Use and effectiveness of prothrombin complex concentrate in an emergency department: a review of 15 cases

Abstract

Aim

Hemostatic management of patients on oral anticoagulant therapy with critical bleeding continues to be a major challenge. The present study aimed to validate the efficacy, safety, and optimal dosage of prothrombin complex concentrate for rapidly normalizing elevated international normalized ratio (INR) values and achieving control of hemorrhage at an emergency department in Japan.

Methods

We retrospectively collected data from all patients who were treated with PCC at our emergency department between January 2013 and September 2014. We used a commercially available prothrombin complex concentrate.

Results

Fifteen patients (male / female, 7/8; average, 71.4 years) received prothrombin complex concentrate (14 for bleeding, including trauma‐related bleeding, and one for invasive intervention) without complications. All but one patient received warfarin and the INR value declined in all patients with 500 IU (average, 8.98 IU/kg) prothrombin complex concentrate (average INR value before and after treatment: 2.20 versus 1.26). Although two patients died because of multiple organ failure, a relatively satisfactory hemostatic response was obtained in at least 11/15 patients. However, patients with a baseline INR value above 2.5 never achieved an optimal response (INR value < 1.35).

Conclusion

A single dose of 500 IU prothrombin complex concentrate is insufficient for normalization of INR value, especially in patients with prolonged INR values. Administration strategies for trauma, the ideal dose (e.g., higher than 500 IU/patient), target optimal INR values, as well as the confirmation of safety should be addressed in the future. Further clinical trials are warranted to confirm this preliminary report.

Introduction

Long‐term coumarin oral anticoagulant therapy (OAT) is widely prescribed for prevention of thromboembolism. Warfarin has a narrow therapeutic window and can cause a variety of frequent hemorrhages. The annual incidence of major bleeding ranges from 1.1% to 1.5%, which can be potentially life‐threatening.1, 2, 3 Because this risk of hemorrhage increases in parallel with an increase in international normalized ratio (INR) level, rapid reversal of OAT is crucial in case of acute major bleeding or emergency invasive intervention with elevated INR values.4

Warfarin inhibits the biosynthesis of factors II, VII, IX, and X, which are vitamin K‐dependent procoagulant factors. Because restoration of hemostasis with vitamin K relies on hepatic synthesis of vitamin K‐dependent procoagulant proteins, a process that takes over 6 h, fresh frozen plasma (FFP) is commonly used for quick, but partial correction of coagulopathy. However, FFP has isohemagglutinins, and blood group‐specific FFP should be provided to patients. Therefore, time is required to prepare FFP, which may result in delayed treatment. Moreover, FFP generates a risk of infection, and large quantities of FFP are necessary for patients with a high INR level.5 In recent clinical guidelines, including in Japan, either prothrombin complex concentrate (PCC) or FFP has been recommended for rapid reversal of OAT.6, 7, 8, 9, 10, 11, 12, 13 Prothrombin complex concentrate reverses the INR value faster than FFP or vitamin K.14 Despite the fact that it has been known for many years that PCC reverses the effect of warfarin, few studies have established the efficiency of PCC in the emergency setting in Japan.15 Moreover, the data collected in Europe and the USA is not necessarily the same as Japan because the Japanese population has a relatively small frame and light body weight compared to patients in Europe and North America.

The present study aimed to validate the efficacy and safety of PCC administration for rapidly normalizing elevated INR values and achieving control of hemorrhage at an emergency department (ED) in Japan.

Materials and Methods

Selection of patients

This was a retrospective, single‐center study of consecutive patients with OAT and/or with prolonged INR values who were admitted to our ED and required acute reversal of elevated INR values from April 2012 to October 2014. Patients were eligible for study entry if they required INR value normalization as a result of acute bleeding, or an emergency surgical or urgent invasive diagnostic intervention. This study was carried out in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines, the 1996 Declaration of Helsinki. The study protocol, including the administration of PCC as off‐label, was approved by the ethics committees of our institution. In principle, informed consent was obtained from the patients or their family before PCC was administered.

