Plasma Transfusion

Plasma transfusion in the setting of trauma and massive haemorrhage

Plasma is integral to the transfusion-supportive management pathways defined by massive transfusion protocols (MTPs). The biological rationale is correction of multi-factor coagulopathy. Acute traumatic coagulopathy (ATC) refers to the coagulation derangement that develops rapidly following significant traumatic insult, and is evident in over 25% of trauma patients arriving to the hospital emergency department (before fluid resuscitation) [5]. Patients who arrive at hospital with ATC are four times more likely to die compared to those without acute coagulopathy; they have significantly higher transfusion requirements, in addition to an increased incidence of organ dysfunction [5]. Many studies report that resuscitation without plasma, or with low-dose plasma compared to the number of red blood cells (RBCs) transfused, is associated with poorer clinical outcomes [6–8].

MTPs have been developed to provide rapid blood product resuscitation in the setting of major haemorrhage. The number, type, timing and ratio of blood components issued in each MTP pack will depend on the clinical setting, institution and local guidelines. Plasma is important in initial haemostatic resuscitation of trauma patients and may be given as part of MTP packs in fixed-ratio component resuscitation.  Fixed-ratio component transfusion attempts to mimic resuscitation with whole blood. For each RBC unit a set number of plasma and platelet unit(s) is administered.  In contrast, goal-directed component therapy is often based on the use of VHAs, rotational thromboelastography (ROTEM) and thromboelastography (TEG). These allow early diagnosis and management of ATC by providing global and functional assessments of coagulation and allow directed transfusion therapy. However, the Implementing Treatment Algorithms for the Correction of Trauma-Induced Coagulopathy (iTACTIC) trial, a multicentre randomized controlled trial (RCT), evaluated trauma patients who received MTPs augmented by VHAs compared with conventional coagulation tests and found no difference in mortality or other clinical outcomes between study arms [9].

Robust clinical trial evidence to support a clear role for high-dose or empiric plasma transfusion remains a subject of debate. The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial, a large multicentre RCT, was conducted to evaluate the effect of two different fixed ratios on massive haemorrhage. Trauma patients were randomized to receive a ratio of 1:1:1 or 1:1:2 of platelets: plasma and RBCs, with the primary outcome being mortality [10]. There was no statistically significant difference in 24-h or 30-day mortality between transfusion strategies.  However, in post hoc analyses, there were fewer deaths from bleeding at 24 h with the 1:1:1 transfusion strategy [10]. More recently, trials have focused on plasma transfusion delivery prior to hospital.  The Pre-hospital Air Medical Plasma (PAMPer) trial was a multicentre, cluster-randomized trial, designed to determine the efficacy and safety of pre-hospital plasma compared with standard crystalloid resuscitation [6]. The study enrolled 501 severely injured patients and reported 30-day mortality was almost 10% lower in the plasma group compared to the standard-care group. However, interpretation is limited by incomplete outcome data, non-standardized fluid management in the standard-care group, and many patients seemingly not requiring plasma (or platelets) after admission and there were no effects on 24-h mortality (after adjustment) [6]. The Control of Major Bleeding After Trauma Trial (COMBAT) was a single-centre placebo-controlled RCT in 125 trauma patients with haemorrhagic shock [11]. There was no statistical difference in mortality at 28 days between the plasma group (15%) and crystalloid group (10%). Coagulation factors, transfusion requirements and safety outcomes were similar between groups [11]. However, comparing the two trials, hospital transit times were much shorter in the COMBAT trial, and only 32% of patients in the COMBAT plasma group had received the full dose of 2 units of plasma pre-hospital, compared with 84% in the PAMPer trial, which also featured longer transit times [6, 11].

Some transfusion services will maintain an inventory of thawed group AB or group A plasma for immediate transfusion.  The availability of thawed AB plasma in the emergency department has been demonstrated to expedite the time to transfusion of plasma components in severely injured patients and, in a single-centre retrospective study, was associated with better survival [12].  As noted above, high wastage rates are often observed unless the thawed plasma has an extended shelf-life.

