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Pathogen-reduced platelets for the prevention of bleeding

  • Review
  • Intervention

Authors


Abstract

Background

Platelet transfusions are used to prevent and treat bleeding in people who are thrombocytopenic. Despite improvements in donor screening and laboratory testing, a small risk of viral, bacterial, or protozoal contamination of platelets remains. There is also an ongoing risk from newly emerging blood transfusion-transmitted infections for which laboratory tests may not be available at the time of initial outbreak.

One solution to reduce the risk of blood transfusion-transmitted infections from platelet transfusion is photochemical pathogen reduction, in which pathogens are either inactivated or significantly depleted in number, thereby reducing the chance of transmission. This process might offer additional benefits, including platelet shelf-life extension, and negate the requirement for gamma-irradiation of platelets. Although current pathogen-reduction technologies have been proven to reduce pathogen load in platelet concentrates, a number of published clinical studies have raised concerns about the effectiveness of pathogen-reduced platelets for post-transfusion platelet count recovery and the prevention of bleeding when compared with standard platelets.

This is an update of a Cochrane review first published in 2013.

Objectives

To assess the effectiveness of pathogen-reduced platelets for the prevention of bleeding in people of any age requiring platelet transfusions.

Search methods

We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 9), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 24 October 2016.

Selection criteria

We included RCTs comparing the transfusion of pathogen-reduced platelets with standard platelets, or comparing different types of pathogen-reduced platelets.

Data collection and analysis

We used the standard methodological procedures expected by Cochrane.

Main results

We identified five new trials in this update of the review. A total of 15 trials were eligible for inclusion in this review, 12 completed trials (2075 participants) and three ongoing trials. Ten of the 12 completed trials were included in the original review. We did not identify any RCTs comparing the transfusion of one type of pathogen-reduced platelets with another.

Nine trials compared Intercept® pathogen-reduced platelets to standard platelets, two trials compared Mirasol® pathogen-reduced platelets to standard platelets; and one trial compared both pathogen-reduced platelets types to standard platelets. Three RCTs were randomised cross-over trials, and nine were parallel-group trials. Of the 2075 participants enrolled in the trials, 1981 participants received at least one platelet transfusion (1662 participants in Intercept® platelet trials and 319 in Mirasol® platelet trials).

One trial included children requiring cardiac surgery (16 participants) or adults requiring a liver transplant (28 participants). All of the other participants were thrombocytopenic individuals who had a haematological or oncological diagnosis. Eight trials included only adults.

Four of the included studies were at low risk of bias in every domain, while the remaining eight included studies had some threats to validity.

Overall, the quality of the evidence was low to high across different outcomes according to GRADE methodology.

We are very uncertain as to whether pathogen-reduced platelets increase the risk of any bleeding (World Health Organization (WHO) Grade 1 to 4) (5 trials, 1085 participants; fixed-effect risk ratio (RR) 1.09, 95% confidence interval (CI) 1.02 to 1.15; I2 = 59%, random-effect RR 1.14, 95% CI 0.93 to 1.38; I2 = 59%; low-quality evidence).

There was no evidence of a difference between pathogen-reduced platelets and standard platelets in the incidence of clinically significant bleeding complications (WHO Grade 2 or higher) (5 trials, 1392 participants; RR 1.10, 95% CI 0.97 to 1.25; I2 = 0%; moderate-quality evidence), and there is probably no difference in the risk of developing severe bleeding (WHO Grade 3 or higher) (6 trials, 1495 participants; RR 1.24, 95% CI 0.76 to 2.02; I2 = 32%; moderate-quality evidence).

There is probably no difference between pathogen-reduced platelets and standard platelets in the incidence of all-cause mortality at 4 to 12 weeks (6 trials, 1509 participants; RR 0.81, 95% CI 0.50 to 1.29; I2 = 26%; moderate-quality evidence).

There is probably no difference between pathogen-reduced platelets and standard platelets in the incidence of serious adverse events (7 trials, 1340 participants; RR 1.09, 95% CI 0.88 to 1.35; I2 = 0%; moderate-quality evidence). However, no bacterial transfusion-transmitted infections occurred in the six trials that reported this outcome.

Participants who received pathogen-reduced platelet transfusions had an increased risk of developing platelet refractoriness (7 trials, 1525 participants; RR 2.94, 95% CI 2.08 to 4.16; I2 = 0%; high-quality evidence), though the definition of platelet refractoriness differed between trials.

Participants who received pathogen-reduced platelet transfusions required more platelet transfusions (6 trials, 1509 participants; mean difference (MD) 1.23, 95% CI 0.86 to 1.61; I2 = 27%; high-quality evidence), and there was probably a shorter time interval between transfusions (6 trials, 1489 participants; MD -0.42, 95% CI -0.53 to -0.32; I2 = 29%; moderate-quality evidence). Participants who received pathogen-reduced platelet transfusions had a lower 24-hour corrected-count increment (7 trials, 1681 participants; MD -3.02, 95% CI -3.57 to -2.48; I2 = 15%; high-quality evidence).

