Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature | Coagulation | Bleeding

See the corresponding editorial in this issue, p 8.

J Neurosurg 114:9–18, 2011

Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature
A review
Kelly L. West, M.D., Ph.D.,1 Cory Adamson, M.D., Ph.D., M.P.H., M.H.Sc., 2,3 and Maureane Hoffman, M.D., Ph.D.1
Departments of 1Pathology, 2Surgery (Neurosurgery), and 3Neurobiology, Duke University and Durham Veterans Administration Medical Centers, Durham, North Carolina
Prophylactic fresh-frozen plasma (FFP) transfusion is often undertaken in hemodynamically stable patients with a minimally elevated international normalized ratio (INR) prior to invasive procedures, despite little evidence in support of this practice. The authors review the current literature in an attempt to clarify best clinical practice with regard to this issue. Although the activated partial thromboplastin time and prothrombin time–INR are useful laboratory tests to measure specific clotting factors in the coagulation cascade, in the absence of active bleeding or a preexisting coagulopathy, their utility as predictors of overall bleeding risk is limited. Several studies have shown an imperfect correlation between mild elevations in the INR and subsequent bleeding tendency. Furthermore, FFP transfusion is not always sufficient to achieve normal INR values in patients who have mild elevations (< 2) to begin with. Finally, there are risks associated with FFP transfusion, including potential transfusion-associated [disease] exposures as well as the time delay imposed by laboratory testing and transfusion administration prior to initiation of procedures. The authors propose that the current concept of a “normal” INR value warrants redefinition to make it a more meaningful clinical tool. Based on their review of the literature, the authors suggest that in a hemodynamically stable patient population there is a range of mildly prolonged INR values for which FFP transfusion is not beneficial, and is potentially harmful. (DOI: 10.3171/2010.7.JNS091857)

Key Words      •      coagulation      •      neurosurgery      •      transfusion      • prothrombin time–international normalized ratio      •      fresh-frozen plasma

emostasis is attained through the coordinated effects of multiple factors and is often described as a 2-step process. First, during primary hemostasis, vascular damage initiates vasoconstriction and exposes subendothelial collagen. This leads to platelet adhesion, aggregation, and activation, and culminates with the formation of a platelet plug (Fig. 1). During secondary hemostasis, coagulation factors of the extrinsic and intrinsic pathways promote deposition of insoluble fibrin, thereby stabilizing the platelet plug (Fig. 2). It is important to recognize that deficiencies of both primary and secondary hemostasis may lead to abnormal bleeding. The laboratory values most commonly used to assess coagulopathy are the PT and aPTT. However, these


Abbreviations used in this paper: aPTT = activated partial thromboplastin time; FFP = fresh-frozen plasma; GCS = Glasgow Coma Scale; HMWK = high-molecular-weight kininogen; ICP = intracranial pressure; INR = international normalized ratio; ISI = international sensitivity index; PCC = prothrombin complex concentrate; PK = prekallikrein; PT = prothrombin time; RBC = red blood cell; rFVIIa = recombinant activated factor VII; TBI = traumatic brain injury.

values represent the isolated in vitro activity of specific coagulation factors involved only in secondary hemostasis (Fig. 2). The aPTT depends on activity of the intrinsic pathway coagulation factors HMWK, PK, and factors XII, XI, IX, and VIII, as well as the common pathway coagulation factors X, V, thrombin, and fibrinogen. The PT represents activity of the same common pathway factors (X, V, thrombin, and fibrinogen) as well as activity of the extrinsic pathway coagulation factor VII. Neither test takes into account mechanisms of primary hemostasis, the action of factor XIII, which is required for stabilization of the fibrin thrombus, or the anticoagulant factor activities of proteins C and S. The aPTT was initially developed to measure factor VIII in the diagnosis of hemophilia A, and not to predict whether someone will bleed.35 This is underscored by the fact that there are instances in which the aPTT may be markedly prolonged in the absence of any clinical bleeding tendency (for example, deficiencies in HMWK, PK, factor XII, or the presence of a lupus anticoagulant). Likewise there are clinically significant bleeding disorders that exhibit a normal aPTT, such as hyperfibrinoly9