Ongoing plasma transfusion requirements in the trauma and critical bleeding setting will be guided by clinical assessment and response, in addition to results of standard laboratory-based coagulation testing or VHA testing. 

Small RCTs have compared FFP with four-factor PCC in the management of bleeding cardiac surgery patients [13, 14]. Karkouti et al. included 101 patients randomized to FFP (median dose 12.5 mL/kg) or PCC (median dose 24.9 IU/kg). Patients receiving PCC had less chest tube drainage and reduced red cell transfusion requirements in the first 24 h after surgery, without safety concerns [14]. The PROPHESY study, a pilot feasibility trial where bleeding adult cardiac surgery patients were randomized to 15 mL/kg FFP or four-factor PCC (500 IU weight <60 kg; 1000 IU if 61–90 kg; and 1500 IU if >90 kg). The study demonstrated feasibility for recruitment in a larger clinical trial with no safety concerns, but due to its size it was not powered to make any conclusions about bleeding or transfusion outcomes [13]. Larger, well-designed clinical trials are warranted to evaluate the role, efficacy, and safety of PCCs compared with plasma in cardiac surgery. 

Disseminated intravascular coagulopathy

Disseminated intravascular coagulopathy (DIC) is a poorly defined entity. The International Society of Thrombosis and Haemostasis consensus guidelines define acute coagulopathy as a prolonged PT/activated partial thromboplastin time (APTT; >1.5 times normal) or decreased fibrinogen (<1.5 g/L) [15]. DIC is an acquired syndrome characterized by coagulation and haemostatic dysfunction, with risks of both haemorrhage and thrombosis. There is systemic coagulation activation with coagulation factor and platelet consumption and a propensity to bleed, in addition to microvascular thrombosis and a risk of end-organ ischaemia. DIC may occur as a complication of sepsis, solid tumours, pregnancy complications, trauma, severe liver disease and vascular abnormalities, as well as others.  Diagnosis involves both clinical features and abnormalities of laboratory parameters: PT, platelet count, fibrinogen and fibrin-related markers, such as fibrinogen degradation products and D-dimer [15].

The mainstay of treatment for established DIC is aggressive and timely treatment of the underlying clinical condition [15]. Plasma transfusions may have a role in the treatment of active bleeding associated with acute coagulopathy and prior to invasive procedures in patients at risk of bleeding complications [15].

Response to plasma transfusion should be monitored clinically and be followed by reassessment of the patient’s coagulation profile.  

Warfarin reversal

Warfarin is the most commonly prescribed oral vitamin K antagonist and is used to prevent arterial and venous thromboembolism in a range of settings. It exhibits its anticoagulant effect by inhibiting the vitamin K-facilitated carboxylation of factors II, VII, IX and X. 

A key component of any urgent warfarin reversal strategy is prompt intravenous vitamin K (phytonadione) administration, which allows synthesis of new, functional vitamin K-dependent coagulation proteins.  However, in the setting of life- or limb-threatening bleeding, more rapid reversal is required to restore the coagulation potential of plasma. PCCs are virally inactivated products containing concentrated amounts of vitamin K-dependent factors either formulated with four factors (factors II, VII, IX and X) or three factors (II, IX and X). PCCs have the advantage of a small volume for infusion, rapid reconstitution, ease of administration, fast onset of action, no requirements for ABO compatibility, and minimal risk of viral transmission, TRALI or TACO.  

Two RCTs have evaluated urgent warfarin reversal with FFP compared to PCC in patients undergoing cardiac surgery [16] or with mechanical heart valves [17]. Demeyere randomized 40 patients to receive two units (2 × 200 mL) S/D-treated FFP or four-factor PCC (dose individualized based on international normalized ratio [INR] and weight) prior to cardiopulmonary bypass and after bypass. PCC was found to reverse warfarin-related coagulopathy quicker and more patients in the PCC group reached the target INR than in the FFP group [16]. Fariborz Farsad et al. compared three-factor PCC (dose determined by INR and weight) versus FFP (10–15 mL/kg) in patients with mechanical heart valves requiring urgent reversal and found PCCs were more effective at reversal to a target INR of <2.5 than plasma and more patients in the plasma arm required additional doses to reach the target INR [17].

