10931_Reversal Of Warfarin-Associated Coagulopathy Prothrombin Complex Concentrates

Yale University
Yale University
EliScholar – A Digital Platform for Scholarly Publishing at Yale
EliScholar – A Digital Platform for Scholarly Publishing at Yale
Yale Medicine Thesis Digital Library
School of Medicine
January 2020
Reversal Of Warfarin-Associated Coagulopathy: Prothrombin
Reversal Of Warfarin-Associated Coagulopathy: Prothrombin
Complex Concentrates Versus Fresh Frozen Plasma In Elderly
Complex Concentrates Versus Fresh Frozen Plasma In Elderly
Patients Presenting With Intracranial Hemorrhage
Patients Presenting With Intracranial Hemorrhage
Shunella Grace Lumas
Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl
Recommended Citation
Recommended Citation
Lumas, Shunella Grace, “Reversal Of Warfarin-Associated Coagulopathy: Prothrombin Complex
Concentrates Versus Fresh Frozen Plasma In Elderly Patients Presenting With Intracranial Hemorrhage”
(2020). Yale Medicine Thesis Digital Library. 3928.
https://elischolar.library.yale.edu/ymtdl/3928
This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A
Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital
Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more
information, please contact elischolar@yale.edu.

1
Reversal of Warfarin-Associated Coagulopathy: Prothrombin Complex
Concentrates versus Fresh Frozen Plasma in Elderly Patients Presenting with
Intracranial Hemorrhage

A Thesis Submitted to the
Yale University School of Medicine
in Partial Fulfillment of the Requirements for the
Degree of Doctor of Medicine
By Shunella Grace Lumas
2020

2
Table of Contents
Title Page

1
Table of Contents

2
Acknowledgements

3

Abstract

4

Introduction

6

The Case for Anticoagulation Therapy

6

Benefits and Dangers of Warfarin

8

Efficacy of Warfarin Reversal Agents

15

PCC vs. FFP: A Superior Agent?

21

Statement of Purpose

28

Methods

29

Results

32

Discussion

37

References

43

3
Acknowledgements

I would like to thank my thesis advisor Dr. Kevin Schuster for his guidance
in helping me pursue this project over the years. I would also like to thank the Yale
Department of General Surgery, Trauma, and Surgical Critical Care for allowing me
to pursue my interests in trauma clinical research.

I would like to acknowledge the Yale Office of Student Research for helping
me engage my interests in clinical research, and for giving me the support in
helping my research projects flourish both on-campus and beyond, at the many
conferences and meetings where I was given the unique opportunity to present my
research to my colleagues nationwide. I am also appreciative of the incredibly
supportive research environment cultivated at the Yale School of Medicine

Lastly, I would like to thank all my family and friends, whose unconditional
support allowed me to thrive throughout medical school and no doubt will
continue to uplift me in my upcoming medical training and beyond.

4
Abstract

Background: Patients on warfarin with traumatic intracranial hemorrhage (ICH)
often require pharmacological reversal of warfarin-induced coagulopathy. We
compared outcomes among patients who received 4-factor prothrombin complex
concentrate (PCC), fresh frozen plasma (FFP) or no reversal to assess the real-world
impact of PCC on elderly patients with traumatic intracranial hemorrhage on
warfarin.

Study Design: This was a retrospective analysis of 150 patients on preinjury
warfarin. Data was abstracted from the electronic medical record (EMR) of an
academic level 1 trauma center for patients age 65 years and greater on warfarin
therapy admitted with a traumatic ICH between January 2013 and December 2018.
Primary outcomes were ICH progression on follow-up computed tomography (CT)
scan, in-hospital mortality, need for surgical intervention. Trends in use over time
and costs of the reversal agents were also analyzed.