J Neurosurg / Volume 114 / January 2011

Platelets then aggregate via fibrinogen binding with multiple platelet GPIIb/IIIa surface proteins to form the initial platelet plug. Hoffman Fig. This means that 5% of normal. which is less sensitive to alterations in the common pathway factors than it is to the extrinsic pathway. Furthermore. the PT-INR is simply the PT ratio. and M. The values defined as the “normal range” (more correctly. C. Commercial reagents are measured and adjusted against international standards. if the ISI = 1. The “mean normal PT” is the geometrical mean of the PT values for healthy. the PT.  During primary hemostasis. is best interpreted as a measure of factor VII activity.K. normal individuals. the slope of which represents the ISI. platelet adhesion is mediated by interactions of the platelet surface proteins GPIb and GPIa/IIa with exposed von Willebrand factor (VWF) and collagen on the endothelial surface.48 Similarly. healthy individuals will have values outside the “normal” range. Thus. the “reference range”) is the range of values encompassing 95% of healthy individuals. This usually consists of INR values of approximately 0. and defects in the extrinsic pathway of secondary hemostasis (factor VII deficiency). The INR is calculated with the following formula: INR = (patient PT/mean normal PT)ISI. and not as an overall marker of bleeding risk. 1. factor XIII deficiency. L. West.8–1. which was developed to account for variability due to different thromboplastin reagents. The PT is often expressed in terms of the INR. primary hemostatic disorders (von Willebrand disease). Adamson. sis.2 for most coagulation analyzer/reagent systems. The PT-INR was initially used only to standardize J Neurosurg / Volume 114 / January 2011 . the degree to which the aPTT is prolonged does not correlate with the severity of bleeding. these standards have been developed using plasma obtained in 10 patients taking vitamin K antagonists to generate a regression line.

and II (thrombin). it has become common practice J Neurosurg / Volume 114 / January 2011 to monitor the PT and aPTT as indicators of bleeding risk.5–4. XI. fasting state of the patient. Lipe­ mic.33 However. laboratory values for monitoring patients taking vitamin K antagonists. as well as proteins involved in the common pathway.55 Our goal is to review the recent literature with respect to the question of whether mild elevation of the INR warrants FFP transfusion prior to invasive procedures in patients who have no history of abnormal bleeding and who are not actively bleeding. antithrombin. that the INR is a reliable predictor of bleeding. a sample with an elevated hematocrit (RBC mass) has a proportionately reduced volume of plasma (supernatant).32 For example. and VIII). and to attempt to correct “abnormal” values before undertaking invasive procedures.62 Both the PT and aPTT results can be influenced by numerous pretest variables such as hematocrit. resulting in an artificially prolonged bleeding time. or proteins C or S (Prot c/s). The question of whether a mild elevation of INR indicates significant bleeding risk in patients undergo11 Does a Mild Elevation in Preprocedural INR Indicate a Significant Risk of Bleeding? . icteric. This process of secondary hemostasis is performed by proteins of the intrinsic and extrinsic arms of the coagulation cascade. However. and hemolyzed plasma have increased turbidity. and second. the initial platelet plug is stabilized by the generation and deposition of fibrin. However. interfering with the light transmittance used for clot detection and thereby potentially altering PT and aPTT values. V. because the INR is only an arithmetic transformation of the PT. The aPTT is a reflection of these same common pathway factors (X. this practice is based on little scientific evidence. V. it is no less valid than the PT in seconds or the PT ratio. and some have argued that it should only be applied to this patient population. Despite these issues.Correcting the INR in neurosurgery: a brief review Fig. and citrate concentration.  Ultimately. it should be noted that the INR is most reliable in the range of 1. with cross-talk and feedback regulation at multiple steps.5.1 and 1. The PT measures the activity of the extrinsic pathway factor VII. and factors X. and as a result the effective ratio of anticoagulant to plasma is increased. and is shaped by 2 assumptions: first. Neither assay accounts for activities of factor XIII. that administration of FFP will correct an abnormal INR. IX. with the variability of results increasing dramatically at higher values. Fresh-frozen plasma is the acellular component of blood and contains all of the soluble clotting factors. This product is commonly transfused in an attempt to “correct” INR values between 1. and II) as well as components of the intrinsic pathway factors (XII. time from sample collection.5. 2.