Treatment and laboratory tests

We used a commercially available four‐factor PCC (PPSB‐HT Nichiyaku; Nihon Pharmaceutical, Tokyo, Japan), which contains 500 IU of factors II, VII, IX, and X, as well as 380 U protein C, in each 25 mL. For each patient, the decision to treat with PCC with vitamin K and/or FFP, as well as the decision regarding how much to administer, was made by the attending physician. The INR values and blood samples of all patients were examined on admission, and INR values after PCC treatment, were followed up within 120 min if possible. We used the Wilcoxon singed‐rank test for analysis using statistica software (StatSoft, Tulsa, OK, USA). P‐values less than 0.05 were considered significant.

End‐points and assessments

The primary study end‐point was normalization of INR values (<1.35) at least 120 min after the end of the PCC infusion. The secondary end‐points were clinical hemostatic efficacy and the safety of PCC. According to a previous report,6 attending physician rating categories for clinical hemostatic efficacy were as follows: (1) very good (prompt cessation of existing bleeding and/or a rapid decline in INR); (2) satisfactory (>1–2 h delay in bleeding cessation and a decrease in INR); (3) questionable (>2 h delay in cessation of bleeding and a decrease in INR or the efficacy of PCC could not be determined); (4) none (an absence of effect on bleeding and INR). The corresponding definitions among patients undergoing invasive interventional procedures were as follows: (1) very good (normal hemostasis during the procedure); (2) satisfactory (mildly abnormal intraprocedural hemostasis as judged by the quantity or quality of blood loss); (3) questionable (moderate abnormality); (4) none (severe hemostatic abnormality). The safety of PCC was evaluated by acute thromboembolic events and viral infection. Viral exposure (antibodies to HIV‐1 and ‐2, hepatitis B virus surface antigen, and antibodies to hepatitis C virus) was evaluated at baseline and approximately 60 days after infusion.

Results

Clinical characteristics

The baseline clinical characteristics of the patients are shown in Table 1. A total of 15 patients were selected and all were Japanese. The male : female ratio was 7:8 and the average patient age was 71.4 years (range, 41–84 years; median, 71 years). The average body weight was 58.0 kg (range, 38.2–80.0 kg; median, 57.0 kg) A total of 80.0% of patients' body weight ranged from 50–69 kg. Among the 14 patients who required OAT, 13 (92.9%) received warfarin and one (7.1%) received apixaban. The baseline average INR value was 2.20 (range, 1.04–4.14; median, 1.95). The patient with a normal INR value of 1.04 received apixaban. Four patients also received concomitant antiplatelet agents.

Table 1.

Baseline characteristics of patients treated with prothrombin complex concentrate at an emergency department in Japan, January 2013–September 2014 (n = 15)

Characteristic		Characteristic
Sex, n (%)		INR value, median	2.2 (1.95)
Male	7 (47)	INR value, n (%)
Female	8 (53)	<2	8 (53)
Age, years (median, years)	71.4 (71)	2–3	4 (27)
Age, years, n (%)		3–4	2 (13)
<60	1 (7)	≥4	1 (7)
60–69	4 (27)	Indication for OAT, n (%)
70–79	7 (47)	Atrial fibrillation	11 (79)
≥80	3 (20)	Heart valve replacement	2 (14)
Body weight (kg), median (kg)	58 (57)	Deep venous thrombosis	1 (7)
Body weight (kg), n (%)		Medication for OAT, n (%)
<50	2 (13)	Warfarin	13 (93)
50–59	7 (47)	Apixaban (Eliquis)	1 (7)
60–69	5 (33)
≥70	1 (7)

Total number of patients who received oral anticoagulant therapy (OAT) was 14. Four patients also received concomitant antiplatelet agents.

Indications for PCC treatment

The details of indications for PCC administration are shown in Table 2. All but one (93.3%) of the patients were given PCC for acute bleeding. Interestingly, there were many indications for trauma (seven [46.7%] patients) compared with endogenous bleeding (four [26.7%] patients). Additionally, PCC was given for iatrogenic injury (three [20%] patients). There was only one (6.7%) patient who received PCC for an urgent operation because of obstructive ileus.