Results: Of 150 patients eligible for analysis, 41 received FFP, 60 received PCC, and
49 were not reversed with either of those reversal agents. On multivariable analysis,
patients who were not reversed [OR 0.25, 95% CI (0.31 – 0.85)] or were female [OR
0.38, 95% CI (0.17 – 0.88)] were less likely to experience progression of their initial
bleed on follow-up CT. SDH increased the risk of hemorrhagic progression [OR

5
3.69, 95% CI (1.27 – 10.73)]. There was no difference between groups with respect to
in-hospital mortality or the need for neurosurgical intervention. Over time, the use
of reversal with PCC increased, while use of FFP and not reversing declined (p
<0.001). Regarding costs, PCC was significantly more expensive to administer per patient than FFP. Conclusion: In older patients with traumatic ICH on warfarin, use of a reversal agent was associated with progression of the ICH. The choice of reversal agent did not impact mortality or the need for surgery. Therefore, some ICH patients may not require warfarin reversal, and the apparent benefits to PCC use in retrospective studies may be related to the increased use of PCC in patients who would have not have otherwise been reversed. 6 Introduction The Case for Anticoagulation Therapy Hypercoagulable states are associated with many adverse outcomes, including disabling stroke and deadly pulmonary emboli (PE). Other common pathologies that predispose patients to poor outcomes related to blood clotting are atrial fibrillation (AF) and venous thromboembolism (VTE), the latter of which includes deep venous thrombosis (DVT) and PE. Due to the significant vascular risks, AF and VTE are significantly associated with increased morbidity and mortality. Therefore, medical management becomes crucial in controlling overall prognosis. AF is caused by an underlying cardiac abnormality that leads to uncoordinated atrial arrhythmias and irregular ventricular responses. Inflammation and fibrosis within the cardiac tissues, valvular abnormalities, or even an ectopic signal arising within the pulmonary veins can all be underlying causes of this abnormal atrial rhythm. With the loss of coordinated atrial contractions comes a decrease in adequate ventricular filling and stroke volume. While some cases of AF are asymptomatic and therefore clinically silent, more severe manifestations can include dyspnea, palpitations, and pulmonary edema [1], as the heart becomes unable to propel blood systemically. Additionally, the loss of forward blood flow means more blood is static within the heart, which contributes to an increased risk 7 of intracardiac thrombus formation. Dislodgement of these thrombi can then lead to stroke [2]. AF is the most common clinically significant cardiac arrhythmia in the world, with an estimated global burden of 33.5 million people [3]. In the United States alone, approximately 2.3 million people have a diagnosis of AF, with that number being projected to increase to 5.6 million by 2050 due primarily to a substantial increase in the elderly population, who develop AF in greater numbers than their younger counterparts. In the United States, AF is more often seen in elderly, Caucasian men, and can affect anywhere from 8 – 10% of people over 80 years old [4]. In fact, the prevalence of AF doubles with each increasing decade of age [5]. AF incurs a four-to-fivefold increased risk of stroke, and has been estimated to be responsible for up to 15% of all strokes nationwide [6]. Due to both the high prevalence and significant stroke risk, AF is the most common dysrhythmia treated in medical practices, and is responsible for up to a third of hospital admissions associated with dysrhythmias [5], making it a significant clinical burden in the healthcare realm. VTE is another significant condition caused by an underlying pathology in the coagulation cascade that leads to the inappropriate formation of clots within the vasculature. DVT refers to the formation of clots within the deep veins, most often those of the lower limbs and the pelvis. Also included under the category of VTE are PE, which are due to dislodged thrombi that travel within the venous system and become fixed in the pulmonary vasculature. DVT is a significant risk factor for 8 the development of PE: nearly half of all patients with untreated DVT can develop a PE in as little as 3 months [7]. Acquired risk factors that are known to contribute to an increased risk of VTE development include advanced age, immobility, recent surgery, obesity [8], hormone replacement therapy [9], and malignancy [10]. Genetic conditions, albeit rarer, are also important to consider as underlying causes of