consisting of clinically insignificant hemorrhage (1–2 mm in size) at the site of ICP monitor insertion. and no differences were observed in patients who were actively bleeding versus those who were not. 1 occurred in each of the 3 stratification well as posttransfusion INR values. Hoffman ing invasive procedures was systematically reviewed in 2005. The PT-INR measure12 ments reflect only procoagulant activity.2.7. anemia causing systemic hypoxia. and M.5 and by 79. Of the 157 patients studied. and 2. and mixed paracenteses/thoracocenteses/lumbar punctures/central vein cannulations (2). Patients from 3 institutions were included in the study if they had received FFP transfusion and had documented pre.85. None of the studies found that a mild prolongation of the clotting times correlated with an increased bleeding tendency.7). Of the 13 patients with an INR > 3. Together. The authors proposed that in illness. Thus. C. or amount of FFP used.1 changes in coagulation laboratory values after FFP transfusion were followed for a group of patients with initial INR values between 1. 1. Administration of FFP alone failed to show a significant reliable change in the INR. yet none required FFP to prevent a life-threatening hemorrhage.5% of the group with an INR < 1. 22 received transfusion. The authors concluded that the transfusion of plasma to “normalize” the PT-INR was not warranted in patients with an INR ≤ 1. 1. and metabolic disturbances causing pH changes may be barriers to ever achieving normal INR values. this value is only partially normalized in a small subset of patients. One must use caution.42 Blood product transfusion was required by 83. because a delayed time to intervention tends to correlate with a worse outcome.4 hours. 12 patients). in extrapolating the results of a study conducted in patients with cirrhosis to those undergoing neurosurgery.5 hours prior to transfusion at the 3 institutions. in this study 46 patients had an INR > 2. these results suggest that for a patient population with mildly elevated INR. and also found that FFP treatment was minimally effective in correcting mild elevations in INR (< 1. the PT-INR is prolonged due to reduced procoagulant activity.2.1) after FFP transfusion. bleeding status. More recently..7–5. 42 patients). and at the same time.. only 25 studies were appropriately designed to answer this question.85. in patients with INR values of 1. This has important implications in the management of neurosurgical patients.4.8–1. central vein cannulation (3). this study42 does demonstrate a finding that can be more universally applied. the patients’ coagulation parameters (PT. 103 patients). and relevant to the field of neurosurgery.2.5.8% of 121 total patients obtained a normal INR (defined as < 1. there are few data: of 682 abstracts identified. the efficacy of using FFP to do so has been called into question. Unlike in the study by Abdel-Wahab et al. this study suggests that the INR level is not predictive of bleeding risk during placement of an ICP monitor. borderline (INR 1.2 hours in the group receiving transfusions. when the change in INR was analyzed with respect to the amount of FFP transfused. femoral angiography (3). The average time from admission to ICP monitor placement was 19. a dose-response effect was lacking.5. and increased (INR 1.K. The authors surveyed a variety of medical and surgical patients receiving FFP transfusion at Massachusetts General Hospital over a 10-month period.5. Eligibility requirements included an initial INR between 1. There was no relationship between the extent of PT prolongation and the degree of normalization achieved. Remarkably. which is the imperfect correlation between INR and bleeding risk. patients undergoing liver transplantation were divided into 2 groups: INR < 1. 2. therefore. The issue of whether mild elevations in INR truly need to be corrected remains controversial. Of the 157 patients. Of these 3 events. In a prospective study published in 2008. A second very important finding of that study was that the time to ICP monitor placement was significantly delayed in patients receiving blood component therapy.29 included 250 adult and pediatric patients.6.1 these authors furthermore propose that the pretransfusion INR J Neurosurg / Volume 114 / January 2011 Can FFP Effectively Correct a Mild Elevation in INR? . These investigators found that only 0.3.8 hours in those in whom transfusion was not done. instead. kidney biopsy (2). RBCs (1 U each) were administered in 3 patients. The studies encompassed the following procedures: bronchoscopy (2 studies). A second study. followed by a repeat INR assessment within 8 hours of product administration. factors such as dehydration causing hypoperfusion of the liver.1 and 1. patients undergoing fiberoptic intraparenchymal ICP monitoring were stratified into 1 of 3 groups based on INR values at the time of monitor placement: normal (INR 0. None of the patients received FFP. L. liver biopsy (13). There were no symptomatic intracranial hemorrhages in any group. whereas posttransfusion INR values were checked at a median of 4. the investigators found that the most effective way to treat a mildly elevated INR was to treat the underlying medical condition. and 13 had an INR > 3. and the need for intraoperative RBC transfusion was assessed. by Holland and Brooks.3–1. West. In the majority of the studies. and only served to delay monitor placement. a patient with cirrhosis has decreased synthesis of both pro.5 (103 patients). and 1. and that normalization is achieved in a manner that is unrelated to degree of INR prolongation. and 1. Furthermore.1 and 1.55 In fact. however. yet the patient may be able to maintain a delicate hemostatic balance because anticoagulant levels are similarly reduced. with or without INR and aPTT) were 1.62 With impaired liver function.and anticoagulant factors. a study was performed to determine whether strictly “normal” coagulation parameters are a prerequisite to the safe placement of standard ICP monitors. Adamson.2–2 times normal values.14 In this retrospective review.6. The laboratory values were obtained at a median interval of 5. 3 adverse outcomes were recorded. However. and just 15% had changes in magnitude of the INR that brought values at least halfway to normal. The authors concluded that there was no correlation between INR and intraoperative bleeding. In a prospective audit by Abdel-Wahab et al. a difference that was not statistically significant.5 (97 patients) or ≥ 1. and 20 of these received FFP.6% of the group with an INR ≥ 1. and 8.

