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Hemostasis and Thrombosis: Original Clinical Research Report

Changes in International Normalized Ratios After Plasma Transfusion of Varying Doses in Unique Clinical Environments

Warner, Matthew A. MD*,†; Hanson, Andrew C. BS; Weister, Timothy J. MSN†,§; Higgins, Andrew A. RN; Madde, Nageswar R. MS†,§; Schroeder, Darrell R. MS; Kreuter, Justin D. MD; Kor, Daryl J. MD*,†

Author Information
doi: 10.1213/ANE.0000000000003336

Abstract

KEY POINTS

  • Question: What is the relationship between plasma transfusion dose and changes in coagulation test results in a broad and diverse cohort of patients with wide variability of laboratory coagulation abnormalities?
  • Findings: Changes in coagulation screening tests after plasma transfusions of varying doses were modest, with the majority of plasma administered perioperatively and to those with mild abnormalities in the international normalized ratio.
  • Meaning: Plasma transfusion at typically used clinical doses was not associated with robust improvement in laboratory screening tests, yet future studies are required to assess the relationships between plasma transfusion and clinical outcomes.

Plasma therapy for the correction of an elevated international normalized ratio (INR) or prolonged prothrombin time (PT) result is remarkably common, with the majority of transfusion episodes occurring in those without active bleeding.1 Indeed, the most commonly cited reason for plasma transfusion is correction of an abnormal coagulation test value before an invasive procedure.2,3 Such transfusions are commonly driven by 3 assumptions: (1) an elevated INR confers increased risk of bleeding, (2) correction decreases the incidence of bleeding, and (3) plasma is effective in achieving the desired level of correction.

Nevertheless, each of these assumptions lacks the support of robust evidence. For example, many invasive procedures are safely performed in patients with abnormal hemostatic variables without increased rates of bleeding.4–11 Additionally, prophylactic plasma has paradoxically been associated with increased bleeding complications in surgical and procedural environments.12,13 With regard to the third assumption, there is markedly limited evidence regarding the ability of plasma to reliably correct abnormal INR or PT values. In several investigations that have explored this topic directly or indirectly, plasma administration was rarely associated with coagulation parameter normalization.3,14–22

The goal of this investigation was to explore the relationship between the dose of plasma transfusion and changes in coagulation test results in a broad and diverse cohort of patients with wide variability of laboratory coagulation abnormalities. We hypothesized that normalization of coagulation test values (ie, INR ≤ 1.1) would occur in <1% of patients and partial normalization (ie, INR < 1.5) would occur in <50% of patients. We hypothesized that greater decreases in INR would be observed with greater pretransfusion coagulation test abnormalities and higher plasma volumes. We also aimed to assess changes in INR in unique clinical settings and with concomitant administration of factor concentrates or vitamin K.

MATERIALS AND METHODS

This historical cohort study was conducted under the approval of the Mayo Clinic (Rochester, MN) Institutional Review Board with a waived requirement for written informed consent. The Strengthening the Reporting of Observational Studies in Epidemiology guidelines were used in the design and conduct of this study, as well as in the reporting of results.23

Inclusion criteria were adults (≥18 years of age) receiving plasma at a single tertiary care medical center between January 1, 2011, and December 31, 2015, with a pretransfusion INR (PreINR) value measured in the 24 hours before plasma transfusion and a posttransfusion INR (PostINR) value measured in the 24 hours after plasma transfusion. A plasma transfusion episode was defined as all plasma units administered in the time period extending from measurement of the PreINR until measurement of the first PostINR. Exclusion criteria included a normal PreINR (ie, ≤1.1), lack of authorization for medical record use in clinical research, plasma utilized as part of therapeutic plasma exchange or apheresis, and prior inclusion in the study. For patients with multiple plasma transfusion episodes during the study period, only the first episode with valid PreINR and PostINR values was included.

