Örebro University School of Medicine Bachelor thesis, 15 ECTS May 2018
Is there a need for additional blood products in civilian health
care for the therapeutic treatment of acute hemorrhage?
Version 1
Author: Max Waenerlund Supervisor: Olle Berséus – MD, PhD Senior consultant in transfusion medicine
ABSTRACT: Background
New military experiences of cryopreserved platelets and whole blood for the therapeutic treatment of acute hemorrhage have led to an extensive academic debate on whether to include these blood products into civilian healthcare, where blood components and room temperature platelets serve as a one-size-fits-all product for both prophylactic and therapeutic transfusions.
Purpose
To evaluate the possible benefit of other preparation methods of platelets, as well as whole blood, in civilian health care.
Method
Platelet transfusions of two Swedish counties were analyzed, and divided into three groups depending on which department that made the transfusion. One group for hematology and oncology departments/wards, one group for intensive care units (ICU), emergency departments (ED) and acute care wards (AC), and one group for all other departments/wards that made transfusions during the studied period. Each group was then divided into more specific categories.
Results
Depending on the region, 7%-20% of all platelet transfusions were made in ICUs, 5%-14% were made in surgical wards and 1%-3% were made in ACs and EDs, and may be platelet transfusions made in conjunction with an active bleeding. 44%-72% of all platelet transfusions were made in hematology departments/wards.
Conclusion
According to this limited study, about 38% of all platelet transfusions in a county with a university hospital and 13% in a county without a university hospital, could benefit from transfusion with activated platelets, instead of those platelets that is today’s routine for prophylactic treatment.
ABBREVIATIONS
AC Acute care ward DMSO Dimethylsulfoxide ED Emergency department Hem. Hematology ward ICU Intensive care unit
Inf. Infection ward
Med. Medical ward
Onc. Oncology ward
Ped. Pediatric ward
PT Platelet transfusion RBC Red blood cell
Introduction ... 1
Platelets in traumatic hemorrhage ... 2
Limitations of today’s routine for storing platelets ... 2
Other storage methods ... 3
Whole blood transfusion in traumatic hemorrhage ... 4
Material and method ... 5
Örebro county ... 5 Värmland county ... 6 Study design ... 6 Ethics ... 7 Results ... 7 Örebro county ... 7 Yearly analysis ... 7 Värmland county ... 9 Yearly analysis ... 10
Örebro county - Monthly analysis ... 13
Discussion... 15
Conclusion ... 17
Acknowledgements ... 17
Introduction
Transfusion of platelets can be divided into two main patient categories.
1 - Prophylactic platelet transfusions. This group contains patients who are in need of platelet transfusions because of an underlying thrombocytopenia, that can be either caused by a disease or be a result immunosuppressive treatment, such as irradiation treatment. The reason for platelet transfusion in these settings is to elevate the patient’s platelet level in order to prevent a spontaneous bleeding, hence a prophylactic transfusion. This group of platelet transfusions will henceforth be referred to as prophylactic transfusions.
2 - therapeutic platelet transfusions are given to patients with active bleeding, i.e. as treatment of ongoing bleeding as a result of physical trauma or during surgery in order to enhance the patient’s hemostatic capabilities and to stop the bleeding. This group of platelet transfusions will henceforth be referred to as therapeutic platelet transfusions.