VTE development. These conditions are linked to either decreased levels of or inadequate responses to the body’s natural anticoagulants, and include Factor V Leiden, prothrombin G20210A, and inherited deficiencies in proteins C, S, and/or antithrombin [8]. VTE is the third most common acute cardiovascular disease after myocardial infarction (MI) and stroke. The condition affects a large portion of the U.S. population with an incidence rate ranging between 300,000 – 600,000 new cases per year. VTE also disproportionately affects the elderly, with nearly 60% of all cases occurring in patients over 70 years old [11]. The mortality rate is significant: up to 30% of patients die within 30 days of diagnosis, and as high as 25% of PE cases alone present as sudden death. Even with appropriate medical management, nearly one third of all patients can experience a recurrence of VTE within 10 years, with a “definite” recurrence rate of 17.6% and a “probable” rate of 30.4% [12]. With such significant morbidity and mortality associated with these disease states, pharmacological management becomes key in improving outcomes. Anticoagulation therapy has been a mainstay of the medical regimen for these conditions for decades. One important and popular therapy that has had significant 9 benefit in targeting the coagulative sequelae associated with AF and VTE is warfarin, an oral anticoagulant with a mechanism of action that works by preventing the activation of several coagulation factors necessary for clot formation. From its discovery in 1933 [13] to its approval for stroke prevention in AF patients by the Federal Drug Administration (FDA) in 1954 [14], warfarin use has exploded over time, with nearly 30 million prescriptions for the medication now written annually in the United States [15]. In the following section, we will begin to explore both the benefits as well as the adverse effects associated with warfarin use when managing these hypercoagulable conditions. Benefits and Dangers of Warfarin Warfarin is in a class of medications known as the vitamin K antagonists (VKAs). VKAs work by inhibiting the enzyme vitamin-K epoxide reductase [16], which is responsible for the post-translational carboxylation of multiple factors necessary in the coagulation cascade. These include factors II, VII, IX, X, as well as proteins C and S [17]. Inhibition of this step results in the inactivation of these factors and creates an antithrombotic effect that counteracts the prothrombotic state seen in conditions like AF and VTE. Multiple trials have proven the clinical benefit to warfarin use in stroke prevention for patients with nonvalvular AF. The 1990 study by the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) investigators found an 86% reduction in stroke risk in patients receiving long-term, low-dose warfarin therapy 10 compared to control patients who did not receive warfarin but who could choose to take aspirin [18]. In the 1991 Stroke Prevention in Atrial Fibrillation (SPAF) randomized trial, warfarin was found to significantly reduce the rate of ischemic stroke and systemic embolism when compared to placebo, with an overall 54% reduction in disabling ischemic stroke or vascular deaths in those patients who received the medication [19]. The 1992 Veterans Affairs Stroke Prevention in Nonvalvular Atrial Fibrillation (SPINAF) study was another randomized trial that found warfarin was associated with a 0.79 relative reduction in cerebral infarction risk compared to placebo [20]. Additional studies directly compared the benefits of warfarin to another popular antithrombotic medication, aspirin, which was considered to be the gold standard antiplatelet for the prevention of arterial thromboses [21]. These further studies also found significant benefits to warfarin over aspirin therapy in preventing stroke in AF patients, including the European Atrial Fibrillation Trial (EAFT) [22] and the SPAF II trial [23]. Given the ample evidence for warfarin’s clinical benefit in reducing thromboembolic risk in AF patients, it becomes clear why for years the American Heart Association, American College of Cardiology, and Heart Rhythm Society (AHA/ACC/HRS) guidelines consistently included warfarin as a class I recommended pharmacotherapy for antithrombotic AF management [24]. Of note, warfarin was eventually overtaken by the non-vitamin K anticoagulants (NOACs) in January 2019 as the preferred therapy for stroke prevention in AF 11 patients following the publication of several seminal randomized trials [25], yet this particular topic is beyond the scope of this paper. Similarly, VKAs have long been a staple in the medical management