Platelet Transfusion in Perioperative Medicine

AbstractPlatelet transfusions aim to improve primary hemostasis and to prevent or treat bleeding in patients with reduced platelet numbers and/or platelet function. In this review, the authors address the role of platelet transfusions with a focus on perioperative medicine. They summarize different causes of thrombocytopenia in perioperative patients, describe general characteristics and potential adverse effects of different platelet concentrates, describe principles of perioperative platelet transfusion strategies, and highlight specific perioperative scenarios, for example, in patients undergoing antiplatelet therapy. The evidence for any transfusion threshold in perioperative patients based on platelet numbers is low. The evidence supporting prophylactic platelet transfusions in the perioperative setting is very low, and all recommended thresholds for preintervention platelet transfusions are based on weak evidence or expert opinion. Besides the platelet count, platelet function, additional risk factors for bleeding, and the pharmacokinetic properties of concomitant antiplatelet drugs are important criteria for the decision to transfuse or not to transfuse platelets. The few available prospective trials give at least a signal that a liberal platelet transfusion strategy might be associated with poorer outcomes compared with a restrictive platelet transfusion strategy in critically ill patients. Given the unknown risks for adverse outcomes, a therapeutic transfusion strategy during surgery (eventually guided by point of care testing in cardiac surgery, major liver surgery, and major trauma) may be most appropriate for interventions, in which intraoperative bleeding can be controlled until platelets are available, and during the postsurgery period.

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How well do platelets prevent bleeding?

Hematology ◽

10.1182/hematology.2020000136 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 518-522

Author(s):

Darrell J. Triulzi

Keyword(s):

Platelet Transfusion ◽

Anticoagulation Therapy ◽

Outpatient Setting ◽

Severe Thrombocytopenia ◽

Transfusion Threshold ◽

Spontaneous Bleeding ◽

Risk Of Bleeding ◽

Increased Risk ◽

High Incidence ◽

Platelet Transfusions

Abstract Prophylactic platelet transfusions are used to reduce the risk of spontaneous bleeding in patients with treatment- or disease-related severe thrombocytopenia. A prophylactic platelet-transfusion threshold of <10 × 103/µL has been shown to be safe in stable hematology/oncology patients. A higher threshold and/or larger or more frequent platelet doses may be appropriate for patients with clinical features associated with an increased risk of bleeding such as high fevers, sepsis, disseminated intravascular coagulation, anticoagulation therapy, or splenomegaly. Unique factors in the outpatient setting may support the use of a higher platelet-transfusion threshold and/or dose of platelets. A prophylactic platelet-transfusion strategy has been shown to be associated with a lower risk of bleeding compared with no prophylaxis in adult patients receiving chemotherapy but not for autologous transplant recipients. Despite the use of prophylactic platelet transfusions, a high incidence (50% to 70%) of spontaneous bleeding remains. Using a higher threshold or larger doses of platelets does not change this risk. New approaches to reduce the risk of spontaneous bleeding, including antifibrinolytic therapy, are currently under study.

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Platelet Transfusion Thresholds In Neonates: Substantial Differences Between U.S. and Europe

Blood ◽

10.1182/blood.v116.21.3356.3356 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3356-3356

Author(s):

Malte MD Cremer ◽

Martha Sola-Visner ◽

Stephanie Roll ◽

Cassandra Josephson ◽

Zeynep Yilmaz ◽

...

Keyword(s):