The introduction of blood components, i.e., the separation of the blood into its components, red blood cells, plasma and platelets, was made with regard to the benefits of being able to treat conditions were supplementary transfusion of either component is indicated. Anemias can be treated with red blood cell (RBC) transfusions and thrombocytopenias can be treated with platelet transfusions. Thus, blood components are a good tool when you want to increase the value of only one specific component. But what about the treatment of acute hemorrhage? How well does the component system accommodate the needs of patients with acute hemorrhage? It has been put forward that this system of blood components have not been made with regard to these clinical issues. [1]
In normal hospital routine platelets are stored in room temperature, which make them prone to bacterial contamination. Other storage methods, including cryopreservation, are available but are not used by the clinics today. Mostly because the cryopreservation process of the platelets transforms them into an active state, which in turn leads to a shorter circulation time after transfusion, rendering them useless for prophylactic use. [2]
Platelets in traumatic hemorrhage
Platelet transfusions are widely used in the setting of acute hemorrhage. In this setting, the patient is often in need of more blood components than just platelets and platelets are therefore given together with other blood products. The research differs on the ratio between the blood products to be used, but the standard today is to give RBCs platelets and plasma with a 1:1:1 ratio [3]. Whatever the ratio, administration of blood platelets have proven positive effects on mortality and morbidity in the case of acute hemorrhage. [3,4]
Limitations of today’s routine for storing platelets
Transfusion of blood platelets are not without risk. Platelet bags are stored in room temperature, which makes them prone to bacterial contamination leading to a risk for developing sepsis in the recipient. This limits the time it is possible to store platelets to 5-7 days depending on the country. Septic risk because of platelets transfusion is one of the greatest risks associated with transfusion. [5] To combat the risk of bacterial contamination, methods of pathogen reduction have been developed, with good results, and the incidence of platelet transfusion induced sepsis have decreased as a result of these measures. However, the bacterial risk of platelets stored in room temperature remain. [6,7] Increased storage duration of platelets have shown to be associated with increased risk of developing sepsis, [7] but there are also research that have shown that storage duration does not lead to an increased mortality or morbidity. [8]
Other risks related to platelet transfusions, that are not related to the storage method, include several adverse events as stroke, myocardial infarction, acute lung injury and acute respiratory distress syndrome, as well as acute renal failure have been described. [9,10]
Apart from the risks associated with platelet transfusions, platelets stored in room temperature have other limitations. One of the biggest problems facing platelet storage, is something called the storage lesion. Beside bacterial contamination, the storage lesion is a problem that limits the time it is possible to store platelets. The storage lesion refers to a set of structural and chemical alterations in the platelets that arise when platelets are stored in room temperature for longer periods of time. These structural alterations lead to a worse function on the platelets. [11] Several experiments have made efforts to minimize the storage lesion by finding the cellular signaling pathways that give rise to these alterations and intervene in different steps of these pathways. Results of in vitro research have found several such pathways and ways to
diminish their effect on the platelets, but these instruments are not used in the clinics today. [10–15]
Other storage methods
Beside storing platelets in room temperature, other storage methods have arisen for two reasons. One, to minimize the risk of bacterial contamination so that two, platelets can be stored for longer periods of time, enabling building up a stock of platelets which is not possible today. These storage methods include: refrigerated platelets, cryopreserved platelets, and lyophilized platelets. [16] Out of these, cryopreserved platelets is the most tested alternative and is used by the military of several countries. [1,17,18]
Refrigerated platelets means cooling them down to 2-6 degrees Celsius without agitation. Refrigerated platelets enables an increased storage time, but at the cost of a shorter circulation time of 2-3 days. [4]
Cryopreservation of platelets means storage of platelets in -80 degrees Celsius. This is done by suspending the platelets in a DMSO-(dimethylsulfoxide-)solution, removing the DMSO right before freezing, then thawing the platelets by suspending them in room temperature plasma. The thawing process takes 10 minutes. [19] Cryopreservation of platelets enables a storage time for at least two years.
Lyophilized platelets are platelets that have been freeze-dried, producing so called thrombosomes. [20] Lyophilized platelets were first developed in the 1950’s, but as the platelets lost their hemostatic capabilities due to the thawing process, the idea was abolished. However, newer techniques have been developed and now lyophilized platelets have proven to be an effective hemostatic agent, with less logistical demands than cryopreserved platelets. [20,21] Lyophilized platelets can be stored for long periods of time, and is ready to use after a thawing time of around 10 minutes. [20]
Today’s routine of room temperature stored platelets, have a focus on maximal time in circulation. The alternative platelet preparations produce platelets with a short circulation time, this is why they have not been introduced into clinical routine. [2,22] However, these platelet preparations have shown to possibly be a superior hemostatic agent compared to those stored in room temperature, caused by an activation of the platelets and thereby higher hemostatic capabilities. [19,23–25]
Besides finding new ways of storing platelets, research has also focused on finding ways of increasing the circulation time of the colder storage alternatives, these include suppressing the metabolic activity of the platelets [26] and treating the platelets with PGE1, which inhibits the activation of the platelets,[27] which in turn leads to a longer circulation time.
