Purposes: Hypofibrinogenemia is usually complicated with severe and massive upper gastrointestinal (GI) bleeding, especially in liver cirrhosis. In Japan, neither fibrinogen concentrate nor cryoprecipitate (CRYO) is available for cases of acquired hypofibrinogenemia to recover the hemostatic level of fibrinogen rapidly. We prepared and produced in-house CRYO from fresh frozen plasma, and compared mortality between pre-implementation and post-implementation of CRYO. Methods: We performed a retrospective cohort study of patients admitted to our single tertiary medical center with upper GI bleeding from January 2011 to December 2016. The observational control period was from January 2011 to February 2013. From March 2013 to December 2016, we implemented the transfusion of CRYO, which was prepared and produced in our hospital. Clinical outcomes were compared between the patients in the two periods. Patients: Eleven patients in the control period and 10 in the intervention period were eligible for analysis. Results: In-hospital mortality (55% vs. 20%, P = 0.238) and mortality within 24 hour after admission (27% vs. 0%, P = 0.246) tended to be lower in the intervention period than in the control period, although the patients had more severe coagulation on admission than those in the control period. The plasma fibrinogen level before the treatment of hemostasis in the intervention period was higher than that in the control period (80 ± 9 mg/dL vs. 127 ± 15 mg/dL, P < 0.05). Conclusion: Implementation of in-house CRYO transfusion may reduce the rate of mortality due to severe upper GI bleeding.
Fresh frozen plasma (FFP) is commonly used to correct acquired hypofibrinogenemia due to massive hemorrhage as a result of trauma, postpartum hemorrhage, and other conditions, as neither fibrinogen concentrate nor cryoprecipitate (CRYO) is available in Japan. CRYO contains a high concentration of fibrinogen, clotting VIII factor (FVIII), clotting XIII factor (FXIII), von Willebrand factor, fibronectin, and other clotting factors [
On the basis of hypofibrinogenemia in severe upper GI bleeding, which is similar to massive bleeding and associated with increased mortality, we therefore hypothesized that the implementation of CRYO transfusion would contribute to preventing the development of hypofibrinogenemia and to reducing mortality in the patients with severe upper GI bleeding. However, CRYO is neither produced nor supplied by the Japanese Red Cross Society. In-house CRYO is produced in our hospital using a method described by the Japan Society of Transfusion Medicine and Cell Therapy [
This retrospective cohort study was performed at a tertiary medical center located in the eastern part of metropolitan Tokyo, Japan. In our practice, we routinely perform blood tests immediately after patient arrival and throughout the treatment for hemostasis. In our 24-bed intensive care unit, patients were managed by full-time physicians, including surgeons and intensivists.
We reviewed a prospectively maintained database of all transfused patients who were admitted to our institution from January 2011 to December 2016. This study was divided into two periods. During the first period (January 2011 to February 2013), which was an observational control period, CRYO transfusion was not implemented. During the second interventional period (March 2013 to December 2016), we implemented CRYO transfusion that enabled us to transfuse CRYO to patients who were diagnosed as having severe upper GI bleeding (AIMS65 score ≥ 2) to immediately correct acute hypofibrinogenemia. Severe upper GI bleeding with an AIMS65 score ≥ 2 indicated high mortality [
Transfusion of the blood component was performed based on reference guidelines described by the Ministry of Health, Labour, and Welfare in Japan [
We included all patients who were diagnosed as having severe upper GI bleeding (AIMS65 score ≥ 2) in the first period (control group). They were compared with the patients who were diagnosed as having severe upper GI bleeding (AIMS65 score ≥ 2) and received CRYO transfusion in the second period (CRYO group). No patients were excluded during this research period.
The variables under consideration were patients’ medical history, age, sex, underlying diseases causing the upper GI bleeding, systolic blood pressure on admission, shock index on admission, laboratory values obtained on admission, transfused units administered for 24 hours and during hospitalization, and outcome. Risk for upper GI bleeding was evaluated by the Glasgow-Blatchford score and AIMS65 score [
Blood products, such as an RBC solution, FFP, and platelet concentrate (PC) were supplied by the Japan Red Cross Society (Tokyo, Japan). Although the RBC solution (one unit: 140 mL, two units: 280 mL) and FFP (one unit: 120 mL, two units: 240 mL) are produced from donated whole blood, the PC and 480-mL FFP are obtained by apheresis from donors.