Platelet Transfusion ◽

Term Infant ◽

Odds Ratios ◽

Case Scenario ◽

Transfusion Threshold ◽

Mortality And Morbidity ◽

The Us ◽

Level 1 ◽

International Comparative ◽

Platelet Transfusions

Abstract Abstract 3356 Background: Thrombocytopenia affects 20–35% of patients admitted to Neonatal Intensive Care Units (NICUs). Platelet transfusions are usually administered to thrombocytopenic neonates at higher thresholds than those used for older children or adults, although there is a paucity of evidence to guide these decisions. Methods: In this study, we used a web-based survey to investigate the platelet transfusion thresholds used in level 1 NICUs (equivalent to level 3 in the US) in German-speaking European countries (Austria, Germany and Switzerland, AUT/GER/SUI). This survey was identical to the one previously used to investigate the transfusion practices of US neonatologists, thus allowing for a direct comparison of both populations. Eleven common clinical case scenarios of thrombocytopenia in preterm or term neonates were described and neonatologists were asked at which platelet count they would order a transfusion. For each case scenario, the median and the most frequently selected thresholds were determined. The Mann-Whitney-U-test was applied to compare the distribution of platelet transfusion thresholds between AUT/GER/SUI and US neonatologists. Univariate cumulative logit models (proportional odds model) were used to evaluate the differences between AUT/GER/SUI and US practices. In this analysis, an odds ratio >1 indicates an increased odd to select a higher threshold. Results: At least one neonatologist from 100 of the 171 (58%) eligible level 1 NICUs (AUT n=2; GER n=92; SUI n=6) participated in the survey, for a total of 144 neonatologists. Their answers were compared with those of 1006 U.S. neonatologists previously surveyed. In 9 of the 11 scenarios, AUT/GER/SUI neonatologists selected substantially lower platelet transfusion thresholds than US neonatologists (P<.0001). For example, in a preterm infant (27 weeks of gestation and 950g) who was clinically stable and not bleeding at two days of life, the median platelet transfusion threshold was 30×109/L in AUT/GER/SUI vs. 50×109/L in the US (P<.0001). If the same infant had an intracranial hemorrhage, the most frequent threshold among AUT/GER/SUI neonatologists increased to 50×109/L, while most US neonatologists rose their trigger to 100×109/L (P<.0001). To quantify the differences in transfusion practices between the two groups of physicians, we then calculated (for each case scenario) the odds of US neonatologists selecting a higher transfusion category than their European colleagues. In nine of the eleven scenarios the odds ratios were between 3.25 and 5.05, reflecting the high likelihood that a US neonatologist would choose a higher transfusion threshold than an AUT/GER/SUI neonatologist facing the same patient. Only in two case scenarios (term infant with alloimmune thrombocytopenia and premature infant prior to lumbar puncture) the odds ratios were <2, reflecting more similar (although still significantly different) responses. Finally, in order to estimate the clinical impact of the observed differences, we recorded the platelet counts of every neonate admitted to our NICU over a six month period, and determined whether they would receive a platelet transfusion by extrapolating the answers of AUT/GER/SUI vs. US neonatologists to the first clinical vignette. Using this approach, we estimated that 18 out of 1000 neonates would be transfused if AUT/GER/SUI patterns were applied, compared to 33 transfused infants if US patterns were applied (1.8-fold increase). Conclusion: This first international comparative survey on platelet transfusion practices in neonates revealed substantially higher transfusion thresholds in the US than in AUT/GER/SUI. These differences might have substantial clinical implications, since platelet transfusions are associated with higher neonatal mortality and morbidity. In neonates with necrotizing enterocolitis and thrombocytopenia, receiving a higher number of platelet transfusions has been associated with a higher incidence of short bowel syndrome and cholestasis, and there is evidence to support the hypothesis that platelet transfusions can worsen bowel injury. Thus, well-designed clinical studies are needed to address the risks/benefits of these different approaches. Disclosures: Josephson: Immucor: Speakers Bureau.

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Transfusion Practice Following Intracranial Hemorrhage in Acute Leukemia: An Institutional Review

Blood ◽

10.1182/blood-2018-99-112718 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4740-4740

Author(s):

Shannon Nixon ◽

Dawn Maze ◽

Eshetu G Atenafu ◽

Danielle Brandys ◽

Cindy Susan Murray ◽

...

Keyword(s):