In summary, one can say that these alternative storage methods provide a way of storing platelets that reduces the risk of bacterial contamination, increases the storage time - making it possible to build up a greater stock of platelets, and it creates a more effective agent for treating acute hemorrhage. This could therefore be a possible alternative of platelets stored in room temperature, for treating bleeding patients in cases of trauma and surgery. Suggesting that a one-size-fits-all preparation method of platelets is perhaps not the best alternative. [23]
It should be noted that one reason why other storage methods of platelets have not been implemented in civilian health care, is that practically no clinical trials have been made, comparing ordinary room temperature stored platelets with the other alternatives. However, one is currently underway in Australia. Thus, as of now there are not any sound scientific research that can be the foundation of a decision to implement a new storage method. It is also difficult to determine the hemostatic function in of platelets, making it even harder to determine the actual quality of the platelets, although some methods have been used, such as multiple electrode aggregometry and bleeding time in rats. [28,29]
However, cryopreserved platelets are currently used by the Swedish army and the Dutch army in the MINUSMA (the United Nations Multidimensional Integrated Stabilization Mission in Mali). Both countries’ armies get cryopreserved platelets delivered by air plane from the Netherlands. Their experience is that frozen platelets is a functional hemostatic product, that lives up to current international standards and guidelines. [17,18] Cryopreserved platelets have also been used by the U.S. military in operation Iraqi Freedom, with positive results. [1]
Whole blood transfusion in traumatic hemorrhage
Another way of treating traumatic hemorrhage, is using whole blood instead of components. In civilian health care today, this is not common practice and hasn’t been since the 1970’s with the introduction of blood components. The use of whole blood transfusions has been avoided because of the view that you must transfuse the exact blood type as that of the receiver, but
current research suggest that this must not be the case. [30] Type O blood with low levels of anti-A/B antibodies (called low titer), can be used as a universal product when transfusing patients experiencing massive blood loss. [32]
Today, when a patient is in need of all the components of the blood, the clinician must ordinate red blood cells, platelets and plasma, all of which come in separate bags. This is both impractical and time consuming and there is also the issue of which component to transfuse first. These problems do not exist when using whole blood. Military experience suggest that whole blood transfusion is a better alternative than blood components in cases of trauma and massive blood loss. [33] Furthermore, whole blood can be stored in 4 degrees Celsius for 15 days while retaining platelet function. [32]
As have been presented above, several ways of treating traumatic hemorrhage exist, that today are not part of normal hospital routine. In vitro studies, studies in animals and military experience suggest that these alternatives could be better than the ones available to the clinicians today. The objective of this study is to determine if there is a need of any such product by looking at two Swedish counties, one medium sized and one smaller. This study can thus be an addition to the discussion of the implementation of new blood products for the treatment of traumatic hemorrhage.
Material and method
In order to analyze the need for alternative blood products when treating ongoing hemorrhage, statistics of the platelet transfusions in two Swedish counties in the Örebro region, Örebro county and Värmland county were analyzed. Both these counties have one larger central hospital and additional local hospitals. The data was collected from each county’s central blood bank.
Örebro county
The data from the Örebro county covers platelet transfusions of all three hospitals in the region. The hospitals consist of one university hospital in Örebro and two smaller local hospitals in Karlskoga and Lindesberg. The data available for Örebro county covers the number of platelet transfusions from 2014-2017. The data is sorted by which department that made the transfusion and also by month.
Värmland county
The data from the Värmland county covers platelet transfusions of all three hospitals in the region. The hospitals consist of one central hospital in Karlstad, and two smaller local hospitals, in Arvika and Torsby. The data available for Värmland region covers the number of platelet transfusions from 2011-2016. The data is sorted by which department that made the transfusion but no available data concerning which month the transfusion was made.
Table 1 specifies the data for each county.
Tabell 1 - Data available for each county.