Since CRYO is not supplied by the Japan Red Cross Society, CRYO was prepared and produced by staff of our Department of Transfusion Medicine, using a modified method as previously described [
Clotting test results including the activated partial thromboplastin time, % prothrombin time, fibrinogen, and various clotting factors in the expired in-house CRYO packs (N = 6) were measured by Biomedical Laboratories Company (Tokyo, Japan).
Data are expressed as group means ± standard errors of the mean. All statistical calculations were performed using JMP version 8.0 software (SAS Institute, Inc., Cary, NC). We tested for differences in baseline characteristics between patients of the first period (control group) and those of the second period (CRYO group) using the chi-square or Fisher exact test for categorical data and the Wilcoxon test for continuous data. A P-value < 0.05 was considered significant.
This study was approved by the institutional review board of the Tokyo Metropolitan Bokutoh Hospital. Informed consent for blood transfusion including CRYO was obtained from the patients.
As shown in
From January 2011 to December 2016, 21 patients met the inclusion criteria. Eleven patients in the first period (control group) and 10 in the second period (CRYO group) were eligible for analyses. In the second period, we identified 10
Reference value | Cryoprecipitate N = 6 | |
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Clotting test results aPTT (sec) % PT (%) Fibrinogen level (mg/dL) | 26 - 38 80 - 120 170 - 410 | 32.3 (2.2) 72.1 (3.4) 1992 (515) |
Clotting factor activity Factor II (%) Factor V (%) Factor VII (%) Factor VIII (%) von Willebrand factor (%) Factor IX (%) Factor X (%) Factor XI (%) Factor XII (%) Factor XIII antigen (%) | 66 - 118 73 - 122 54 - 162 78 - 165 50 - 150 67 - 152 58 - 200 75 - 137 36 - 152 70 - 140 | 115 (6) 74 (5) 114 (10) 545 (65) 1117 (158) 92 (7) 94 (4) 111 (7) 75 (17) 238 (42) |
Fibrinolysis test results Anti-plasmin activity (%) Plasminogen activity (%) PAI-1 (ng/mL) | 80 - 130 80 - 130 <50 | 109 (3) 161 (14) 36.5 (4) |
Anticoagulant factor activity Anti-thrombin III (%) Protein C (%) Protein S (%) | 80 - 130 70 - 140 63 - 149 | 101 (3) 119 (9) 33 (5) |
Data represent the means with standard errors in parentheses. The reference value represents the value in healthy Japanese subjects, as measured by Biomedical Laboratories Company. aPTT, activated partial thromboplastin time; % PT, % prothrombin time; PAI-1, plasminogen activator inhibitor-1.
patients who were transfused with CRYO. The demographic characteristics and clinical features of these two groups are summarized in
Laboratory findings at admission, details of transfusion, and outcome are summarized in
The number of transfused units administered for 24 hours was not different in terms of RBC, FFP transfusion, and albumin infusion between the two groups.
Cryoprecipitate group N = 10 | Control group N = 11 | |
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Age (years) Sex (M/F) Vital signs at admission Systolic blood pressure (mmHg) Pulse (beats/minute) Shock index Shock index < 0.7 (n, %) Cardiac arrest (n, %) | 66 (6) 7/3 80 (8) 129 (8) 1.6 (0.2) 1, 10% 3, 30% | 61 (6) 11/0 86 (7) 122 (7) 1.4 (0.1) 0, 0% 1, 9% |
Previous diseases Liver disease (n, %) Heart disease (n, %) | 6, 60% 2, 20% | 8, 73% 2, 18% |
Medication Anticoagulant (n, %) Anti-platelet drug (n, %) | 2, 20% 1, 10% | 0, 0% 1, 9% |
Risk stratification Glasgow-Blatchford score AIMS65 score | 14 (1) 3.6 (0.3) | 14 (1) 3.1 (0.3) |
Underlying diseases Esophageal or gastric varix (n, %) Arterial aneurysm (n, %) Gastric ulcer (n, %) Duodenal ulcer (n, %) | 5, 50% 3, 30% 1, 10% 1, 10% | 8, 73% 0, 0% 2, 18% 1, 9% |
Data represent the means with standard errors in parentheses. F, female; M, male.