Screening for potential study participants was performed using an institutional data mart, which captures transfusion data for all patients at the study institution.24 In addition, this resource contains clinical and procedural data for patients admitted to an acute care environment. Additional pertinent baseline characteristics, particularly for patients in nonacute care environments, were obtained from a second validated database, the Mayo Clinic Life Sciences System.25 Both databases have undergone extensive validation with accuracy superior to manual data collection alone.26 Transfusion indications were obtained from electronic medical record orders.

Statistical Analysis

The primary outcome was the proportion of patients attaining normal posttransfusion coagulation values (ie, INR ≤ 1.1, PT ≤ 13 seconds). Secondary outcomes included the absolute change in INR after plasma transfusion (PostINR − PreINR), the proportion of patients achieving partial normalization of coagulation values (ie, INR ≤ 1.5), and the proportion of patients achieving at least 50% normalization in PreINR with respect to an INR of 1.1, calculated as (PreINR − PostINR)/(PreINR − 1.1) ≥ 50%.

To explore the possibility of a dose-dependent response to plasma therapy, the percent correction in INR was compared by the number of plasma units transfused, with predefined analyses comparing (1) 1 unit of plasma to ≥2 units, and (2) 1 or 2 units of plasma to ≥3 units as consistent with previously published work.14 Additionally, the relationship between volume of plasma transfused (mL/kg) and percent change in INR was assessed at transfusion volumes of 0–4.9, 5–9.9, 10–14.9, and >15 mL/kg. The relationship between PreINR and plasma volume (mL/kg) was assessed with Spearman correlation coefficient.

Multiple sensitivity analyses were planned a priori, including: (1) restriction to patients with very mild (INR ≤ 1.5), mild (INR >1.5 and <2), moderate (INR ≥2 and <3), severe (INR ≥3 and <5), and critical (INR ≥ 5) PreINR; (2) restriction by transfusion location (ie, intensive care unit [ICU] or progressive care unit; operating room, postanesthesia care unit, or procedural suite [OR]; emergency department; hospital floor; or outpatient); and (3) restriction based on the presence or absence of vitamin K and/or factor concentrates (ie, 3- or 4-factor prothrombin complex concentrates, factor VIIa) in the time period extending from 24 hours before plasma transfusion to measurement of the PostINR. In addition, recognizing that some plasma transfusions may have occurred in the setting of resuscitation from active bleeding, predefined analyses were also performed with the exclusion of patients having received red blood cell (RBC) transfusion in the 24-hour period before plasma.

Several post hoc analyses were performed, including utilization of 3 alternative PreINR categories (<2.5, 2.5–3.4, ≥3.5) and the delineation of perioperative transfusions, defined as any plasma transfusion occurring within the 24-hour period before or after a surgical procedure (regardless of the actual physical location of transfusion). As an additional post hoc analysis, PostINR values were compared to predicted PostINR values, as calculated from a previously published mathematical model based on PreINR, plasma transfusion volume, and patient-specific circulating plasma volume.27 Plasma volume was estimated by multiplying (1 − hematocrit) by the calculated total blood volume.28 Comparisons between actual and predicted PostINR values were made utilizing Lin concordance correlation coefficient.

The sample size was estimated by assuming a 0.8% INR normalization rate with plasma,14 which corresponds to 1220 individuals needing to obtain a margin of error of ±0.5% for a 95% confidence interval (CI) of INR normalization frequency. The sample size was increased by a factor of 5 to account for secondary outcome measures and sensitivity analyses. All statistical analyses were performed using SAS 9.3 (SAS Institute Inc, Cary, NC).