Years available Number of PT Sorting by ward Sorting by Month
Örebro County 2014–2017 x x x
Värmland County 2011–2016 x x
Study design
The different preparation methods of platelets result in platelets with different properties. While platelets stored in room temperature are suitable for prophylaxis, cryopreserved, refrigerated and lyophilized platelets are suitable for therapeutic transfusions. Since the data available on the platelet transfusions does not distinguish between the underlying indication of each transfusion, another method has been applied to be able to determine how many of the total transfusions are prophylactic transfusions on the one hand, and therapeutic transfusions on the other. To tackle this, the transfusions have been divided into three groups, with regard to what kind of department/ward can be assumed to make platelet transfusion for either purpose. The groups are presented in table 2.
Tabell 2 - Department/Ward groups.
Group 1 Group 2 Group 3
Hematology Wards Intensive Care Units (ICU) Surgical Wards Oncology Wards Emergency Departments (ED) Medical Wards Acute Care Wards (AC) Pediatric Wards
Infection Wards Other
Ethics
Since this study only looks at already available data over number of platelet transfusions, and contains no personal data, there are no ethical predicaments in regard to this study.
Results
Örebro county
In Örebro, between 2014-2017, a total of 5275 transfusions of platelets were made of which 2587 (49,04%) were transfusions from the first group, 1228 (23,28%) were transfusions from the second group and 1460 (27,68%) were transfusions from the third group. The number of platelet transfusions in Karlskoga and Lindesberg amounted to 345 (6,54%) of all platelet transfusions during the studied period.
Yearly analysis
The transfusions in the first group saw a decrease from 2014-2016, but got back to similar values as 2014 in 2017. The hematology departments did the majority of the platelet transfusion during the studied period. The drop in platelet transfusions in 2015 and 2016 was largely attributed to a decreased number of platelet transfusions by the hematology departments.
Figure 1 - Platelet transfusions in the first group, Örebro county, 20114-2017. Containing hematologic departments (Hem.) and oncology departments (Onc.).
The transfusions in the second group, were relatively similar for the studied period, with around 300 platelet transfusions each year. The ICUs made by far up the largest part of platelet
transfusions, followed by the critical care wards. The EDs only made up a small percentage of the platelet transfusions in this group.
Figure 2 - Platelet transfusions in the second group, Örebro county, 2014-2017. Containing intensive care units (ICU), emergency departments (ED) and acute care wards (AC).
In the third group, the surgical wards made up the single biggest part of the platelet transfusions in which the ward for vascular and thoracic surgery was the biggest contributor. The pediatric wards also contributed to relatively large portion in this group. The medical wards group consisted of several miscellaneous medical wards that together also were a large contributor to this group.
Figure 3 - Platelet transfusions in the third group, Örebro county, 2014-207. Containing Surgical Wards (Surg.), Medical Wards (Med.), Pediatric Wards (Ped.) and other wards.
Table 3 shows the percentage of platelet transfusions for each department, sorted by highest mean percentage.
Tabell 3 - Percentage of platelet transfusions by ward, Örebro county, 2014-2017. Hem= Hematology, ICU = Intensive Care Units, Surg = Surgical Wards, Ped = Pediatrics ward, Onc = Oncology ward, Med = Medical ward, AC = Critical care ward, Infektion = Infection ward, ED = Emergency department.
Mean 2014 2015 2016 2017 Hem. 43,5 49,6 40,5 30,5 53,5 ICU 19,9 18,7 20,3 22,0 18,5 Surg. 14,1 13,8 16,3 15,6 10,9 Ped. 5,8 3,3 5,2 10,3 4,3 Onc. 5,1 4,7 4,3 6,2 5,2 Med. 4,9 3,7 6,0 6,7 3,0 AC 2,6 1,3 2,2 5,4 1,4 Inf. 1,5 1,8 1,3 1,5 1,3 ED 1 0,8 1,4 0,5 1,1 Värmland county
In Värmland, between 2011-2016, a total of 8112 platelet transfusions were made, of which 6162 (75,96%) were in the first group, 608 (7,50%) were in the second group and 1342 (16,54%) were in the third group.
Out of the total number of the platelet transfusions in Värmland region, 353 (4,35%) were made in the two smaller hospitals in Arvika and Torsby.
Yearly analysis
Transfusions in the first group saw a brief increase for the studied period. The hematology departments did the majority of the platelet transfusions, while transfusions by the oncology departments decreased during the studied period. The overall shifting number of platelet transfusions could largely be attributed to the hematology departments.