depending on the specific patient population and the definition of coagulopathy used. 20 patients did receive FFP before ICP monitor insertion. with an increase in death and delayed traumatic intracerebral hematoma. However. including INR. when compared with an equivalent group of 71 patients not receiving FFP who had no statistically significant differences in multiple factors.9 Transfusion-related acute lung injury is estimated to occur in between 1:100 and 1:5000 plasma-containing transfusions. However.3. perhaps the trigger point for treatment should be reanalyzed. plasma is most strongly implicated. but a dose closer to 30 ml/kg may be required to raise coagulation factors reliably enough to normalize clotting assays in critically ill patients.6). Although activation of the coagulation pathway may result in factor consumption and thrombosis. however.3–1. leading to vascular ischemia and exacerbation of cerebral edema and delayed traumatic intracerebral hematoma.20.018). Among these risks are acute lung injury. Prophylactic Use of FFP in TBI been reported to be anywhere from 10% to 97.Correcting the INR in neurosurgery: a brief review is predictive of the response to FFP. with a mortality rate of 6%–23%.61 Some authors advocate administration of FFP to prevent hemorrhage following TBI. 5 had INRs that decreased to borderline range. the circumstances may be similar in the case of TBI. hospital deaths. this number may be lower than is clinically warranted.5%.3. The CNS is unique in that it has high levels of tissue factor. transfusion-related acute lung injury was the leading cause of transfusion-associated death (35%–65% of fatalities). only 1 obtained an INR within the normal range (decreased from 1. The majority of the studies of TBI define normal INR as ranging from < 1.0). With this approach. Also of interest. a finding that was statistically significant (p = 0. after which 8 had elevated INR levels (> 1. and the other 4 remained in the borderline range (1. Although the use of FFP when clinically indicated can certainly be of benefit. whereas 1 experienced an increase in INR (increased from 1. with only 2 normalizing completely (INR < 1. transfusion-transmitted infections.3–1. depletion of coagulation factors and platelets.7.24 The incidence of coagulation disorders in TBI has J Neurosurg / Volume 114 / January 2011 .9) after FFP administration.5 to 2. the group receiving FFP transfusion had a significantly greater incidence of new-onset acute lung injury. For example. Of the 13 patients with INR values > 1.3%) received FFP over a wide range of INR values (median 7-fold increased risk of transfusion-related acute lung injury developing. The apparent inability of FFP transfusion to “correct” a marginally prolonged PT-INR in published studies is probably related to 2 factors: 1) a consumptive process may continue to deplete factors at a greater rate than they are replaced by transfusion.18 The authors hypothesize that FFP transfusion may in fact promote thrombosis.52 Indeed.and hypocoagulable states. recent evidence suggests that routine prophylactic transfusion of FFP may not be as effective as previously thought.58 Because FFP is a blood component.1. In the same way that mildly