RESULTS

A total of 64,171 units of plasma (excluding plasma units administered during therapeutic plasma exchange or apheresis) were transfused during the 5-year study period to 10,922 unique patients. Among these patients, 6779 (62%) met inclusion criteria with no exclusion criteria (Supplemental Digital Content 1, Figure 1, http://links.lww.com/AA/C299). Basic demographic and clinical characteristics for the cohort are shown in Table 1. Briefly, patients comprised a heterogeneous mix of clinical subpopulations, with the majority of transfusion episodes occurring in the OR environment (45%) or the ICU (37%). Only 7 transfusion episodes occurred in the outpatient setting; hence, these transfusions were excluded from analyses delineated by unique transfusion location. Additionally, 85% of transfusions occurred perioperatively in the 24 hours before, during, or in the 24 hours after a surgical or interventional procedure. Indications for plasma transfusion are shown in Figure 1, with the majority of transfusions given postoperatively (30%) or intraoperatively (29%) for nonspecified reasons, followed by prophylactic preprocedural INR reversal (20%). More than one quarter of patients had a solid-organ tumor or hematologic malignancy. Approximately 32% of patients had been on warfarin within 5 days of plasma administration. Furthermore, 24% of patients received vitamin K, and 2% of patients received factor concentrates in the time period extending from 24 hours before plasma transfusion to PostINR measurement.

Table 1.
Table 1.:
Demographic and Clinical Characteristics of Patients Receiving Plasma Therapy (n = 6779)a
Figure 1.
Figure 1.:
Plasma transfusion indications.

The median (quartiles) PreINR was 1.9 (1.6–2.5), with pretransfusion PT values of 21 (17.8–27.9) seconds. Nearly one quarter (22%) of transfusion episodes were given with an INR ≤ 1.5, and more than half (55%) were given with an INR < 2. The relationship between plasma administration and absolute correction in INR values for the entire cohort is displayed in Figure 2. The median absolute decrease in INR and PT values for the entire cohort was 0.4 (0.2–0.8) and 3.7 (1.1–7.1) seconds, respectively. The proportion of patients achieving INR normalization (ie, INR ≤ 1.1) after plasma transfusion was 12%, and 61% of patients achieved partial normalization (ie, INR ≤ 1.5). The INR corrected at least halfway to normal in 62% of patients.

Figure 2.
Figure 2.:
Histogram plot of absolute changes in INR values after plasma transfusion for the entire cohort. INR indicates international normalized ratio; PostINR, posttransfusion international normalized ratio; PreINR, pretransfusion international normalized ratio.

The degree of INR correction based on the severity of PreINR abnormalities is displayed in Figure 3. Absolute reduction in INR was modest in size for those with PreINR <3, but greater reductions were seen in those at high levels of INR. The utility of plasma to correct an abnormal INR was lowest for those with INR ≤ 1.5 (53% achieving 50% correction) and greatest for those with INR ≥ 5 (84% achieving 50% correction; Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/C300).

Figure 3.
Figure 3.:
Absolute changes in INR values after plasma transfusion for unique subgroups of pretransfusion INR abnormalities. INR indicates international normalized ratio; PostINR, posttransfusion international normalized ratio; PreINR, pretransfusion international normalized ratio.

Regarding plasma effects by unique transfusion locations, absolute changes in INR are shown in Table 2 and Supplemental Digital Content 3, Figure 2, http://links.lww.com/AA/C301. The greatest absolute reduction in INR was seen in the emergency department, with median PreINR of 2.5 (2.0–4.1) and PostINR of 1.7 (1.3–2.0). However, only 7% of patients achieved INR normalization, with 43% achieving partial normalization. In the OR, the median PreINR and PostINR values were 1.7 (1.5–2.0) and 1.3 (1.2–1.5), respectively, with 17% of patients achieving INR normalization and 80% reaching an INR ≤ 1.5. The median PreINR and PostINR values in the ICU were 2.1 (1.6–3.0) and 1.6 (1.3–2.0), respectively. In this group, 10% of patients achieved PostINR normalization and 49% achieved partial normalization. Transfusions administered on the hospital floor had the lowest rates of complete (4%) and partial (39%) normalization.

Table 2.
Table 2.:
Absolute Change in INR (PostINR − PreINR) by Transfusion Locationa

The median plasma transfusion volume was 2 (2–3) units. The relationship between the number of plasma units transfused and reduction in INR for the entire cohort is shown in Figure 4A. In addition, changes in INR are displayed for those with INR < 3 (Figure 4B) and INR ≥ 3 (Figure 4C). The proportion of patients achieving at least 50% correction in INR after plasma transfusion was significantly greater in those receiving ≥2 units of plasma (65%) compared to those receiving 1 unit (51%; χ2P < .001). Similarly, there was a significant difference in the proportion of patients achieving at least 50% correction in INR when comparing those receiving 1 or 2 units of plasma versus those receiving ≥3 units (60% compared to 68%; χ2P < .001).