None of the studies reported quality of life.

We did not evaluate any economic outcomes.

There was evidence of subgroup differences in multiple transfusion trials between the two pathogen-reduced platelet technologies assessed in this review (Intercept® and Mirasol®) for all-cause mortality and the interval between platelet transfusions (favouring Intercept®).

Authors' conclusions

Findings from this review were based on 12 trials, and of the 1981 participants who received a platelet transfusion only 44 did not have a haematological or oncological diagnosis.

In people with haematological or oncological disorders who are thrombocytopenic due to their disease or its treatment, we found high-quality evidence that pathogen-reduced platelet transfusions increase the risk of platelet refractoriness and the platelet transfusion requirement. We found moderate-quality evidence that pathogen-reduced platelet transfusions do not affect all-cause mortality, the risk of clinically significant or severe bleeding, or the risk of a serious adverse event. There was insufficient evidence for people with other diagnoses.

All three ongoing trials are in adults (planned recruitment 1375 participants) with a haematological or oncological diagnosis.

Plain language summary

Platelet transfusions treated to reduce transfusion-transmitted infections for the prevention of bleeding in people with low platelet counts

Review question

The aim of this review was to assess whether specially treated pathogen-reduced platelets, work as well as normal platelets when transfused. Specifically, do they stop or prevent bleeding as well as standard platelets; do they produce the same increase in platelet count; and does their use affect further transfusion requirements? This review also assessed whether pathogen-reduced platelets are as safe as normal platelets, for example are they associated with any difference in the rate of death following transfusion, and are there any side effects associated with the use of these products.

Our target population was people of any age with a low platelet count who would usually be treated with platelet transfusions.

Background

Blood for transfusion is collected from donors and then processed and stored as bags of different blood components. One of these components is platelets. Platelets are cells that help the body to form clots and prevent bleeding. Platelet transfusions may be given to prevent bleeding when the platelet count falls below a prespecified threshold platelet count (e.g. 10 x 109/L), or may be given to treat bleeding (such as a prolonged nosebleed or multiple bruises). As for all transfusions, there are risks related to giving platelets transfusions, including a small risk of transfusion-transmitted infections. A number of methods are used to minimise the risk of transfusion-transmitted infections, including careful selection of people who donate blood and rigorous testing of the donated blood. One method of preventing infection is pathogen reduction by which, through a process of adding chemicals to the donated platelets and exposing them to a wavelength of ultraviolet light, the number of infecting organisms can be reduced. We have included two types of pathogen-reduction technique in this review, Intercept® and Mirasol®.

Study characteristics

The evidence is current to October 2016. We found five new studies eligible for inclusion in this update of the review, three of which are still ongoing. We included 12 randomised controlled trials in this review; in 10 trials the Intercept® method of pathogen-reduction was compared with standard platelets and in two trials the Mirasol® method of pathogen-reduction was compared with standard platelets. All trials were conducted between 2003 and 2016 and included a total of 2075 participants. The sources of funding were reported in 12 studies. Most of the included studies were conducted in adults with blood cancers.

Key results

In people with cancer who have a low platelet count due to their disease or its treatment, we found that pathogen-reduced platelet transfusions lead to an increase in the number of platelet transfusions required and an increase in the risk of no longer achieving a rise in the platelet count after a transfusion (platelet refractoriness). Pathogen-reduced platelet transfusions probably do not affect the risk of death, bleeding, or a serious side effect. None of the studies reported on quality of life. No bacterial transfusion-transmitted infections occurred in the six trials that reported this outcome.

There was insufficient evidence for people with other diagnoses.

All three ongoing studies are in adults with blood disorders (planned recruitment 1375 participants), there are no ongoing studies in children or in adults with other diagnoses.

Findings from this review were based on 12 studies and the 1981 participants who received a platelet transfusion.

We did not evaluate any economic outcomes.

Quality of the evidence

The overall quality of the evidence was low to high, as the estimates were imprecise (risk of death or a serious side effect), and there were differences in estimates for the risk of bleeding between studies.

Laienverständliche Zusammenfassung

Aufbereitete Thrombozytentransfusionen zur Reduzierung von durch Transfusionen übertragenen Infektionen zur Vorbeugung von Blutungen bei Personen mit geringer Thrombozytenzahl

Fragestellung

Das Ziel dieses Reviews war die Beurteilung, ob speziell aufbereitete pathogenreduzierte Thrombozyten bei einer Transfusion ebenso wirksam wie normale Thrombozyten sind. Insbesondere stand die Frage im Vordergrund, inwiefern diese eine Blutung ebenso wie normale Thrombozyten stoppen oder einer Blutung ebenso vorbeugen, inwiefern bei ihnen derselbe Anstieg der Thrombozytenzahl zu verzeichnen ist, und inwiefern ihre Anwendung Auswirkungen auf den weiteren Transfusionsbedarf hat. Dieser Review untersuchte darüber hinaus, ob pathogenreduzierte Thrombozyten ebenso sicher wie normale Thrombozyten sind, beispielsweise inwiefern eventuelle Unterschiede bei der Sterblichkeitsrate nach der Transfusion bestehen, und ob mit der Anwendung dieser Produkte Nebenwirkungen verbunden sind.

