems to correlate with plasma activity <0.1 IU/mL. Heterozygous FV deficiency carriers usually present with higher FV activities of 0.2–0.6 IU/mL [56]. Higher activities were associated with either no (asymptomatic condition) or mainly mild bleedings which have been observed in previous studies [55, 56, 57]

For FV deficiency, no factor concentrate is approved on the market. Therapeutic plasma (as either FFP or SD-treated plasma as recommended in the UK) may be required to prevent or treat bleedings in FV-deficient patients. In conjunction with earlier recommendations [54] and based on the existing evidence, the German hemotherapy guideline recommends the administration of 15–20 mL/kg before operations and procedures to maintain plasma levels of 15–20% (recommendation 2C). Due to the relatively short half-life of FV of 12–15 h, the treatment may be repeated after 12 h in severely bleeding patients. In patients whose bleedings are refractory to infusions of therapeutic plasma, a case presentation reported on the successful use of PCs in a patient with an acquired FV inhibitor [58]. The authors hypothesized that either FV released from transfused platelets or the platelets themselves stopped the bleeding. Another case report described the successful use of recombinant activated FVII at a dose of 80 μg/kg for the initial treatment and between 80 and 120 μg/kg on the following doses [59] in a patient with repeat hemarthroses who showed symptoms of dyspnea and hypoxemia following the last infusion of FFP [60]. A pulmonary edema was diagnosed by chest X-ray, and a transfusion-related lung injury was suspected. Although this evidence stems from case reports only, clinicians may find this information useful in patients with FV deficiency refractory to infusions with therapeutic plasma.

FXI is synthesized in the liver and circulates in the plasma for a half-life or around 60 h. The activated FXI stimulates the activation of FIX to form the “tenase-complex” which activates FV and thrombin generation consecutively. FXI-deficient patients show varying clinical phenotype that does not strictly correlate with FXI activity. Severe bleedings were reported in patients with FXI activities of 0.09–0.41 IU/mL, and nonbleeding patients had FXI activities of 0.14–0.39 IU/mL [61].

Since FXI activity does not clearly identify patients with high or low bleeding risk in case of severe bleedings or before invasive procedures and operations, the German hemotherapy guideline suggests to substitute 20 mL/kg of therapeutic plasma in patients with severe congenital FXI deficiency (<5% or 0.5 IU/mL) or mild deficiency with high bleeding risk to maintain factor levels of 20%. This is a conditional recommendation in case a FXI concentrate is not available, or local hemostatic measures and pharmacological treatment including tranexamic acid and desmopressin are not sufficient (recommendation 1C+). However, a FXI concentrate that is usually administered at a dose of 10–15 IU/kg to treat severe bleedings is not approved for the German market. Thromboembolic events after administration of FXI concentrates have been observed in 2/64 and 1/242 treatment episodes documented in registries or retrospective analyses of different hemophilia centers in the UK [62, 63].

However, these data were debated by a report of 12 FXI deficiency patients with thromboembolic events (since 2,002) that were registered by a manufacturer of one concentrate. In each patient, the FXI concentrate was given before surgery to prevent bleeding, and the average dose was <30 IU/mL. The authors suggested to use FXI concentrates following a risk-benefit analysis weighing the particular risk factors or each patient [64]. Taking these data together, it is assumed that FV deficiency will remain an indication for the use of therapeutic plasma until a factor concentrate has been approved. For FXI deficiency, the use of a factor concentrate in patients with a high bleeding risk seems to be superior in terms of efficacy but needs further convincing evidence that it can be safely used without thrombotic events.

Conclusion

Therapeutic plasma remains an important treatment option for different clinical situations, although the evidence for most indications described here remains to be weak as it is reflected by national and international guidelines. Other treatment modalities (e.g., CFC, caplacizumab) may change the value of therapeutic plasma for certain indications in the future and potentially reduce its clinical application. Whether therapeutic plasma will receive a new indication as a resuscitation fluid to treat volume-depleted shock needs further research with strong clinical endpoints.

Conflict of Interest Statement

Christian von Heymann (CvH) declares to have no financial conflict of interest related to the topic of this manuscript. Christian von Heymann declares that he was mandated from the German Society of Anesthesiology and Intensive Care Medicine (DGAI) to write the German Guideline on Preoperative Anemia (published in April 2018, update will be published in 2023) and the guideline on Peripartum Hemorrhage: Diagnostics and Treatment (update published on September 12, 2022). Furthermore, CvH was part of the writing group of the Patient Blood Management Guideline in cardiac surgery on behalf of the European Society of Cardio-thoracic Anaesthesiologists (EACTA) in conjunction with the European Society of Cardiothoracic Surgery (EACTS) (published in September 2017). CvH also declares to have been part of the working group that wrote the revision of the German hemotherapy guidelines. CvH contributed as a co-author to the chapter “Therapeutic Plasma” of this guideline. Outside this work, Christian von Heymann discloses to have received research funding, speaker's and consultancy honoraria, and travel reimbursements from Artcline GmbH, Bayer AG, CSL Behring, Daiichi Sankyo, Grunenthal GmbH, HICC GbR, Mitsubishi Pharma GmbH, Novo Nordisk Pharma GmbH, and Sobi Pharma. Heiko Lier (HL) declares that he was mandated from the German Society of Anesthesiology and Intensive Care Medicine (DGAI) to write the coagulation therapy chapter of the German Guideline on Severe/Multiple Trauma (to be published in December 2022) and the guideline on Peripartum Hemorrhage: Diagnostics and Treatment (update published on September 12, 2022). HL has received travel expenses and lecture fees from Bayer Vital, blood donation service west (DRK = German Red Cross), CSL Behring, Ferring, Novo Nordisk, and Werfen. Christoph Rosenthal (CR) has received lecture fees from CSL Behring and Aspen Pharma. Lutz Kaufner (LK) declares to have no financial conflict of interest related to the topic of this manuscript. Lutz Kaufner declares that he was mandated from the German Society of Anesthesiology and Intensive Care Medicine (DGAI) to write the German Guideline on Preoperative Anemia (published in April 2018). Lutz Kaufner discloses to have received speaker's and consultancy honoraria and travel reimbursements from HICC GbR., CSL Behring, and Novo Nordisk outside the submitted work.

Funding Sources

None.

Author Contributions

Christian von Heymann drafted the manuscript, revised the manuscript critically for important content, and finally approved the manuscript. Heiko Lier revised the manuscript critically for important content and finally approved the manuscript. Christoph Rosenthal revised the manuscript critically for important content and finally approved the manuscript. Lutz Kaufner revised the manuscript critically for important content and finally approved the manuscript.

Funding Statement

None.