Figure 4.
Figure 4.:
Absolute changes in INR based on the number of plasma units transfused. A, Absolute change in INR for the entire cohort. B, Absolute change in INR for patients with pretransfusion INR < 3. C, Absolute change in INR for patients with pretransfusion INR ≥ 3. INR indicates international normalized ratio; PostINR, posttransfusion international normalized ratio; PreINR, pretransfusion international normalized ratio.

Data were available to calculate weight-adjusted plasma doses for 90% of patients, with a median dose of 6.4 mL/kg (4.7–9.1). Approximately 20% of doses were at least 10 mL/kg. There was no significant relationship between the PreINR value and volume of plasma transfused (Spearman ρ, 0.023 [95% CI, −0.001 to 0.047]; P = .06). The relationship between volume of plasma transfused (mL/kg) and absolute change in INR values by transfusion location is shown in Table 2. In all transfusion locations, the greatest decreases in INR were observed at plasma doses between 10.0 and 14.9 mL/kg. Plasma doses >15 mL/kg did not result in greater reductions in INR. The median time of PostINR measurements was 7.8 (2.0–14.9) hours after initiation of the plasma transfusion episode. Absolute changes in INR stratified by time from plasma transfusion to INR measurement are displayed in Table 2.

As a predefined sensitivity analysis, 2618 patients (39%) were excluded due to receiving RBCs in the 24 hours before plasma transfusion. Alterations in INR after removal of these patients are displayed in Supplemental Digital Content 4, Figure 3, http://links.lww.com/AA/C302, and the results were largely unchanged. In addition, changes in INR by transfusion location and stratified by PreINR abnormalities and plasma volume are shown in Supplemental Digital Content 5, Table 2, http://links.lww.com/AA/C303. Analyses were also performed after limitation to or exclusion of patients receiving or not receiving vitamin K and/or factor concentrates in addition to plasma therapy (Supplemental Digital Content 4, Figure 3, http://links.lww.com/AA/C302). The proportion of patients achieving at least 50% correction in INR was greater in patients receiving vitamin K or factor concentrates when compared to those receiving plasma therapy without vitamin K supplementation or factor concentrate administration (67% compared to 61%; χ2P < .001). The greatest change in INR was observed in patients receiving concomitant plasma, vitamin K, and factor concentrate administration, with a median decrease of 0.8 (0.3–1.8). By comparison, those receiving plasma alone had a median decrease of 0.4 (0.1–0.7), and those receiving plasma and factor concentrate therapy without vitamin K supplementation had a median decrease of 0.6 (0.4–1.1).

As a post hoc analysis, changes in INR values based on PreINR categories of <2.5, 2.5–3.4, and >3.5 are displayed in Supplemental Digital Content 6–7, Figure 4, http://links.lww.com/AA/C304, Table 3, http://links.lww.com/AA/C305). Briefly, the median decrease in INR after plasma transfusion in those with INR > 3.5 was 2.4 (1.7–3.7) compared to a median decrease of 0.3 (0.1–0.5) in those with INR < 2.5. Similar findings were seen in all transfusion locations. Regarding comparisons to a previously published model for PostINR prediction, there was moderate agreement in actual and predicted PostINR values (Lin concordance correlation coefficient, 0.59 [95% CI, 0.57–0.61]; Supplemental Digital Content 8, Figure 5, http://links.lww.com/AA/C306). A histogram plot for total number of plasma units transfused is shown in Supplemental Digital Content 9, Figure 6, http://links.lww.com/AA/C307.

DISCUSSION

In this study of nearly 7000 unique patients, plasma transfusion of varying doses was associated with complete INR normalization in a small percentage of patients (12%) and partial normalization in just over half. Reductions in INR were greatest for those with severely and critically elevated values and least for those with mild or moderately elevated values. Despite this, >50% of plasma transfusion episodes occurred in those with INR values < 2.

