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Keywords:

  • anticoagulation reversal;
  • bleeding;
  • prothrombin complex concentrate;
  • warfarin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References

Summary. Background: When life-threatening bleeding occurs in patients on warfarin, timely reversal becomes imperative. In the USA, warfarin effect is commonly reversed with fresh frozen plasma (FFP). The use of FFP is complicated by delays in correction, volume overload and often, inadequate correction. Objective: Evaluate the feasibility and efficacy of a protocol for rapid administration of prothrombin complex concentrate (PCC) in the setting of the urgent need for reversal of warfarin. Methods/patients: We instituted a policy for rapid delivery and administration of PCC. Appropriate patients received 25–50 U kg−1 of PCC. The prothrombin time (PT)/International Normalized Ratios (INR) was recorded before and immediately after dosing, and 24 h postdosing. Patients requiring surgical interventions were cleared for the operating room (OR) immediately. Fifty-eight patients were treated, with a median age of 75.5 years (range 26–92). Results: The median INR on presentation was 3.8 (1.4–52.8). Immediately following PCC administration the median INR was 1.3 (0.9–5.7), only two patients with INRs exceeding 2.0. The benefit was maintained at 24 h with a median INR of 1.5 (1.1–3.4). Four patients experienced thrombotic events during their hospitalization, (two deep vein thrombosis, two non-q-wave myocardial infarction) although none was attributed to PPC therapy. Conclusions: PCC administration is an effective treatment modality for the correction of warfarin anticoagulation in the urgent setting. Advantages over FFP include more timely correction, absence of volume overload and potentially more complete correction. Broader use of PCC in this setting appears to be appropriate.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References

Despite the recent development of alternative anticoagulants, warfarin remains the primary agent used in long-term antithrombotic treatment and prophylaxis. Warfarin exerts its anticoagulant effect by blocking terminal γ-carboxylation of glutamic acid residues of the vitamin K dependent coagulation proteins during hepatic synthesis, lowering both their synthesis and functional levels. Trials in a variety of clinical settings have demonstrated that treatment with warfarin is associated with significant risk of hemorrhage, with a fatal or life-threatening bleeding risk as high as 1–3% per year, and bleeding risk of any severity as high as 15–20% in high-risk patients [1–3].

Patients taking warfarin who are bleeding, excessively anticoagulated or both require reversal of the warfarin effect. When the need for correction is urgent, immediate replacement of functional coagulation factors is indicated. In the USA this is commonly accomplished using fresh frozen plasma (FFP). The time to thaw, prepare and administer plasma can result in clinically significant delays. In patients with exceedingly high International Normalized Ratios (INR), FFP is often ineffective [4]. In addition, volume overload is a frequent complication of rapid transfusion of large volumes of FFP [5].

Prothrombin complex concentrate (PCC) is human plasma derived and undergoes viral inactivation steps similar to other factor concentrates. PCCs contain vitamin K-dependent coagulation factors (F) II, VII, IX, and X [6], the factors deficient in warfarin therapy, thus may be effective for urgent reversal of warfarin. Previous reports have supported efficacy in similar settings [4,7,8]. Our treatment protocol was undertaken in patients on warfarin with life- or limb-threatening hemorrhage, or the need for urgent surgery, to improve care and assess the efficacy of PCC therapy.

Protocol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References

Patients presenting to the emergency department or evaluated on the inpatient service at Christiana Care hospitals (CCMS) with bleeding associated with warfarin use were evaluated for PCC use. The criteria for use of the treatment protocol were: patient taking warfarin, INR >2.0 and active bleeding or the need for immediate surgical intervention. Hematology consultation, typically by telephone, was mandated prior to release of PCC. Patients received 25–50 IU kg−1 [factor (F)IX] of Proplex-T (Baxter, Deerfield, IL, USA). Proplex-T was selected for our protocol because of its significant FVII content compared with other available products. Proplex-T contains 50 units of FII, 400 units of FVII and 50 units of FX per 100 units of FIX [6]. Within our recommended range, dosing was based on baseline INR and severity of bleeding. Patients were evaluated with a disseminated intravascular coagulation (DIC) screen (prothrombin time/INR, partial thromboplastin time, thrombin time, fibrinogen level, Plasma Protamine Paracoagulation Test for fibrin degradation products) before and a prothrombin time/INR immediately after PCC (< 1 h), and then at least daily. Evaluation for thrombotic complications was carried out based on clinical suspicion. All patients received oral or parenteral vitamin K. Fifty percent of patients received FFP in addition to the PCC. FFP was used at the discretion of the primary care team, but was not part of the formal treatment protocol. When indicated, surgical intervention was performed immediately after administration of PCC.