Table 2.

Indications for prothrombin complex concentrate in patients treated at an emergency department in Japan, January 2013–September 2014 (n = 15)

Indication	n (%)
Bleeding	14 (93)
Trauma	7 (47)
Intracranial hemorrhage †	4 (27)
Soft tissue hemorrhage	1 (7)
Bleeding from multiple sites ‡	2 (13)
Endogenous	4 (27)
Intracranial hemorrhage	1 (7)
Aortic rupture	2 (13)
Pulmonary hemorrhage	1 (7)
Iatrogenic	3 (20)
Cardiac tamponade	2 (13)
Retroperitoneal bleeding	1 (7)
Interventional procedure	1 (7)
Abdominal surgery §	1 (7)

†One patient had acute epidural hemorrhage, two had acute subdural hemorrhage, and one had chronic subdural hemorrhage. ‡One patient had traumatic subdural and subarachnoid hemorrhage accompanied by brain contusion, traumatic hemothorax, intra‐abdominal bleeding due to mesenteric injury, and hemorrhagic shock, and one had traumatic subarachnoid hemorrhage, soft tissue hemorrhage, and hemothorax. §Obstructive ileus.

Clinical course and outcomes

A summary of the course and outcomes is shown in Table 3. A single dose of PCC (500 IU) was administered to all of the patients. The average dose per kilogram of body weight was 8.98 IU (range, 6.3–13.1 IU; median, 8.77 IU). Ten of 15 (66.7%) patients received concomitant agents other than PCC (i.v. vitamin K in nine [60.0%] patients; FFP in three [20.0%] patients; platelet concentrate in two [20.0%] patients; and cryoprecipitate in one [6.7%] patient). Overall, the INR value declined from 2.20 to 1.26 after PCC was given. However, the timing of follow‐up blood sampling varied from 20 min to approximately 24 h. Clinical hemostatic efficacy was very good in five (33.3%) patients, satisfactory in six (40.0%) patients, questionable in three (12.0%) patients, and none in only one (6.7%) patient. Approximately 75% of the patients who received PCC achieved relatively good (very good and satisfactory) hemostatic efficacy. Three patients' efficacy was judged as questionable, because they received emergency operations for hemostasis during PCC administration. In‐hospital mortality was 13.3% (two patients; both of them died because of multiple organ failure) and the average stay in the intensive care unit was 14.3 days. None of the patients had viral transmission or acute thromboembolic complications.

Table 3.

Summary of 15 patients who received prothrombin complex concentrate (PCC) infusion for rapidly normalizing elevated international normalized ratio (INR) values and achieving control of hemorrhage (n = 15)