Figure 4 - Platelet transfusions in the first group, Värmland county, 2011-2016. Containg hematologic departments (Hem.) and oncology departments (Onc.).
Transfusions in the second group varied somewhat during the years that were studied. The ICUs did the majority of the platelet transfusions followed by the EDs. The CC wards only made a small amount of the platelet transfusions except for in 2011.
Figure 5 - Platelet transfusions in the second group, Värmland county, 2011-2016. Containing intensive care units (ICU), emergency departments (ED) and acute care wards (AC).
Transfusions in the third group varied greatly between the years that were studied. The majority of the transfusions in the third group varied between the surgical wards, the medical wards and the pediatric wards, depending on the year. The large amount of transfusions in the “other” category in 2011, is attributed to a ward that does no longer exist and of which no information could be found what kind of department it was.
Figure 6 - Figur 3 - Platelet transfusions in the third group, Värmland county, 2011-2016. containing Surgical Wards (Surg.), Medical Wards (Med.), Pediatric Wards (Ped.) and other wards.
Table 4 shows the percentage of platelet transfusions for each department, sorted by highest mean percentage.
Tabell 4 - Percentage of platelet transfusions by ward, Värmland region, 2014-2017. Hem= Hematology, ICU = Intensive Care Units, Surg = Surgical Wards, Ped = Pediatrics ward, Onc = Oncology ward, Med = Medical ward, AC = Critical care ward, Infektion = Infection ward, ED = Emergency department.
Mean 2011 2012 2013 2014 2015 2016
ICU 6,8% 8,5% 7,8% 5,0% 6,1% 8,0% 5,2% Surg. 5,4% 4,0% 4,4% 5,6% 3,8% 7,8% 7,1% Med. 4,3% 4,6% 5,6% 5,0% 2,9% 3,8% 4,2% Ped. 4,0% 4,9% 1,4% 7,2% 4,4% 4,8% 1,5% Onc. 3,9% 6,9% 6,2% 1,7% 2,8% 2,5% 3,0% Inf. 1,7% 3,5% 1,2% 1,7% 0,7% 0,8% 2,5% ED 0,7% 0,3% 1,1% 0,4% 1,1% 0,6% 0,5% AC 0,2% 0,6% 0,5% 0,1% 0,0% 0,1% 0,0%
Örebro county - Monthly analysis
Group 1 transfusions were relatively similar during the first half of the year, but there was inter-year variance on the second half of the inter-year. The maximum number of platelet transfusions in one month varied from 77-121 depending on the year. Figure 7 shows monthly platelet transfusions in the first group in Örebro county, 2014-2017.
Figur 7 - monthly group 1 transfusions Örebro region 2014-2017.
Group 2 transfusions showed big monthly variance, with 2-3 peaks per year. Each year had peaks on different months. The maximum number of platelet transfusions in one month varied from 43-56 depending on the year. Figure 8 shows monthly platelet transfusions in the second group in Örebro county, 2014-2017.
0 20 40 60 80 100 120 140
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Hematology - Oncology Örebro county 2014-2017
Figur 8 - Monthly group 2 transfusions Örebro region, 2014-2017.
Group 3 transfusions showed similar monthly patterns form year to year, with monthly variance. Figure 9 shows monthly transfusions in the third group in Örebro county 2014-2017.
Figur 9 - Monthly group 3 transfusions Örebro county, 2014-2017.
0 10 20 30 40 50 60
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
ICU/ED/AC Örebro county 2014-2017
RÖL 2014 IEC RÖL 2015 IEC RÖL 2016 IEC RÖL 2017 IEC
0 5 10 15 20 25 30 35 40 45 50
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Surg. - Med. - Inf. - Ped. - Other Örebro county 2014-2017
Discussion
In the light of new military insights considering the therapeutic treatment of ongoing bleeding and acute hemorrhage, there has been considerable academic debate on the topic whether to expand the assortment of blood products available for the clinicians treating this condition. These include other storage preparations for platelets, particularly cryopreserved platelets, and whole blood. Cryopreserved platelets have been shown to have superior hemostatic properties and are as such a better product for treating acute hemorrhage, compared to those stored in room temperature which are better suitable for prophylactic use. The aim of this study was to use currently available data in order to see how much of today’s platelet transfusions could be replaced by, and possibly benefit from, either cryopreserved platelets or whole blood. This was made by sorting the platelet transfusions by transfusing ward/department.