The results of this investigation validate the findings of previous studies, now with a significantly larger study population and expanded analyses to include a more full representation of clinical practice. Previously, it was shown that in 121 adults admitted with INR values ranging from 1.1 to 1.85, INR normalization after plasma transfusion occurred in <1% of patients, with 50% correction of INR occurring in just 15%.14 The notably higher rate of INR normalization in our investigation may be secondary to the inclusion of patients with a wider range of PreINR values and the use of a higher threshold for INR normalization (ie, 1.1 rather than 1.0). In a multicenter review of plasma transfusion practices in 10 US hospitals, approximately half of the transfusion episodes occurred in those with PreINR values < 2, but only 42% resulted in PostINR of ≤ 1.5.3

Unlike previous work, this investigation was designed to analyze changes in coagulation screening tests after plasma transfusion in specific transfusion locations, finding that patients transfused in the OR had the highest rates of partial INR normalization, with 80% of patients achieving a value ≤ 1.5. However, the majority of transfusions was initiated with INR values < 2, and complete INR normalization was only obtained in 17%. Given that the OR and ICU environments were identified as the most common sites for plasma transfusion, future clinical investigations and practice improvement efforts may benefit from focus in these areas. In a previous study from the authors’ institution, preoperative plasma transfusion for the correction of abnormal INR values was paradoxically associated with increased RBC requirements in noncardiac surgical patients.12 Lack of perceived clinical benefit has also been shown in patients receiving plasma before percutaneous interventional procedures.13,29 Remarkably, the efficacy of prophylactic plasma for the reduction of perioperative bleeding remains unknown despite widespread use of plasma for this purpose.

The current investigation is also unique in assessing the relationships between plasma transfusion and coagulation test results by the presence or absence of vitamin K or factor concentrates. To this end, patients receiving vitamin K or factor concentrates in addition to plasma received a greater reduction in INR than those administered plasma alone. However, these effects were modest (67% vs 61%, respectively), and it is unclear if plasma therapy contributed in a meaningful way to the magnitude of INR reduction in these patients. Additionally, the administration of plasma with simultaneous vitamin K and factor concentrate supplementation resulted in greater decreases in INR compared to plasma given with either vitamin K or factor concentrates alone. However, given the limited number of simultaneous factor concentrate use, future studies will be necessary to define the utility of concomitant plasma and vitamin K and/or factor concentrate administration for reduction in INR and improvement in clinical outcomes.

It has been previously recognized that the volume of plasma transfusion may have substantial effects on the correction of elevated INR values.14,17,22 In the current investigation, approximately 80% of plasma transfusion episodes were <10 mL/kg, and higher volumes were associated with greater reductions in INR. For example, nearly 70% of patients achieved an INR that corrected at least halfway to normal when 3 or more units of plasma were administered compared to approximately 50% when a single plasma unit was given. Additionally, the greatest reductions in INR were observed with plasma volumes between 10 and 15 mL/kg. Hence, when INR correction is deemed to be a clinically important goal and plasma is selected as the vehicle of choice to achieve this objective, higher volumes are more likely to result in the desired effect.

However, it must also be noted that there is no compelling evidence that higher plasma volumes result in improved clinical outcomes. Conversely, plasma transfusion has been associated with a myriad of complications, including transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and febrile and allergic reactions, among others. In developed countries, TRALI and TACO remain the leading causes of transfusion-related death,30 and the incidences of both entities are likely underestimated due to poor clinical recognition and underreporting. While transfusion complications were not evaluated in this study, previous work from our institution has shown an incidence of TRALI in transfused (plasma, RBCs, or platelets) noncardiac surgery patients of 1.4% and an incidence of TACO of 3.0%, with the occurrence of both conditions associated with substantially increased mortality and hospital lengths of stay.31,32