We evaluated 58 patients treated with PCC for reversal of warfarin in 2002 and 2003. Charts were reviewed for patient age, medical diagnoses including indication for warfarin, bleeding site, specific intervention and any recorded adverse events related to PCC. Thrombotic events at any time during the hospital stay were considered potentially significant. Pre- and posttreatment PT/INR were noted, including next day data points closest to 24 h after initial treatment. The use of vitamin K and/or FFP was noted, as well as mortality and, when applicable, antithrombotic therapy at discharge.

Patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References

Patients ranged in age from 26 to 92 years (median 75.5). The most common indication identified for warfarin therapy was atrial fibrillation, cited in 38 patients (66%) (Table 1). Concomitant bleeding risks were identified in 15 patients (26%). These included renal dysfunction (defined as serum creatinine > 2.0) (four patients), platelet count < 100 000 (four), the use of aspirin and/or clopidogrel (three), chronic liver disease (three) and hypofibrinogenemia (one).

Table 1.  Indications for warfarin use and number of patients
Atrial fibrillation38
Venous thrombosis 5
Prosthetic heart valve 4
Pacemaker or automatic implautable cardioverter-defibrillator 3
Severe cardiomyopathy 1
A-V fistula clot 1
Indication not determined form chart 6

Thirty-six cases (62%) involved central nervous system hemorrhage. Of these 22 patients presented with intracerebral hemorrhage (ICH), 12 with subdural hemorrhage (SDH) and two with subarrachnoid hemorrhage (SAH). Eleven patients presented with gastrointestinal bleeding. Of note, this group had a disproportionate number of patients with markedly elevated INRs (median INR 29.0 for GI bleed patients, 3.8 all patients). Two patients with recent cardiac surgery presented with tamponade. Two patients required reversal for emergency exploratory laparotomies for abdominal pain. One patient each presented with severe epistaxis, chest pain associated with aortic dissection, hemothorax after recent lung biopsy and massive chest wall hematoma. Four patients wee treated outside of the protocol guidelines: two patients on warfarin with head trauma were treated prior to imaging, and subsequently found to have negative computed tomography scans and no other sites of bleeding. PCC therapy was employed in a manner similar to typical clinical management for hemophilic patients with head trauma. Two patients were treated before the INR was available, and had pretreatment levels < 2.0.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References

Pretreatment INRs (Table 2) ranged from 1.4 to 52.8 (mean 11.7/median 3.8). Immediately following PCC administration, INRs ranged from 0.9 to 5.7 (mean 1.4/median 1.3), however only two patients had INRs of 2.0 or greater. Twenty-four hours posttreatment, the INR range was 1.1–3.4 (mean 1.5/median1.5) with two patients with INRs of 2 or greater. Eight patients did not have a data point at 24 h because of change in care status (comfort care only or demise). Twenty-nine patients did not receive FFP as part of their reversal (50%). The median pretreatment, posttreatment and 24 h posttreatment INRs were similar to the overall group at 3.3, 1.2 and 1.4, respectively. Sixteen patients underwent surgical interventions or invasive procedures: eight patients underwent craniotomy for evacuation of hemorrhage. Three patients had laparotomies, two patients underwent placement of ventriculostomy drains, two had pericardial drainage procedures, and one had thoracotomy for evacuation of hematoma. No dictated or hand-written operative notes contained comments regarding excessive blood loss or inadequate hemostasis. One patient underwent a second craniotomy for re-accumulation of blood on postoperative day three from the first procedure. The patient's INR was normal at that time. The corrections with PCC are similar for the spectrum of presenting diagnoses (Table 3).

Table 2.  Mean/median INR before and after PCC administration
 INR pre-PCCINR post-PCCINR 24 h post
MeanMedianMeanMedianMeanMedian
  1. INR, International Normalized Ratio; PCC, prothrombin complex concentrate; FFP, fresh frozen plasma.