of VTE. The earliest landmark randomized control trial in 1960 investigating the use of VKAs for treatment of PE found that patients who received heparin and the VKA coumarin-derivative nicoumalone (of note, warfarin is also a coumarin derivative) had a significant reduction in mortality attributed to PE compared to the untreated control group: 0% vs. 26% [26]. Today, VKAs, primarily warfarin, are recommended as long-term secondary prophylaxis following a VTE event following the initial regimen of IV thrombolytics and/or heparin [27]. There is strong evidence linking the use of VKAs to reduced VTE recurrence rates, a finding with great clinical significance given that 10-year VTE recurrence rates can reach levels as high as 30% [12]. In one trial, patients with acute DVT treated initially with intravenous (IV) heparin were randomized to receive either fixed, low-dose subcutaneous heparin or warfarin sodium as secondary prophylaxis. The total recurrence rate after 12 weeks of follow-up was 47% in the heparin group, as opposed to 0% in the warfarin group [28]. One trial went further, and followed 508 patients for an average of 4.3 years, all of whom had previously received 6.5 months of full-dose anticoagulation therapy for VTE. The patients were randomized to receive either long-term, low-intensity warfarin or placebo. The researchers found a significant risk reduction of 64% for recurrent VTE in the therapeutic group relative to the placebo group. Long-term warfarin use was also 12 found to be associated with a 48% reduction in the overall composite endpoint of recurrent VTE, major hemorrhage, or death [29]. Warfarin has many potential clinical uses beyond AF and VTE. These include warfarin use for the primary prevention of ischemic coronary events as an adjunct to aspirin, as long-term treatment for patients with acute MI, as an antithrombotic in patients with prosthetic heart valves, and even for other less well- supported indications, such as AF due to valvular (as opposed to nonvalvular) heart disease, mitral stenosis, dilated cardiomyopathy, and in patients with one or more episodes of systemic thromboembolism [30]. Altogether, warfarin has proven to be a highly effective anticoagulant for a variety of clinically relevant indications, which explains its vast use among medical practitioners for patients with thromboembolic conditions. However, finding the appropriate balance between antithrombotic activity and the innate risk of bleeding that comes with any anticoagulative medication, especially when considering long-term therapy, can be difficult to achieve. Excessive, systemic anticoagulation with VKAs can lead to bleeding so severe as to prompt rapid, pharmacological reversal in order to prevent catastrophic and fatal hemorrhage. Despite its benefits, warfarin use can be as dangerous as the thrombotic complications it works to prevent if its use is not carefully monitored by patients and care practitioners alike. Bleeding associated with warfarin use is a serious medical complication, and there is a myriad of factors to be aware of that can increase this risk. These include increasing age, a history of uncontrolled hypertension (HTN), acute or chronic 13 alcohol use, liver disease, active or a recent history of bleeding lesions or bleeding disorders, and concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and some antibiotics [31]. Of the non-modifiable factors, the general consensus is that increasing age is the major risk factor that increases bleeding risk [31]. However, another significant risk factor for warfarin-associated bleeding that has been heavily reviewed in the literature is poor control of the International Normalized Ratio (INR), which is a quantitative measure of the time it takes for clot formation to occur in a measured sample of plasma. Since its introduction in the 1980s [32], INR has become the test of choice to monitor patients on VKAs, and the VKA dose is considered adequate if the INR is within a “therapeutic” range. These exact recommended values vary depending on the underlying clinical pathology being treated with VKA therapy, but typically ranges between 2.0 – 3.5 [33]. An elevated INR outside of the therapeutic range might signify that the dose of anticoagulant is too high, which can translate to an increased risk of bleeding [34]. Several studies have shown that bleeding rates in patients taking warfarin increases with higher presenting INR values [35] [36]. INR can therefore be a reliable predictor for bleeding risk in warfarin patients. Up to 20% of patients on warfarin will experience a bleeding complication due to excessive anticoagulation per year, and the fatality rate from such bleeds can range between 1 – 3% [37]. In a study investigating rates of hemorrhage in AF patients specifically, bleeding risk was found to be the highest during the first 30 days of warfarin therapy, while the cumulative incidence of associated hemorrhage 14 increased over time to a value of 8.7% at 5 years following initiation of therapy. Patients older than 75 years of age were at significantly higher risk, with a 4.6% risk per person-year compared to a 2.9% risk in those 75 or younger. 