Case	Age (sex)	OAT	Indication	Dose of PCC	BW	IU/kg	Concurrent medication	Pre‐INR	Post‐INR	Elapsed time	INR next day	Hemostatic efficacy	Treatment	Throm‐bosis	Outcome	ICU stay (days)
1	71 (M)	WF	AEDH	500	52	9.6	VK	2.01	1.45	90 min	1.21	Very good	Conservative	–	Survived	1
2	76 (M)	WF	ASDH	500	64	7.8	–	1.71	1.14	100 min	1.08	Very good	Conservative	–	Survived	12
3	72 (F)	WF	ASDH	500	40	12.5	VK, FFP	4.14	1.59	35 min	1.28	Questionable	Operation	–	Survived	6
4	67 (M)	WF	CSDH	500	80	6.3	VK	1.46	1.17	24 h	1.17	Satisfactory	Operation	–	Survived	8
5	67 (F)	WF	Soft tissue hemorrhage	500	52	9.6	–	3.29	1.4	120 min	2.04	Very good	Conservative	–	Survived	4
6	67 (F)	WF	Multiple hemorrhages	500	60	8.3	VK, PC	1.63	1.04	120 min	1.05	Satisfactory	IVR	–	Survived	4
7	69 (M)	–	Multiple hemorrhages	500	65	7.7	VK, FFP, PC, Cryo	1.94	0.75	5.5 h	1.06	None	Operation	–	Died	6
8	75 (M)	WF	ICH	500	57	8.8	VK	2.11	1.23	30 min	0.98	Very good	Conservative	–	Survived	4
9	80 (F)	WF	Aortic rupture	500	52	9.6	VK	1.52	1.15	15 h	2.05	Questionable	Operation	–	Survived	60
10	84 (M)	WF	Aortic rupture	500	58	8.6	VK	1.95	1.21	10 h	1.21	Questionable	Operation	–	Survived	29
11	71 (F)	WF	Pulmonary hemorrhage	500	57	8.8	VK	1.88	1.11	7 h	1.28	Satisfactory	Conservative	–	Died	43
12	77 (F)	WF	Cardiac tamponade	500	66	7.6	FFP	2.37	1.41	35 min	1.41	Satisfactory	Drainage	–	Survived	15
13	70 (M)	EL	Cardiac tamponade	500	66	7.6	–	1.04	0.99	12 h	1.04	Satisfactory	Drainage	–	Survived	14
14	84 (F)	WF	Retroperitoneal bleeding	500	38	13.1	–	3.1	1.55	120 min	1.23	Satisfactory	IVR	–	Survived	2
15	41 (F)	WF	Abdominal surgery	500	57	8.8	–	2.84	1.71	20 min	1.11	Very good	Operation	–	Survived	7

–, none; AEDH, acute epidural hemorrhage; ASDH, acute subdural hemorrhage; BW, body weight; Cryo, cryoprecipitate; CSDH, chronic subdural hemorrhage; EL, Eliquis (apixaban); F, female; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; ICU, intensive care unit; IVR, interventional radiology; M, male; OAT, oral anticoagulation therapy; PC, platelet concentration; VK, vitamin K; WF, warfarin.

Changes in INR values

Changes in INR values at baseline and post‐PCC infusion in individual patients are shown in Figure 1. The INR value significantly declined after PCC infusion (P = 0.0003), except for the patients who received apixaban, but these values varied with the timing of follow‐up blood sampling. Therefore, to simply focus on the efficacy of PCC, we next extracted the patients who had follow‐up INR value testing within 120 min (Fig. 2). In this subgroup (n = 9), the follow‐up INR value was taken at 73 min and it also significantly declined by an average of 2.58 to 1.39 (P = 0.0039). However, only three (33.3%) patients achieved an INR value below 1.35. Additionally, patients with a baseline of INR value above 2.50 never achieved such an optimal response (INR value < 1.35).

Figure 1.

Changes in international normalized ratio (INR) values at baseline and post‐prothrombin complex concentrate infusion in individuals (closed circles). The INR value declined after prothrombin complex concentrate infusion from an average of 2.20 to 1.26 (open circles). The INR value did not change in patients who received apixaban.

Figure 2.

Changes in international normalized ratio (INR) values in individuals who had follow‐up INR value testing within 120 min of prothrombin complex concentrate infusion. The INR values declined from an average of 2.58 to 1.39, but only three patients achieved INR values below 1.35. No patients with a prolonged INR value (>2.5) at baseline achieved such an optimal response.

Discussion

This retrospective study showed the effective potential of PCC for trauma and iatrogenic injury, however, contrary to the clinical efficacy, 500 IU PCC is insufficient for normalization of INR values, especially in patients with prolonged INR values (e.g., >2.5).

Currently, there is little published evidence to support the use of PCC in the management of trauma‐related massive bleeding or iatrogenic injury.16, 17, 18 Our study showed that use of PCC for such an indication yielded a satisfactory level of efficacy in clinical practice. We lost one patient who had hemorrhagic shock and who developed dilutional coagulopathy concomitant with hypofibrinogenemia. In the trauma population, this may be detrimental because volume deficits are frequently present and patients typically present with a hyperfibrinolytic state and hypofibrinogenemia.18 Unlike FFP, PCC does not contain fibrinogen, therefore, restoration of fibrinogen is required before PCC administration. Taking these facts into consideration, especially in cases without excessive blood loss (e.g., intracranial hemorrhage, cardiac tamponade, and soft tissue injury) PCC may be a good indication. Prothrombin complex concentrate may play a role in reducing blood transfusion volume if it is given during the FFP preparation time, before hypofibrinogenemia emerges.