All patients (n = 58)11.73.81.41.31.51.5
No FFP use (n = 29)12.33.31.21.21.31.4
FFP given (n = 29)11.14.01.61.51.61.6
Table 3.  Summary: results by diagnosis at presentation
PresentationNo.Median agePre-RxMedian INR post-Rx 24 h postSurgery/ procedure no.Deaths no.Thrombosis/ complications
  1. ICH, intracerebral hemorrhage; SDH, subdural hemorrhage; SAH, subarachnoid hemorrhage; GI, gastrointestinal; INR, International Normalized Ratio; DVT, deep vein thrombosis; MR, myocardial infarction; OR, operating room.

ICH22763.51.31.439 
SDH13802.71.21.4731-DVT (line)
SAH257.52.01.31.601-MI
GI bleed117529.01.51.6131-MI, 1-DVT
Tamponade (post-OR)235.513.73.71.62 
Emergency laporotomy27541.01.31.62 
Head trauma (no bleed)27925.31.11.40 
Hemothroax (postbiopsy)1565.91.711 
Chest wall hematoma1825.61.31.30 
Epistaxis14720.11.91.60 
Aortic dissection1792.41.81.60 

Sixteen of 58 patients (28%) died during their hospitalization, while an additional five were discharged to hospice or other comfort care settings with demise anticipated. Thirty-six patients were discharged to home or rehabilitation settings (62%), and one was transferred to another institution for an interventional procedure not available at CCHS. Of note, of the 36 patients discharged, coumadin was resumed in only 10. In the remaining 26, coumadin was judged to be either unnecessary or associated with excessive risk of re-bleeding. Of the subset of 22 patients presenting with ICH, 10 died or were discharged to a hospice or comfort care setting (45%).

Possible complications of PCC treatment were observed in four patients. One patient developed a line-associated left upper extremity deep venous thrombosis (DVT). This diagnosis was made 17 days after PCC therapy. A second patient was evaluated for possible recurrence of a right lower extremity DVT. This patient had had previous thrombosis in this region, and on Doppler examination was interpreted as revealing chronic thrombosis with a possible acute component.

Two patients had apparent non-Q myocardial infarctions (NQMI) associated with their hospitalization. Both patients were diabetic with known coronary artery disease. The first patient was a 55-year-old man who presented with syncope, hypotension and melena. On presentation, his hemoglobin was 8.6 and his INR was 6.2. The patient received PCC therapy as part of his initial therapy. Cardiac enzymes performed as part of his syncope evaluation revealed a small transient rise in troponin to a peak of 1.1 and creatine kinase (CK) to 141 with an myocardial band (MB) fraction of 4.4. The patient recovered well and was discharged in stable condition. The second patient was a 61-year-old female who presented with SAH because of an aneurysmal bleed. She was transferred from an outside community hospital, on ventilator support and with a decreased level of consciousness. She received PCC for her INR of 2.0 with presumed active bleeding. During her brief stay at CCHS, monitoring of cardiac enzymes revealed a transient rise in CK to a peak of 220 with an MB fraction of 4.66, felt to be consistent with a small NQMI. She was subsequently transferred to another facility and follow-up was not available.

No patient had a diagnosis of fluid overload associated with the reversal process.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References

Warfarin anticoagulation management presents myriad clinical challenges. These include careful risk assessment, adequate monitoring and dose adjustment, and management of bleeding events. A spectrum of clinical trials places the risk of bleeding complications of severe and life-threatening bleeding at 1–3% per year in high-risk groups. Minor bleeds in stable patients are often safely managed by withholding or reducing warfarin dose, or by administration of vitamin K. Correction of the hemostatic mechanism is not immediate with the use of these interventions, and more significant bleeds require replacement of deficient coagulation FII, FVII, FIX and FX in an urgent manner. Infusion of FFP is the most commonly employed intervention for factor replacement. Reversal using FFP has several limitations: FFP contains isohemagglutinins, requiring a pretransfusion evaluation for ABO blood group in most patients. Thawing, issuing and transporting FFP may take 30–60 min, depending on institutional protocol. Required volumes often exceed 1000 mL, requiring significant infusion time, and additional problems in patients with volume constraints because of impaired renal or cardiac function. In addition, FFP is frequently inadequate in fully reversing markedly elevated INRs [9]. We focused on patients in whom evidence suggested delay of reversal had potential significant negative consequences. As PCC can be reconstituted in a small volume, administered in a matter of minutes and does not require ABO typing, it represents an attractive option for reversal of warfarin effect.