62.6% of those hemorrhages involved the gastrointestinal (GI) tract, and 18.1% of those admitted to the hospital for warfarin-related bleeds died within 7 days of discharge [38]. Due to such high mortality rates related to warfarin-associated bleeding, they are a large topic of discussion in the literature. ICH, particularly when related to traumatic injury, is a feared complications of anticoagulation use and has been associated with significantly higher mortality rates. For example, in one retrospective analysis warfarin use was found to be associated with a 6-fold increased mortality risk for ICH after blunt traumatic brain injury (TBI) compared to patients with TBI who were not on preinjury anticoagulation [39]. Another study investigating elderly patients with head injuries found that preinjury warfarin use both increased the ICH risk by 40% and doubled the risk of 30-day mortality compared to those not on warfarin [40]. One possible reason that could explain the high mortality rates seen in warfarin-associated ICH that has been supported in the literature may relate to the increased risk of hemorrhagic expansion in anticoagulated patients compared to non-anticoagulated patients. In a 2001 French study, researchers compared 3 groups of patients for analysis: those admitted due to anticoagulant-related ICH, a randomly selected group of patients admitted with spontaneous ICH, and those without ICH but who were on anticoagulation therapy. It was found that ICH 15 volumes in anticoagulated patients were significantly higher than those seen in spontaneous ICH based on CT scan measurements [41]. Another study conducted by Flibotte and colleagues at the Massachusetts General Hospital saw no effect of warfarin on initial ICH volume at presentation, but warfarin was found to be the only predictor of in-hospital hemorrhagic expansion. ICH expansion was then found to trend towards increased mortality, with warfarin patients overall being at significant risk for death, even after controlling for the initial ICH volume [42]. ICH is a significant adverse effect of anticoagulation therapy with severe effects on morbidity and mortality. Warfarin plays a considerable role in these outcomes, and the risk factors associated with adverse bleeding can be difficult to control, given that the major contributing risk factor, age, is non-modifiable. In acute situations where bleeding must be promptly addressed, reversal of anticoagulation is warranted. There are multiple pharmacological reversal agents that can counteract the antithrombotic mechanisms of warfarin and help prevent the sequelae of major bleeding. Prompt correction of coagulopathy associated with over-anticoagulation is recommended by current guidelines [43], and the following section aims to give a comprehensive discussion of important reversal agents that can achieve this. 16 Efficacy of Warfarin Reversal Agents There are 3 pharmacological therapies available that can reverse the effects of warfarin: fresh frozen plasma (FFP), the prothrombin complex concentrates (PCCs), and phytonadione (vitamin K). Each agent has its own advantages and disadvantages, but the general consensus is that prompt reversal of warfarin in patients presenting with dangerous bleeds, such as an ICH, can contribute to decreased morbidity and mortality. Although a supratherapeutic INR is often implicated in increased bleeding risk, current guidelines suggest that for any patient presenting with a life-threatening bleed, prompt administration of reversal agents is warranted regardless of the presenting INR value [44]. In one study comparing times to reversal in anticoagulated traumatic ICH patients, patients in whom reversal therapy was initiated in under 2 hours as part of a rapid treatment protocol had both decreased rates of worsening ICH progression, as well as significantly lower mortality, than patients receiving reversal under an older protocol, in which it took more than 4 hours to initiate treatment [45]. Multiple guidelines, including those by the AHA/ASA [46] and the Neurocritical Care Society/Society of Critical Care Medicine [47], highly recommend immediate reversal in VKA patients presenting with ICH. The greatest source of debate within the literature in recent years, therefore, has not been whether reversal is warranted for warfarin-related hemorrhage, but instead involves the question of which of the 3 available reversal agents are most effective at both quickly counteracting the effects of the medication and improving overall outcomes in bleeding patients. 