elevated INR does not appear to be a reliable indicator of the need for FFP transfusion in patients undergoing procedures.5 who experienced hemorrhage had been treated with FFP. which can lead to excessive activation of the coagulation system in response to head trauma. this correlation is strongest for INR values > 2.10 Transfusion of 2 U of FFP (approximately 400–450 ml or 6 ml/ kg in a 70-kg patient) would only be expected to increase coagulation factor levels slightly (by approximately 6%.14 In this study. Prophylactic transfusion has been suggested for patients with TBI whose GCS scores were < 6.6.24 When it was defined as an INR value > 1. and 2) an inadequate dose of FFP is commonly used. These studies suggest that the routine use of FFP in patients with TBI who have mild elevations in INR may not be warranted. and may in fact be harmful.1 to 1.43 However. and a bleeding diathesis. change in INR in response to FFP transfusion was examined in critically ill.40 Reports from the US FDA show that between the fiscal years 2005 and 2008. Of note. and some support an approach of FFP transfusion based on the GCS score.13 Of 115 patients. plus a platelet count < 100. Additional evidence comes from the study of ICP monitors discussed above. based on the data of Chowdhury et al. or length of stay in the intensive care unit. with a relative risk of 2. The 1 patient with an INR of 2. there were no differences in bleeding episodes. Doses of approximately 15 ml/ kg are often given. which had failed to correct the INR. and would be unlikely to change the PT significantly.3).24 Ultimately this can result in diffuse fibrin deposition.10) defined patients as suffering from coagulopathy if they exhibited a clinical condition frequently associated with this disorder.000 and/or INR > 1.5 to 1.3–1. and fluid overload. and only 1 corrected to a normal value with FFP. significant hemorrhage may need to be treated. Of the 6 patients with borderline INR values (1. with a 5. of all blood component products. a double-blind randomized controlled trial was undertaken to compare prophylactic transfusion of FFP versus saline in patients with severe head injury (GCS score < 8) and no history of coagulopathy.6. range 1–22). coagulopathy was found in 17% of patients with TBI.7) and 10 had borderline values (1.5 in just 36% of those treated with FFP (16 of 44 patients). with FFP being the most commonly transfused product in these cases.9. and not for mildly elevated INR. nonbleeding medical patients. as we will discuss. its administra13 Adverse Effects of FFP Traumatic brain injury has been associated with both hyper. the median dose of FFP was higher in the group whose INR decreased to < 1. 7 still had values > 1.5). 36% of patients with TBI were classified as having coagulopathy.92– 1. 44 (38.6) to begin with. its administration is not without risks. In a retrospective cohort study.22.5 than in those whose INR did not decrease below this level (17 ml/kg vs a median of 10 ml/kg). Outcomes were worse in patients receiving FFP transfusion.67 A second study with a very limited range of “normal” INR (0. and in fact may contribute to overall patient morbidity. allergic and anaphylactic reactions.10). The INR decreased to < 1.