However, the number of PC units given for 24 hours and during hospitalization was significantly higher in the CRYO group than in the control group. The number of transfused RBC units and FFP administered during hospitalization tended to be higher in the CRYO group than in the control group.
Although it did not reach statistical significance, in-hospital mortality (55% vs. 20%, P = 0.238) and mortality within 24 hours after admission (27% vs. 0%, P = 0.246) tended to be lower in the CRYO group than in the control group.
In this study, we found that the patients who were treated with CRYO transfusion experienced less frequent hypofibrinogenemia development and lower 24-hour, in-hospital mortality, as shown in
Cryoprecipitate group N = 10 | Control group N = 11 | |
---|---|---|
Hematology results Hb level (g/dL) Platelet count ×104/µL Clotting test results % PT (%) aPTT (sec) FDP (µg/mL) D dimer (µg/mL) | 5.6 (0.7) 13 (4) 37 (5) 67 (13) 18 (7) 8 (4) | 6.6 (1.0) 13 (3) 56 (8) 34 (2) 34 (23) 3 (1) |
Fibrinogen level (mg/dL) At admission Before treatment After treatment | 146 (32) 127 (15)* 172 (13) | 156 (32) 80 (9) 189 (40) |
Transfusion volume 24-hour transfusion RBC solution (U) FFP (U) PC (U) PC (n, %) Albumin (bottle) Albumin (n, %) Total transfusion volume RBC solution (U) FFP (U) PC (U) | 18 (3) 13 (3) 15 (2)* 9, 90% 2 (1) 6, 60% 28 (5) 19 (4) 42 (15)* | 17 (3) 11 (3) 6 (3) 4, 36% 2 (1) 6, 55% 20 (3) 13 (4) 8 (3) |
Outcome 24-hour mortality (n, %) Mortality at discharge (n, %) | 0, 0% 2, 20% | 3, 27% 6, 55% |
Data represent the means with standard errors in parentheses. *: P < 0.05 vs. the control group. Hb, hemoglobin; aPTT, activated partial thromboplastin time; % PT, % prothrombin time; FDP, fibrinogen degradation product; RBC, red blood cell; FFP, fresh frozen plasma; PC, platelet concentrate.
control group of the present study, hypofibrinogenemia was significantly complicated with severe and massive upper GI bleeding, as compared with the CRYO group (
As shown in
The reason why the volume of transfusion was higher in the CRYO group than in the control group might be due to the survivor effect. Compared with patients in the control group (55%), those in the CRYO group could receive massive transfusion more frequently with less mortality (20%).
Inappropriate indications for CRYO are warfarin reversal, surgical hemostasis, and hepatic coagulopathy [
We recognize several limitations in this study. First, this study was a retrospective cohort study and was, therefore, prone to the biases associated with this research design. Second, the sample size was small, and statistical power was low. The differences did not reach statistical significance in some analyses. Further research with a larger sample size is warranted.
This study’s results suggest that the implementation of our in-house CRYO transfusion may reduce the rate of 24-hour mortality after trauma and in-hospital mortality in patients with severe upper GI bleeding, with improvement of hypofibrinogenemia.
Hiroshi Fujita, M.D., Ph.D., Shigeko Nishimura, M.D., Ph.D., and Kazuhiro Sugiyama, M.D. thank the staff of the Clinical Laboratory in Tokyo Metropolitan Bokutoh Hospital for their cooperation and efforts with the cryoprecipitate transfusions. The authors did not receive financial or material support for this study.
This research was presented at the 66th annual meeting of the Japan society of Transfusion Medicine and Cell Therapy held in May, 2018.
The authors declare no conflicts of interest regarding the publication of this paper.
Fujita, H., Nishimura, S. and Sugiyama, K. (2019) Evaluation of a Possible Effect of In-House Cryoprecipitate Transfusion on Outcome of Severe Upper Gastrointestinal Bleeding: A Retrospective Cohort Study. Open Journal of Blood Diseases, 9, 20-29. https://doi.org/10.4236/ojbd.2019.91003