17 Full discussion of phytonadione will be limited in scope, primarily because it has little use as an agent for acute bleeding in emergency situations due to inappropriately long response times in reversing warfarin. In one randomized trial comparing omission of warfarin therapy to omission of warfarin therapy combined with oral phytonadione therapy, the mean time to achieve an INR £4 for over- anticoagulated patients presenting with an initial INR of 6 – 9 was 1.4 days. Although significantly faster than omission of warfarin therapy alone (which took 2.6 days in comparison) [48], this would be an inadequate treatment for a patient presenting with a more time-sensitive, warfarin-related coagulopathy, such as an ICH. Another disadvantage to vitamin K, especially if given at high doses, is that it can make patients refractory to future warfarin therapy when anticoagulation is eventually restarted [49]. Use of low doses of oral phytonadione as a monotherapy is therefore currently limited to patients who do not require urgent warfarin reversal [50]. Historically, FFP in combination with vitamin K had long been the standard of care in reversing the effects of over-anticoagulation [51] [52]. FFP can be prepared from either whole blood or plasma, and contains all of the clotting factors inhibited by warfarin and more, including fibrinogen, antithrombin and tissue factor pathway inhibitor. With appropriate dosing, FFP administration can increase the levels of deficient clotting factors by up to 30% [53], making it an effective therapy for warfarin reversal. In the United States, FFP is the most widely used coagulation factor replacement therapy [54], and this use has only been increasing over time. In 18 2008, 4.5 million units of FFP were transfused in the United States, compared to 3.9 million units in 2001 [55], for an average of now nearly 12,000 units used daily nationwide. One of the most common indications for FFP use is for warfarin reversal, as has been consistently cited in analyses conducted within both the United States [56] and abroad [57]. Despite its widespread use, administration of FFP is limited by several factors. Significant effort is required in preparing the infusions, FFP has a relatively slower therapeutic onset compared to other reversal alternatives (i.e. PCC), and there are many clinical adverse side effects associated its use. To adequately prepare a unit of FFP, the sample first undergoes type-specific matching, thawing, and delivery from the blood bank [54]. The thawing step can take anywhere from 30 – 60 minutes alone [58]. These steps can delay initiation of treatment, which is significant especially in time-sensitive situations. Even if prepared promptly, FFP has a rather slow therapeutic effect and can take 7 – 32 hours to achieve effective INR reversal in warfarin patients presenting with major hemorrhage [54], which is not ideal for life-threatening bleeding in which prompt reversal is required. After transfusion, there are several serious adverse effects associated with FFP to be aware of. Of all blood products, FFP is the major cause of the life- threatening condition known as transfusion-related acute lung injury (TRALI). The underlying pathophysiology of TRALI is speculated to be related to an inappropriate immune response involving either donor antibodies, human leukocyte antigen (HLA) responses, and/or active recipient lung leukocytes that are 19 reacting to certain biological components of the donor’s blood products. The endpoint of these aberrant immune responses is significant pulmonary endothelial damage [59]. Symptoms and clinical findings of TRALI include acute respiratory distress, non-cardiac pulmonary edema, bilateral infiltrates on chest x-ray, tachycardia, and hypoxemia within 6 hours of the transfusion. The absence of concomitant risk factors for the development of lung injury, such as sepsis, pneumonia, and shock, increase the clinical suspicion for TRALI in a recently transfused patient [60]. Statistically, transfusion of every 1 in 2,000 units of a plasma- containing blood component leads to an episode of TRALI, and fatality rates after diagnosis can range between 5 – 25% [61]. In one 5-year retrospective review