The INCH trial randomized patients with vitamin K antagonist-associated intracranial haemorrhage, to four-factor PCC (30 IU/kg) versus FFP (20 mL/kg) in addition to 10 mg vitamin K, with a primary endpoint of INR ≤1.2 within 3 h of treatment [18]. The study was stopped prematurely due to concern about increased haematoma expansion in the FFP arm.  Analysis supported earlier correction of the INR with PCC and less haematoma expansion in those patients treated with PCC compared with FFP [18].

PCC (preferably four-factor) in addition to vitamin K should be used first-line for warfarin reversal. In cases of severe bleeding, such as intracranial haemorrhage, if PCC is not available, then plasma transfusion is appropriate to allow adequate factor VII replacement. However, reassessment of the INR and follow-up plasma or PCC doses may be needed. 

Preoperative coagulation testing and plasma transfusion

The two most common global coagulation tests used in clinical practice are the PT and APTT. The PT detects deficiencies in factors II, VII, IX and X, and varies depending on the laboratory coagulation platform and type of thromboplastin used.  The INR was developed to standardize the assessment and monitoring of warfarin and is the ratio of the patient’s PT compared to a normal PT and corrects for thromboplastin sensitivity. The APTT was developed to screen for congenital bleeding disorders, specifically factor VIII, IX or XI deficiency. It will also be prolonged with factor XII deficiency (not associated with bleeding), in the setting of coagulation factor inhibitors, heparin effect and phospholipid inhibitors (lupus anticoagulants). These laboratory tests were never developed to assess perioperative bleeding risk: the INR was developed to monitor warfarin and the APTT was designed to screen for bleeding disorders and monitor heparin.

Unselected coagulation testing with PT/INR and APTT prior to surgery or invasive procedures is not recommended, as these tests have not been validated to predict bleeding risk in surgical patients [20, 21]. Coagulation results may become abnormal with mildly reduced factor deficiencies at factor levels that are not associated with bleeding. Attempts to treat or correct these perceived laboratory-defined coagulopathic values are largely inappropriate and mildly increased INRs and mildly prolonged PTs do not normalize when treated with therapeutic doses of plasma [19, 22]. Plasma transfusions will only impact the INR when there is a relatively large difference between the patient’s INR and the coagulation activity of the plasma. Therefore, the higher the INR the more effective plasma is in reducing the INR [19, 23]. The effect of a plasma transfusion on an INR can be transient and therefore if plasma is used to correct an INR preoperatively, the plasma transfusion should occur immediately prior to the procedure to maximize its effect [24]. 

Plasma transfusion should not be given to correct abnormal coagulation tests in the absence of bleeding in neonates, children and adults. Evidence from clinical trials (RCTs and observational studies) has failed to support prophylactic plasma transfusions in minimizing bleeding outcomes in the following patients undergoing procedures: critically ill adults with an INR of 1.5 to 3.0 [25]; non-cardiac surgery and INR >1.5 [26]; patients with cirrhotic liver disease and central venous catheter placement [27]; and those undergoing procedures outside the operating room and an INR of 1.5 to 2.5 [28].

Transfusion practice based on  PT/INR thresholds for use of prophylactic plasma is likely to have very little impact on reducing the PT/INR when the abnormalities are mild/ moderate (e.g., INR of 1.5–2.4) [23]. Plasma is unlikely to be warranted in most surgical patients when the PT/INR is prolonged. There is very little evidence to support the use of prophylactic plasma transfusion perioperatively.  