12. microvascular bleeding was not observed until factor levels reached a value of < 20%. in recent years. between 1979 and 2001. In one study.000 for hepatitis B virus. residual virus risks for FFP transfusion are estimated at 1:90.41. Hoffman tion carries a small but real risk of transfusion-related infection. However.54 One should bear in mind that it is not always the degree to which coagulation parameters are prolonged.6. in the small number of studies directed at transfusion of plasma in hemodynamically stable patients with minimal elevations in the INR. However.K. The primary goal of this review was to discuss the available data on the prophylactic administration of FFP in the nonbleeding patient. Adamson. In the United Kingdom. such reactions contribute to overall morbidity and may necessitate termination of transfusion. In fact. and that the US in particular uses a disproportionate amount of FFP when compared with other countries with similar health care provisions.3–1. This evolution of reagents has progressed without a corresponding reevaluation of the definition of normal coagulation parameters. sensitive reagents are often not within the range that would be expected to lead to hemorrhage.65 Bacterial contamination of FFP is rare.49 Data show that over the last 20 years the amount of FFP used has been steadily rising in the US. there may be benefits to a more conservative approach to FFP transfusion. C. Comparison of liberal and conservative approaches to blood transfusion in critically ill patients has established that liberal transfusion provides no additional benefit and may in fact be harmful to recipients. L.5.19 The risk of bleeding increases with INR values above the therapeutic range: the incidence of bleeding in patients on coumadin therapy rises 4-fold with INRs over 4. the management of treatment in the bleeding patient with abnormal coagulation test results deserves mention. Several treatment options are available to provide urgent reversal of anticoagulation in the patient on coumadin therapy (these are summarized in Table 1).43. However.06 per 10.8.11 In a study comparing patients with liver disease and patients on warfarin over a range of INR of 1. one should bear in mind that only 5%–30% of normal factor activity levels are required to attain normal hemostasis.53 Virus-inactivated preparations such as methylene blue–treated and solvent detergent–treated plasma are now being offered. and have been estimated to occur in 1%–3% of plasma transfusions. which seems to be the most reliable predictor of bleeding risk. New Zealand. 40%–70% (factor V). this is not to diminish the therapeutic role of FFP.38. relying on the PT and aPTT may not be an effective way to do so. Furthermore. factor levels that prolong the PT-INR by using modern. with published estimates of 0. In considering the need to transfuse. Fluid overload due to FFP transfusion is relatively uncommon. there are no data to support FFP transfusion. as are transmission of cytomegalovirus and human T-lymphotropic virus due to FFP transfusion. In contrast to critical care studies. West. Anaphylactic and allergic reactions are not infrequent in response to FFP. No well-designed clinical trials clearly support the superiority of any one treatment strategy. there is little evidence to support transfusion.0. As a result.31. reagents used in the laboratory testing have evolved such that sensitivity of reagents to factor levels has increased significantly. Third.6–2. there is a body of literature in the trauma field supporting a more liberal and aggressive approach to transfusion.5 increase in the INR increases the risk of intracranial bleeding by 1.15.000 transfusions in some European countries.60 These studies have helped redefine the hemoglobin threshold at which RBC transfusion should be undertaken for that particular patient population.2 Intravenous vitamin K is the J Neurosurg / Volume 114 / January 2011 What Should we do When the Patient is Bleeding? 14 .64 This is associated with significant costs to the health care system.17.9. although the mechanisms are unclear.5. further studies are clearly needed. defining the patient population of interest is key. 51 and each 0. and 1:30 million for hepatitis C virus.50 Although generally not severe. but rather the reason for prolongation that matters. making patients more susceptible to infection in general. There are at least 3 major reasons for redefining a “normal” INR. The most common such scenario is the reversal of anticoagulation in the patient receiving coumadin therapy who has evidence of intra­ cranial bleeding. even for an isolated elevation of the INR in the range of 1.56 although this remains somewhat controversial.9. and Norway. however.1–2. leading to blood product wastage. the United Kingdom.4 Bleeding in this setting requires rapid and effective correction of the coumadininduced coagulopathy. virus inactivation is also associated with a decrease in coagulation factor levels. Redefining the “Normal” INR First.35 Although it is certainly important to identify patients preoperatively who may sustain life-threatening hemorrhages.8 times control values. 1:8 million for HIV. a number of studies have cast doubt on the usefulness and necessity of routine preoperative screening of the PT and aPTT.6 to 1 per 3. if screening INR values are < 1. compared with 4–8. so opinion is divided about the best approach. Data in support of prophylactic use of FFP for transfusion in the setting of a mildly elevated INR are lacking.36.25.6. Nearly 20% of spontaneous intracranial hemorrhage is associated with therapeutic anticoagulation. it has been suggested that FFP may have adverse immunomodulatory effects. and 22%–60% (thrombin). particularly in the absence of a personal or family history of a bleeding tendency.40 In addition to transmitting infectious agents.64 The number of units of FFP per 1000 people in the US in 2001 was 13. low-normal or marginally reduced levels can result in a prolonged PT or aPTT that is of little clinical significance. For example. factor levels were estimated to be 22%–60% (factor VII). Second.28. this was calculated to correspond to PT and aPTT values at least 1. the number of units of FFP given per unit of packed RBCs rose from 1 per 6.66 Our appraisal of the literature revealed that.7 U per 1000 people in countries such as France.59 Thus. and M. rather perhaps a redefinition of the “normal” INR is in order.