study, FFP was associated with 50% of fatal TRALI cases, with red blood cells (RBCs), platelet products, and cryoprecipitate-reduced plasma responsible for the rest [59]. TRALI is overall the highest leading cause of transfusion-related morbidity and mortality in the United States [62], making it a serious clinical consequence of FFP use. Another significant risk to FFP use is volume overload, otherwise known as transfusion-associated circulatory overload (TACO). FFP in particular is a major risk factor for developing TACO due to the high volumes of plasma required to achieve adequate therapeutic effects. The number of FFP units transfused has also been shown to strongly correlate with the subsequent development of fluid overload [62]. After TRALI, TACO is the second-leading cause of transfusion-related mortality in the United States. Rates of TACO following FFP administration varies, 20 with studies reporting values between 1.5 – 6%. Patients with TACO were found to have increased rates of in-hospital mortality, and both significantly longer hospital and intensive care unit (ICU) stays [63] [64]. FFP use is associated with other unique side effects. Since FFP is derived from donated human blood products, its administration can increase the risk of infectious disease transmission and immune reactions. These include viral, bacterial, parasitic, and prion diseases, febrile and allergic reactions, and ABO blood group incompatibility [65]. In a 2008 study, FFP transfusion in critically ill patients in an inpatient surgical ICU (SICU) was found to be significantly associated with higher rates of subsequent ventilator-associated pneumonias, bloodstream infections, and septic shock. The researchers attributed these increased risks to a transfusion-related phenomenon known as immunomodulation, which involves alterations in the systemic immune response due to transfusion of immunosuppressive proteins and/or disrupted white blood cell (WBC) products within the plasma [66]. These reactions, taken together with previously mentioned complications such as TRALI and TACO, are serious adverse effects that should be weighed with the benefits to FFP use prior to administration. An alternative to FFP as a VKA-reversal therapy are the PCCs. PCC is a plasma-derived factor concentrate that was originally developed for the treatment of hemophilia B as a source of factor IX [67]. PCC contains variable amounts of the vitamin K-dependent coagulation factors II, VII, IX, and X, and can be further classified based on the quantity of factor VII present in the concentrate: 3-factor 21 PCC contains negligible amounts, while 4-factor PCC contains therapeutically restorative levels (for the remainder of this paper, any mentions of PCC will refer solely to the 4-factor preparation, unless otherwise specified). The first successful documentation of PCC as an anticoagulation reversal therapy was in a 1976 randomized trial comparing 3-factor PCC to intravenous vitamin K therapy. The researchers found that PCC was associated with more rapid, albeit less sustained, reversal of both the prothrombin and partial thromboplastin times compared to vitamin K alone [68]. A 2007 comprehensive 30- year review of all prospective trials comparing PCC to other reversal agents, conducted prior to PCC’s official approval as a reversal therapy by the FDA, found that PCC was associated with multiple clinical benefits, including more rapid INR correction, effective factor replacement, and decreased risks of thrombotic adverse events [52]. In 2013, PCC was officially approved by the FDA for the reversal of coagulopathy in over-anticoagulated patients [69], which is now the primary indication for its use. It is now rarely indicated as replacement therapy in patients with congenital factor deficiencies [70] – the original reason for its development – and has largely been replaced either by concentrates of individual clotting factors or recombinant factor products, especially following the introduction of these products in the 1990s [67] [71]. First, preparing PCC units for infusion is a significantly less intensive process relative to FFP. PCC does not require cross-matching, is stored at room temperature (and therefore does not require thawing), undergoes viral inactivation to reduce the 22 risk of infectious transmission, and can be completely infused in 15 – 30 minutes [72] [50]. These benefits are especially ideal for acute situations in which preparation time should be minimized. Additionally, TRALI, a feared complication of FFP use, is unlikely with PCC because the concentrates do not contain leukocytes that could trigger aberrant immune responses