Unsere Zielpopulation waren Personen jeglichen Alters mit einer niedrigen Thrombozytenzahl, die normalerweise mit Thrombozytentransfusionen behandelt würden.

Hintergrund

Blut für Transfusionen wird Blutspendern entnommen, anschließend aufbereitet und in Beuteln mit verschiedenen Blutbestandteilen gelagert. Einer dieser Bestandteile sind Thrombozyten. Thrombozyten sind Zellen, die dem Körper bei der Gerinnung helfen und Blutungen vorbeugen. Thrombozytentransfusionen können zur Vorbeugung von Blutungsereignissen verabreicht werden, wenn die Thrombozytenzahl unter eine vorab festgelegte Thrombozytenzahl sinkt (z.B. 10 x 109/l), oder können zur Behandlung einer Blutung verabreicht werden (wie bspw. länger andauerndem Nasenbluten oder mehrerer Hämatome). Wie bei allen Transfusionen bestehen auch bei einer Thrombozytentransfusion Risiken, darunter auch ein geringfügiges Risiko für die Übertragung von Infektionen durch die Transfusion. Eine Reihe von Methoden wird angewandt, um das Risiko solcher, durch die Transfusion übertragener Infektionen zu minimieren - darunter fallen die sorgfältige Auswahl der Personen, die das Blut spenden und strikte Testverfahren zur Untersuchung des gespendeten Blutes. Eine Methode zur Vorbeugung von Infektionen ist die Pathogenreduktion, bei der die Anzahl der Infektionserreger vermindert werden kann, indem Chemikalien zu den gespendeten Thrombozyten hinzugefügt werden und die Thrombozyten ultraviolettem Licht einer speziellen Wellenlänge ausgesetzt werden. Wir haben zwei Arten von Techniken zur Pathogenreduktion in diesen Review aufgenommen, Intercept® und Mirasol®.

Studienmerkmale

Die Evidenz ist auf dem Stand von Oktober 2016. Wir fanden fünf neue Studien, die für einen Einschluss in diese Aktualisierung des Reviews geeignet waren. Drei dieser Studien laufen derzeit noch. Wir schlossen 12 randomisierte, kontrollierte Studien in diesen Review ein. Bei 10 Studien wurde die Intercept®-Methode zur Pathogenreduktion mit normalen Thrombozyten verglichen, zwei Studien verglichen die Mirasol®-Methode zur Pathogenreduktion mit normalen Thrombozyten. Sämtliche dieser Studien wurden zwischen 2003 und 2016 durchgeführt und schlossen insgesamt 2.075 Teilnehmer ein. Bei 12 Studien wurden die Finanzierungsquellen genannt. Der Großteil der eingeschlossenen Studien wurde an Erwachsenen mit Blutkrebs durchgeführt.

Hauptergebnisse

Bei Personen mit Krebs, die aufgrund ihrer Erkrankung oder deren Behandlung eine geringe Thrombozytenzahl aufweisen, stellten wir fest, dass pathogenreduzierte Thrombozytentransfusionen zu einem Anstieg der Anzahl der erforderlichen Thrombozytentransfusionen führten, und dass das Risiko dafür zunahm, keinen Anstieg der Thrombozytenzahl nach der Transfusion (Thrombozytenrefraktärität) mehr zu erzielen. Pathogenreduzierte Thrombozytentransfusionen haben wahrscheinlich keinen Einfluss auf das Sterbe- oder Blutungsrisiko bzw. auf eine schwerwiegende Nebenwirkung. Keine der Studien berichtete über die Lebensqualität. In den sechs Studien, die diesen Endpunkt berichteten, traten keine, durch die Transfusionen übertragenen, bakteriellen Infektionen auf.

Zu Personen mit anderen Diagnosen lag keine ausreichende Evidenz vor.

Alle drei laufenden Studien betrachten Erwachsene mit Blutkrankheiten (geplante Rekrutierung 1.375 Teilnehmer). Es sind keine laufenden Studien zu Kindern oder Erwachsenden mit anderen Diagnosen vorhanden.

Die Ergebnisse dieses Reviews basieren auf 12 Studien und den 1.981 Teilnehmern, die eine Thrombozytentransfusion erhielten.

Wir untersuchten keine wirtschaftlichen/finanziellen Endpunkte.

Qualität der Evidenz

Die Gesamtqualität der vorliegenden Evidenz war niedrig bis hoch, da die Einschätzungen ungenau (Sterberisiko oder Risiko für schwere Nebenwirkung) waren, und es Unterschiede bezüglich der Einschätzungen des Blutungsrisikos zwischen den einzelnen Studien gab.

Anmerkungen zur Übersetzung

B. Fiess, freigegeben durch Cochrane Deutschland.