Liver disease

The liver serves an important role in the manufacture of most pro-coagulant and anticoagulant proteins, in addition to proteins involved in fibrinolysis. Due to the reorganized balance of coagulation factors and associated anticoagulants, haemostasis is largely preserved in patients with chronic liver disease. Patients will frequently have prolongations of the PT and INR, yet as discussed previously, these tests poorly predict bleeding risk. A prospective observational study of critically ill patients with liver cirrhosis found that, instead of INR, fibrinogen levels <0.6 g/L, platelet count <30 × 109/L and APTT >100 s were the strongest predictors of major bleeding [29]. The conventional coagulation testing (PT/INRs and APTTs) do not reflect the parallel and compensatory reductions in the anticoagulants protein C, protein S and antithrombin. 

Global tests of haemostasis, such as thrombin generation potential and VHAs, are preserved in patients with chronic liver disease and may offer better predictors of bleeding risk, although they are yet to be validated in this setting [30]. In a small open-label RCT, 60 patients with cirrhosis and significant coagulopathy undergoing invasive procedures were randomized to a TEG-guided transfusion strategy or standard of care (guided by INR and platelet count). Those who received the TEG-guided transfusion strategy received significantly fewer blood products, without an increased risk of bleeding [31].

Plasma is frequently used prophylactically prior to procedures in patients with chronic liver disease, despite the absence of evidence from clinical trials to support its benefit.  Plasma transfusions at standard doses are largely ineffective in correcting the coagulopathy associated with chronic liver disease [32] and for this reason prophylactic plasma transfusions should not be used to correct abnormal coagulation tests in non-bleeding patients or prior to low-risk bleeding procedures. An RCT of cirrhosis patients undergoing ultrasonography-guided central venous catheter insertion, randomized to standard laboratory-based coagulation test-guided plasma transfusion 10 mL/kg when the INR was >1.5 or APTT was >32 s, TEG-guided transfusion when the CT – EXTEM was >80 s, or restrictive plasma transfusion when the INR was >5.0, found no difference in bleeding outcomes. [27].

Large volumes of plasma are required to significantly increase clotting factor levels in chronic liver disease, and this can increase portal vein pressures, which may in turn lead to an increased risk of gastrointestinal bleeding.  Plasma transfusions have a limited role of treating the coagulopathy associated with liver disease and should be saved as an adjunctive therapy for those patients with active bleeding. 

Rare inherited bleeding disorders

The treatment of choice for inherited bleeding disorders is treatment with the specific fractionated factor concentrate, where available.  Single factor plasma-derived or recombinant concentrates are available for factors I, VII, VIII, IX, XI and XIII, although access to these products is limited in some countries [33]. Factor V deficiency is the only single-factor deficiency where a factor concentrate does not currently exist [33]. Plasma transfusion is indicated for the treatment of factor V deficiency to treat active bleeding or prevent bleeding prior to a procedure. 

Vitamin K deficiency bleeding

Vitamin K is an essential vitamin, necessary to help the blood clot. Newborns have very low levels of vitamin K compared with adults, and deficiency in vitamin K can result in life-threatening bleeding in the first few hours to months of life. Early (<24 h after birth) vitamin K deficiency bleeding (VKDB) can occur in infants whose mothers are taking medications that interact with vitamin K metabolism, such as anticoagulants, anti-convulsants and anti-tuberculosis medications. Classic VKDB occurs between days 2 and 14 of life and may be due to poor feeding.  Early and late VKDB are associated with bleeding, most commonly gastrointestinal or umbilical bleeding.  However, late VKDB, onset between weeks 2 and 12, typically occurs in exclusively breast-fed babies, who most frequently have received no or inadequate vitamin K or have intestinal malabsorption defects. The typical presentation of late VKDB is with intracranial haemorrhage [34]. To prevent VKDB it is standard of care that all newborns receive vitamin K supplementation. The American Academy of Pediatrics recommends that all newborns receive a single dose of intramuscular vitamin K at birth [35]. In cases of suspected VKDB, immediate treatment with intravenous vitamin K is necessary and, in life-threatening cases, plasma transfusion may be necessary to rapidly replenish coagulation factors [36].