in donors [73]. PCC is also very unlikely to cause TACO because the units are freeze-dried to remove all water particles (e.g. lypophilized), and PCC can therefore be administered in smaller volumes [74]. For comparison, FFP is typically administered at a dose of 15 mL/kg, while an equivalent PCC dose can be given at a volume of 1-2 mL/kg [74]. In one randomized control trial comparing the two reversal modalities for patients presenting with VKA-associated coagulopathy, the median infusion volumes needed to achieve therapeutic effect for PCC and FFP were 99.4 and 813.5 mL, respectively [75]. However, PCC is not without its own set of adverse side effects. As with any transfusion of blood products, anaphylactic reactions have been associated with PCC administration, and since most PCC preparations contain heparin, heparin- induced thrombocytopenia (HIT) has been documented as well. Although PCC is pretreated to inactivate most viral pathogens, contamination of the products with non-enveloped viruses has occurred. Thrombogenic complications including stroke, MI, disseminated intravascular coagulation (DIC), and DVT have also all been attributed to PCC use [70] [74], albeit that composite risk remains low at 1.4%, according to a recent literature review [52]. Since most of these adverse effects are quite rare, PCC is overall a safe and effective therapy for warfarin reversal. 23 Armed now with a better understanding of the primary agents available for VKA reversal, the next important question to consider is whether there is a superior reversal therapy that is associated with the best clinical outcomes in situations requiring reversal of anticoagulation in patients presenting with severe bleeding, especially ICH. In the upcoming section, we conduct a brief literature review of the clinical studies that directly compare PCC to FFP for urgent reversal, with a primary focus on life-threatening ICH associated with anticoagulation therapy. PCC vs. FFP: A Superior Agent? Current guidelines have now shifted their recommendations to PCC for the urgent reversal of VKAs in life-threatening warfarin-related bleeds [76], given that PCC has been shown repeatedly in numerous clinical trials and reviews to have many advantages over FFP. One of the earliest such reports that aimed to directly compare the 2 reversal therapies for this purpose was a 1997 prospective investigation by Makris and colleagues conducted in the United Kingdom, in which patients requiring urgent reversal of their oral anticoagulation therapy received either FFP or PCC. PCC use was associated with complete INR correction in all patients and greater restoration of hemostatically effective levels of clotting factors (especially factor IX), whereas in contrast, the INR failed to correct adequately in all patients receiving FFP. Nearly 2 decades before the FDA would officially approve PCC as a reversal agent for severe, anticoagulation-associated bleeding, the authors 24 of this study strongly concluded that PCC is the only effective option for correcting coagulopathies in patients with life-threatening hemorrhage [77]. Several systematic analyses of studies comparing reversal agents in patients requiring urgent warfarin reversal also have found benefits to PCC use. One meta- analysis of 13 relevant studies found that PCC use was associated with a lower risk of all-cause mortality, higher proportion of hemostasis, greater and more rapid INR normalization, and lower risk of post-transfusion volume overload compared to FFP [78]. Another 2017 analysis by Harrison et al. found that PCC was associated with a 3.65% risk reduction in 30-day mortality relative to FFP [79]. Benefits to PCC were also seen in the results of several randomized controlled trials, some of which were included for review in the meta-analyses discussed above. In one prospective trial conducted across numerous sites in both the United States and Europe, VKA patients presenting with both acute major bleeding and elevated INR ³2.0 were randomized to receive either FFP or PCC for urgent reversal. PCC use was found to be associated with more rapid INR reduction (defined as an INR £1.3 half an hour after infusion) and higher levels of plasma coagulation factors relative to FFP [75]. In a similar randomized trial by Goldstein et al., patients received vitamin K with either concomitant PCC or FFP therapy for rapid VKA reversal. PCC was found to be superior to FFP in achieving both effective hemostasis and rapid INR reduction [80]. In both of these trials, rates of adverse events such as thromboembolism, fluid overload, late bleeding, and death, were similar between treatment groups.