Apart from transfusion-related risks, coagulation tests are imperfect predictors of actual factor levels.22 This may be explained, in part, by the nonlinear exponential relationship between factor levels and coagulation test results, with adequate hemostatic reserve often persisting until factor levels fall to <30%.2 In patients receiving oral vitamin K antagonists, most factor levels remain >30% until INR is >2.5.33 In addition, the levels of individual coagulation factors required for adequate hemostasis are extrapolated from the management of patients with single inherited deficiencies and may not be broadly applicable to all patient populations.34

There are several limitations to this observational study, including most notably its retrospective nature, which does not allow for the precise determination of circumstances surrounding transfusion decisions. Transfusion indications were missing for 13% of patients, and indications were not specified for intraoperative (29%) and early postoperative transfusions (30%). Although many of these episodes were likely related to surgical bleeding, it is also possible that some were reactive in response to abnormal coagulation tests without evidence of bleeding or clinical coagulopathy. In an attempt to ameliorate the potential effects of bleeding on coagulation test results, a predefined sensitivity analysis was performed, with the exclusion of patients having received RBCs in the 24-hour period before plasma administration, and the results were largely unchanged. Additionally, this study was not designed to compare changes in INR values based on the presence or absence of plasma transfusion as all included patients were indeed administered a plasma transfusion. Hence, it is not possible to assess the impact of plasma transfusion on coagulation test results. Rather, this study simply provides a descriptive analysis of changes in INR values after varying doses of plasma transfusion in a variety of clinical contexts. As another limitation, a 24-hour time frame for inclusion of PostINR values was utilized, which is a wider window than several prior investigations.3,14 While some argue that the effects of plasma transfusion may have dissipated at time frames >8 hours, we believe that the inclusion of patients in a broader time frame offers clinically meaningful information regarding PostINR responses. Importantly, this study was specifically designed to assess changes in coagulation screening tests after plasma transfusion rather than assessing plasma-mediated effects on clinical outcomes. As such, we are unable to comment on the benefit of plasma in preventing (eg, prophylactic preprocedural transfusion) or ameliorating (eg, intracranial hematoma expansion) hemorrhagic complications, irrespective of changes in INR values. Finally, the dose and specific timing of factor concentrate and vitamin K administration were not considered in these analyses but certainly warrant examination in future investigations.

In conclusion, varying doses of plasma transfusion were associated with only modest changes in coagulation screening tests in a large and diverse cohort of patients. Plasma was most often administered to patients with mild abnormalities in INR who were least likely to respond with laboratory improvement. Future prospective investigations are needed to ensure external validity and assess relationships among plasma transfusion, changes in coagulation test results after transfusion, and clinically important outcomes such as bleeding complications and transfusion-associated adverse effects.

DISCLOSURES

Name: Matthew A. Warner, MD.

Contribution: This author helped with concept and design, analysis and interpretation of the data, critical writing and revision of intellectual content, and final approval of the manuscript.

Name: Andrew C. Hanson, BS.

Contribution: This author helped with concept and design, analysis and interpretation of the data, critical revision of intellectual content, and final approval of the manuscript.

Name: Timothy J. Weister, MSN.

Contribution: This author helped with concept and design, analysis of data, critical revision of intellectual content, and final approval of the manuscript.

Name: Andrew A. Higgins, RN.

Contribution: This author helped with concept and design, analysis of data, critical revision of intellectual content, and final approval of the manuscript.

Name: Nageswar R. Madde, MS.

Contribution: This author helped with concept and design, analysis of data, critical revision of intellectual content, and final approval of the manuscript.

Name: Darrell R. Schroeder, MS.

Contribution: This author helped with concept and design, analysis and interpretation of the data, critical revision of intellectual content, and final approval of the manuscript.

Name: Justin D. Kreuter, MD.

Contribution: This author helped with concept and design, analysis and interpretation of the data, critical revision of intellectual content, and final approval of the manuscript.

Name: Daryl J. Kor, MD.

Contribution: This author helped with concept and design, analysis and interpretation of the data, critical revision of intellectual content, and final approval of the manuscript.

This manuscript was handled by: Roman M. Sniecinski, MD.

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