The major laboratory endpoint followed was correction of the INR following administration of PCC. All but patients two corrected to < 2.0, and 44 (76%) corrected to INRs of 1.5 or less on the immediate posttreatment point (< 1 h). The effect was maintained at 24 h. Results appeared similar in patients who did not also receive plasma during their care, although the posttreatment and 24 h INRs were slightly higher in the FFP group. This observation is not easily explained, however the authors suspect that FFP was often given in response to a post-PCC INR that was clinically viewed as marginally elevated. We believe the overall observations suggest that the acute INR correction with PCC, coupled with the subsequent impact of administered vitamin K eliminates the need for FFP. This is reflected in our current treatment protocol, which actively excludes FFP.

Clinical observations also supported efficacy. In the group undergoing surgery or procedures, no recorded comments reflected hemostasis issues, and reported estimated blood losses were felt to be appropriate for the clinical setting.

Concerns regarding adverse events associated with the use of this product have been an impediment to its broader use. We observed four possible thrombotic events. In each case, following careful evaluation of the medical history and clinical presentation these events were felt to be most likely attributable to predisposing underlying medical issues and not directly to PCC therapy, although clearly potential PCC effect cannot be excluded with certainty. Myocardial infarction and other thrombotic events have been reported as a possible adverse event related to PCC use in other clinical settings [10]. Although concerns about thrombotic potential are reasonable, important differences in clinical settings should be acknowledged: first, hemophilia inhibitor patients were commonly challenged with intense, multi-dose treatment regimens, compared with a single replacement dose used for warfarin correction. Conversely, patients on warfarin are likely to have a significantly higher thrombotic risk associated with their underlying medical condition. Both factors complicate attribution of thrombotic events to PCC in our patients.

Recombinant FVIIa (rFVIIa) has also been reported as an effective hemostatic agent in the setting of bleeding with warfarin effect [11]. rFVIIa has several attractive properties in this setting. It is a recombinant product with no risk of viral transmission, corrects FVII deficiency, and has significant ‘bypassing’ activity. PCC also corrects FVII deficiency, but in addition corrects all of the warfarin-induced coagulation factor deficiencies, resulting in a true physiologic correction to normal. Recent reports of rFVIIa limiting bleed volume in patients with hemorrhagic stroke and normal clotting mechanisms suggest that rFVIIa may have hemostatic benefit beyond return to normal physiology [12], although that has not been clearly demonstrated in other clinical settings, and has not been confirmed in a phase three trial. Finally, assuming a PCC dose of 50 U kg−1, PCC may be less costly than rVIIa.

Serious bleeding events secondary to warfarin use remain a significant issue. Monitoring of patients on warfarin therapy often occurs in diverse settings, including warfarin clinics, private physician's offices and patient self-monitoring. Laboratory support for warfarin monitoring is similarly variable including office and home based systems as well as use of commercial laboratories with results conveyed to physician's offices. In contrast to the rigorously controlled monitoring dictated by most clinical trials, our experience likely represents the ‘real world’ of warfarin complications in a typical community practice setting. Given these realities, optimal care of patients with these complications is likely to remain a critical issue.

In summary, our experience over 2 years supports previous reports that PCC offers an effective option for reversal of warfarin effect in the urgent setting. Organized order and delivery protocols can be used to facilitate reversal of warfarin related coagulation defects within minutes, and eliminate the need for plasma and its potential for delays and complications. PCC is used widely in the European community, and has previously been cited as the agent of choice for urgent warfarin reversal by The British Committee for standards in Haematology, Transfusion Task Force [13] and The American College of Chest Physicians [14]. In accordance with these recommendations, wider availability and use of PCC in the USA in this setting may be appropriate.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Protocol
  5. Patients
  6. Results
  7. Discussion
  8. References
  • 1
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    Lusher JM, Thrombogenicity associated with factor IX complex concentrates. Semin Hematol 1991; 28: 35.
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    Ansel J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The Pharmacology and management of vitamin K antagonists. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 204S33S.