Although the balance between therapeutic efficacy and safety are critical components in evaluating the use of PCC, consideration of cost cannot be overlooked.19 Vitamin K is inexpensive and should be chosen in less urgent situations. However, the price of 500 IU PCC is slightly lower than that of 4 IU FFP in Japan. Some reports have shown improvement in neurological status in patients who received PCC compared with FFP.15 Prothrombin complex concentrate may reduce the overall healthcare cost and shorten the intensive care stay.

In this study, we experienced no complications related to PCC use. Two major complications of PCC administration are viral transmission and thromboembolic complications.6 Because PCC is generated from blood, it carries a potential risk for viral transmission; however, such a risk is estimated to be low compared with FFP because PCC is prepared using viral inactivation methods.6 Prothrombin complex concentrate use is associated with the emergence of serious thromboembolic events, especially at a high dose.6 According to the results of a recent search of published reports, thromboembolic events occur in up to 1.8% of patients receiving four‐factor PCC.17 Further validation is required with a larger number of cases, because the number of patients included in this study is too small to adequately evaluate the safety of PCC. Currently, PCC for acute reversal of OAT and restoration of INR values is off‐label in Japan, and is associated with a small, but clinically relevant, risk for thrombogenicity. Therefore, careful consideration should be applied to determine PCC use.

The most effective dosing regimen for PCC in critically bleeding patients is still uncertain. Because the recommended dose of PCC is 25–50 IU/kg, which was originally developed for the treatment of hemophilia, many previous reports have used that dosing regimen.5, 6, 17 These doses may be excessive in patients with OAT and increase the risk for thrombogenicity. Yasaka et al. reported that 500 IU PCC is likely to be the optimal dose for emergent reversal of INR in patients requiring rapid correction of INR below 5.0, but inadequate in patients with INR of 5.0 or more;20 however, there are conflicting results related to PCC dosing. Therefore, we cannot conclude whether tailored doses should be based on the patients' weight, baseline INR value, or goal INR value, or whether a fixed single dose should be used. According to our results, the efficacy for normalization of INR value with a fixed dose of 500 IU PCC could not be confirmed. Because the response of PCC is related to the patient's weight and presenting INR, a higher dose (>500 IU/patient) should be considered in patients with a heavy body weight (e.g., over 80 kg) and/or an INR value over 2.5, even in Japanese patients. Further studies with higher doses of PCC comparable to the current study are warranted. Moreover, the INR value may not be the best surrogate marker for reversal of anticoagulation at present, because patients in our study who did not achieve optimal INR values also had relatively good clinical hemostatic efficacy. We should validate these results by not only the laboratory values, but also using thromboelastogram in the future studies.

There are several limitations to this study. First, it was carried out retrospectively in a single institution with a small number of patients and cannot be generalized. Second, treatment policy depended on the treatment by physicians, and therefore, had potential for bias. The patients received a variety of combination therapies. Administration criteria for PCC, vitamin K, FFP, platelet concentration, and cryoprecipitate were not well defined. Third, the complexity of the disease varied in our study, especially with patients who had trauma‐related bleeding. Finally, regarding safety, the number of patients included this study was too small to confirm this very important issue. Prospective trials involving large numbers of patients who require urgent restoration of INR values are required to overcome these limitations and clarify the remaining unsolved issues.

In conclusion, a single dose of 500 IU PCC is insufficient for normalization of INR value in the Japanese ED. We need administration strategies for trauma, and the ideal dose (e.g., higher than 500 IU/patient), target optimal INR values, as well as confirmation of safety should be addressed in the future.

Conflict of Interest

None.