the therapeutic effect of rFVIIa cannot be monitored using the PT-INR. At the high concentrations of rFVIIa used therapeutically. Clearly. urgent reversal of   coumadin effect for active bleeding or invasive proce  dure. Japan. It is important to begin FFP infusion quickly.23 However. nor is the optimal dose clear. because they replace specifically those factors that are decreased by coumadin. Fresh-frozen plasma is associated with complications such as transfusion-related acute lung injury. optimal coumadin reversal with FFP requires a high level of monitoring to ensure that the desired amount of plasma is administered as rapidly as the patient can tolerate. but requires many hours to take effect. A phase IIb randomized clinical study showed that rFVIIa reduced hematoma expansion in patients without coagulopathy in whom hemorrhagic stroke was diagnosed within 3 hours of the onset of symptoms. PCCs have the advantage that they are a concentrated source of coagulation factors. Thus.21 and there is evidence that hemorrhage can continue even after normalization of the INR has been achieved. rFVIIa. Developed as a “bypassing” agent to manage bleeding in hemophiliacs with antibody inhibitors. the guidelines proposed at the Seventh American College of Chest Physicians Conference recommend the consideration of rFVIIa for the acute reversal of warfarin-induced bleeding events. Supraphysiological levels of rFVIIa compensate for a deficiency of other factors by enhancing platelet surface thrombin generation. FFP.7. Theoretically these products would be the ideal therapy for reversing coumadinization. another study reported a more rapid mean correction time of approximately 9 hours.26 It has also been extensively used “off label” to manage bleeding in a wide variety of patients who did not respond to transfusion therapy. one more use of rFVIIa relevant to neurosurgery deserves mention. These are criteria for transfusion without further review. verify correction of the INR. are based on evidence derived from published literature and have been adopted at the Durham Veterans Administration Medical Center. it can take several hours to administer the required dose (5–8 ml/kg has been recommended3). and possibly give additional plasma if correction has not been achieved. correction of the INR by administration of rFVIIa does not necessarily mean that hemostasis has been corrected in the patient. or who cannot tolerate the volume required for full correction with FFP. 57 and without the risk of volume overload. including vitamin K. There is evidence that rFVIIa can reduce intracranial hematoma expansion in patients who are not receiving anticoagulation therapy. and other countries. Unfortunately.34 It is also not clear whether the use of different PCCs results in different levels of risk of thrombosis. It seems likely to us that rFVIIa is best used in patients who are not responding as expected to FFP. alone or as adjunct to FFP PCC urgent reversal of coumadin effect for active bleeding   or invasive procedure. However. were improved in the rFVIIa-treated patients.37 but it is not clear that all PCC products are equivalent in this regard. Europe. vitamin K administration alone is inadequate for urgent reversal. so replacement can be achieved more rapidly than with FFP.30 Although rFVIIa can enhance hemostasis in the setting of anticoagulation treatment.57 The time required for correction of the INR probably depends heavily on the clinical setting. Transfusion of any blood product should ultimately be based on the clinical picture. They are more commonly used for this purpose in Europe than in the US. rFVIIa is not given only to replace a deficient factor. but it only took approximately 9 hours when rFVIIa was added to the regimen. at this time no good test is available to monitor rFVIIa therapy. Optimal therapy has been suggested to combine administration of PCCs with vitamin K.7 Although good clinical trials are lacking. especially factor VII and the antithrombotic factors proteins C and S.39 However. This factor has also been used for coumadin reversal. 15 . The risk of thrombosis has also not been well defined. as measured by death and degree of disability. in combination w/ vitamin K or as   adjunct to FFP *  The following indications for transfusion of various blood components for urgent reversal of coumadin anticoagulation. rFVIIa is approved for that use in the US. definitive therapy.16 In a retrospective chart review study.45 There was a suggestion that outcomes. rFVIIa has the potential to enhance thrombin generation in the presence of heparins as well as vitamin K antagonists. it is difficult to determine precisely the dose of plasma that will be required. Some of these have been approved to manage bleeding in patients with hemophilia A (factor VIII deficiency) with antibody inhibitors. Finally.27 Lower levels of rFVIIa are needed to shorten the INR than are needed for a hemostatic effect. Coagulation factor products collectively called PCCs can rapidly provide many or all of the vitamin K–dependent coagulation factors.57 The possibility of thrombotic complications of PCCs has not been well addressed. Prothrombin complex concentrates have been shown to speed coumadin reversal when given in concert with FFP. and are recommended by guidelines from several national organizations.39 Thus.   used in combination w/ other modality for urgent   reversal FFP urgent reversal of coumadin effect for active bleeding or   invasive procedure rFVIIa severe bleeding in patients who do not respond to FFP/   cryoprecipitate/platelet transfusion. and deserves further study in this population.47 Unlike PCCs. Two retrospective studies reported the mean time to normalization of the INR to be approximately 30 hours after the start of therapy with FFP or FFP plus vitamin K. it artifactually shortens the PT-INR. However. Coagulation factor replacement with FFP is the most commonly used approach in the US. alone or as an adjunct to FFP.Correcting the INR in neurosurgery: a brief review TABLE 1: Products used for reversal of coumadin anticoagulation* Blood Product Indication vitamin K used alone for non-urgent reversal of coumadin effect. and PCCs. not all PCCs have the J Neurosurg / Volume 114 / January 2011 same content of clotting factors.63 or as an adjunct to FFP. reversal was accomplished in a mean time of approximately 32 hours with FFP and vitamin K. 5 In contrast to the administration of PCCs. Therefore.