The main results of this study are that a majority of the platelet transfusions are made by three different types of wards/departments, namely the hematologic wards, the intensive care units (ICU) and the surgical wards. Of the total platelet transfusions, the hematologic wards accounted for a mean of 43,5% in Örebro and 71,9% in Värmland. The ICUs accounted for a mean of 19,9% in Örebro and 6,8% in Värmland and the surgical wards accounted for a mean of 14,1% in Örebro and 5,4% in Värmland. The sum of the platelet transfusions in the EDs and ACs was 3,6% in Örebro and 0,9% in Värmland. The number of platelet transfusions in the ICUs, surgical wards, ACs and EDs can tell us something about the amount of platelet transfusions for the therapeutic treatment of acute hemorrhage, since these are the wards that mainly transfuse platelets to this end. As such, this may suggest that up to 37,6% of the platelet transfusions in Örebro region and 13,1% in Värmland region could be platelet transfusions for the therapeutic treatment of acute hemorrhage, and could thus be replaced by cryopreserved, activated, platelets or whole blood.
Furthermore, in Värmland the hematology wards’ share of the platelet transfusion were considerably larger than Örebro’s, 71,9% vs 43,5%. This could be because Örebro county has a regional university hospital, and is likely to have more trauma and surgery than a smaller central hospital, as that of Värmland. However, the distribution of platelet transfusions within the different groups were similar in both counties.
The changes in yearly total platelet transfusions was in large due to changes in number of platelet transfusions by the hematologic wards in both counties. In contrast, platelet transfusions in the second group, containing the ICUs, EDs, and ACs, showed more stable values between the years. However, as the year-to-year differences were not large, they demonstrated great
monthly variance. As such, the total amount of platelet transfusions for one year in the second group, could be attributed to two or three months in that year that experienced a high number of platelet transfusions. As the platelet demand varies greatly during a year, the blood banks need to be ready for sudden peaks in platelet demand from the ICUs, which could result in higher cassation due to outdating in times when the demand is not as high. Here a backup of cryopreserved platelets could serve more purposes than just being a capable hemostatic agent, namely preventing cassation, or the need for ordering platelets from other blood banks when the demand is extra high. This could create an economic incentive for the introduction of cryopreserved platelets.
The main limitation of this study is that it tries so answer the question of which indication is behind a platelet transfusion, by looking at which department that made the transfusion. Since a part of the transfusions in the second group and in the surgery category are likely to be prophylactic, this is not a definitive answer on how many of the transfusions are therapeutic. However, a small part of the transfusions in the hematologic wards can likewise be assumed to be therapeutic. (Personal communication) As such, this could compensate for the number of prophylactic platelet transfusions in the ICUs and the surgical wards. Nevertheless, this study gives a detailed description on what kind of wards that give the most platelet transfusions, and it is possible to draw conclusions from this.
Another limitation of this study is that it only looks at two Swedish regions, two middle-to-small size ones. Only in these two counties, big differences could be observed, and it is likely that the results would be different if one would look at smaller and bigger counties.
In order to get more answers on this topic, future studies could focus more precisely on the indication underlying each platelet transfusion. One could base such study on this one, by mainly looking at platelet transfusions in the hematology wards, the ICUs, and the surgical wards, since these three groups make up the biggest amount of the total platelet transfusions. Future studied could also include more regions, especially regions that experience more trauma such as the bigger cities, were the need of other blood products is likely to be larger.
Conclusion
According to this limited study, about 38% of all platelet transfusions in a county with a university hospital and 13% in a county without a university hospital, could benefit from transfusion with activated platelets, instead of those platelets that is today’s routine for prophylactic treatment.
Acknowledgements
I would like to thank my supervisor Olle Berséus who have been a big help through the entire writing of this paper. Thank you for answering all my emails, for agreeing to meet with me so often to discuss the study and for all that you have taught me about how to write an academic paper.
I would also like to say a big special thanks to Lena Göransson at Örebro University Hospital blood bank and Inger Eng at Claratappen, for having taken the time to meet with me and providing the data necessary for the making of this study.
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