1997   5. Ann Neurol 42:857–865. and M. requiring analysis of the complete clinical picture. which includes laboratory values as well as the patient’s signs and symptoms. A followup phase III trial confirmed the reduction in hematoma expansion. Hoffman. Disclosure The authors were supported. However. active bleeding & patient has   recently received antiplatelet agent. Critically revising the article: Adamson.5 or   aPTT >50 sec. Hylek E: The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. PVD = peripheral vascular disease. Author contributions to the study and manuscript preparation include the following. does not require attempted correction prior to invasive procedures. urgent   reversal of warfarin effect cryoprecipitate active bleeding & fibrinogen <100 mg/dl. Mayo Clin Proc 82:82–92. coagulopathy after transfusion of   >10 U RBCs. Poller L. MI = myocardial infarction. Anesthesiology 105:198–208. Hct = hematocrit.5. and we could find little convincing evidence that prophylactic FFP transfusion was necessary prior to neurosurgical procedures. there are numerous situations in which the decision to transfuse is not as clear cut. Kase CS. Specifically. we propose that an INR value of < 1. L. Dzik WH: Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities.0/24% if: documented   pulmonary disease. attempts to correct a marginally prolonged PT may not only be futile. previ  ous MI. in the absence of bleeding. We focused primarily on the question of mildly elevated INR values in patients who were otherwise hemodynamically stable. Chest 126 (3 Suppl):204S–233S. Abbreviations: EKG = electrocardiographic. First. Second. Hb = hemoglobin. In these cases in which thoughtful review is required. there is mounting evidence that the harm from FFP transfusion may outweigh its benefit. It seems likely that a subset of patients may benefit from such hemostatic therapy.000/µL.000/µL.  Ansell J. along with optimization of other factors. García RC. it is unclear what role rFVIIa may play in management of intracerebral hemorrhage (not related to concurrent anticoagulation). Hoffman has received research funding from and has served as a consultant to Novo Nordisk. difficulty oxygenating. may be of more general benefit in patients with hemorrhagic stroke. Hirsh J. Dr. TABLE 2: Guidelines for blood component transfusions* Blood Component RBCs Transfusion Indications Conclusions Hb/Hct <7. Hoffman there was also a suggestion that arterial thrombotic events were increased in the rFVIIa-treated groups. unexplained   tachycardia platelets platelets <10.K. Conception and design: Adamson. These guidelines have been adopted at the Durham Veterans Administration Medical Center and may help provide guidance to other institutions as well. C. as we discuss in this paper. In fact. Drafting the article: West. The other authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. minimal prolongation of these values does not necessarily indicate that a clinically significant bleeding risk is present. Healy B. major surgery & platelets   <100.46 or that rFVIIa. are based on evidence derived from published literature and have been adopted at the Durham Veterans Administration Medical Center. There are certain clinical situations in which transfusion or other hemostatic therapy should unquestionably be undertaken. if not even higher. However. Freeman WD. the processes of laboratory testing and transfusion may impose a significant delay on necessary procedures.000/µL FFP active bleeding or invasive procedure & INR >1. 2006   4. Jacobson A. Analysis and interpretation of data: Adamson. and cryoprecipitate.  American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies: Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. including FFP. Transfusion of any blood product should ultimately be based on the clinical picture. but may delay urgently needed interventions. none of these statements are meant to discourage plasma transfusion in a patient with bleeding or coagulopathy when it is clinically indicated. Hb/Hct <8. EKG evidence   of disturbed ventricular function.  Abdel-Wahab OI. 2004 [Erratum in Transfusion 127:415–416. stroke.44 At the present time. active   bleeding in patient w/ uremia. Bussey H. Adamson. by the US Department of Veterans Affairs. there is mounting evidence that the threshold for plasma administration should be at least 1. especially in unstable and actively bleeding patients. Transfusion 46: 1279–1285. Hoffman.  Anonymous: A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. such as transfusion-related acute lung injury and infection. platelets. However. evidence of   tissue ischemia: ST wave changes. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group.  Aguilar MI. Hart RG. The PT and aPTT do give information about coagulation factor levels. Reviewed final version of the manuscript and approved it for submission: all authors. 2005] 16 J Neurosurg / Volume 114 / January 2011 . Hoffman. minor surgery   & platelets <50. Thus. symptomatic PVD. von Willebrand   disease w/ no other available/effective therapy *  The following indications for transfusion of various blood components.0/21%. but not the improved outcomes. we have developed a set of guidelines for blood component transfusion that are based on published literature as well as institutional experiences (Table 2). West. in part. antithrombin deficiency.5. 2006   2. References   1. These are criteria for transfusion without further review. RBCs. Furthermore. there are risks associated with blood component transfusion. 2007   3. Hoeben BJ. et al: Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. This harm is 2-fold.

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