Platelet Count ◽

Retrospective Study ◽

Acute Leukemia ◽

Intracranial Hemorrhage ◽

Platelet Transfusion ◽

Transfusion Practice ◽

Rank Test ◽

Transfusion Threshold ◽

Platelet Counts ◽

Platelet Transfusions

Abstract Background: Intracranial hemorrhage (ICH) is a common complication in acute leukemia that is associated with significant morbidity and mortality. While evidence supports prophylactic platelet transfusions at a threshold < 10 x 109/L to reduce the risk of bleeding in acute leukemia, there is little data to guide platelet transfusion practice in patients following ICH. The objectives of this study were to characterize the clinical features and outcomes of acute leukemia patients with ICH and to understand current platelet transfusion practice following ICH. Methods: This was a retrospective study conducted at a large, quaternary, academic cancer centre. We included all adult patients with a diagnosis of acute leukemia who had a documented ICH at our centre between January 1, 2009 and December 31, 2016. We assessed demographics, medications, infection and bleeding history in the week preceding ICH, characteristics of ICH including site of bleed, acute management, transfusion practice in the first 90 days, and clinical outcomes. Radiologic scans were re-assessed by neuroradiology to determine if the ICH was stable or if new or progressive bleeding had developed. Transfusion practice following the ICH was compared between the two groups with longitudinal data analysis using platelet counts as outcome. Kaplan-Meier product limit method was used to estimate overall survival (OS) rates as well as to obtain median survival; log-rank test was used to compare OS among those without new or progressive ICH vs. those with progression. Results: During the study period, of 2576 patients diagnosed with acute leukemia, 101 suffered from ICH and were included in the study. Most patients (94) had AML, of which 9 had APL, 6 had ALL, and 1 had MPAL. At the time of ICH, 61 patients were newly diagnosed or receiving induction chemotherapy, 33 had relapsed disease and 7 were in complete remission. Spontaneous ICH occurred in 76 patients. Within the week preceding ICH, 7 patients were on medications known to increase bleeding risk and 39 were on tranexamic acid. Sixty-four patients had clinical evidence of bleeding elsewhere and 22 had evidence of infection. On the day of ICH, the median platelet count was 16 x 109/L (range 0- 433 x109/L). Thirty-one patients had a platelet count < 10 x 109/L and 10 of these patients received a platelet transfusion prior to the bleed. Seventy patients had a platelet count ≥10 x109/L and 17 of these received a platelet transfusion prior to the bleed. Six patients (6%) exhibited evidence of platelet transfusion refractoriness. In the 90 days following ICH, 21% of platelet transfusions were given for a platelet count < 10 x 109/L, 55% were given with a platelet count between 10-29 x109/L, and 24% were given with a platelet count ≥ 30 x 109/L. New or progressive ICH occurred in 28 patients. The median platelet transfusion threshold was 19 x 109/L (range 0-114 x 109/L) for those without new or progressive ICH and 21 x 109/L (range 0-93 x 109/L) for those with progression (p=0.04; Figure 1). Of the 101 study patients, 79 have died. Median OS was 5.6 months for those without new or progressive ICH and 2.9 months for those with progression (p=0.002) (Figure 2). Cause of death was attributed to non-ICH causes in the majority of patients 65/79 (82%). Conclusions: In this retrospective study, we evaluated the outcomes of 101 patients with acute leukemia and ICH. At the time of the bleed, the majority of patients had active disease and more than two thirds had platelet counts of 10 x 109/L or higher. During 90 days of follow-up, nearly one third of patients developed new or progressive ICH. Platelet transfusion practice was variable and the median threshold was, in fact, higher in those who subsequently developed new or progressive bleeding. The reasons for this were unclear from our chart review, but we hypothesize that these patients may have had additional risk factors, e.g. fever, infection. The outcomes of patients with acute leukemia and ICH are poor. Factors other than platelet transfusion threshold likely contribute to secondary ICH events and the overall poor prognosis. Disclosures Maze: Novartis: Consultancy, Honoraria.

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Interim Analysis of a Prospective Randomised Study Comparing a Therapeutic Platelet Transfusion Strategy with the Prophylactic Platelet Transfusion Standard in Patients after Autologous Peripheral Stem Cell Transplantation (ASCT).

Blood ◽

10.1182/blood.v108.11.577.577 ◽

2006 ◽

Vol 108 (11) ◽

pp. 577-577 ◽

Cited By ~ 3

Author(s):

Kerstin Schaefer-Eckart ◽

Knut Wendelin ◽

Martin Wilhelm ◽

U. Mahlknecht ◽

R. Conradi ◽

...

Keyword(s):

Stem Cell ◽

Platelet Count ◽

Stem Cell Transplantation ◽

Interim Analysis ◽

Platelet Transfusion ◽

Transfusion Strategy ◽

Randomised Study ◽

Peripheral Stem Cell Transplantation ◽

Significant Difference ◽

Platelet Transfusions

Abstract We have previously shown, that a therapeutic platelet transfusion strategy is safe in patients after autologous peripheral stem cell transplantation(ASCT) and can reduce the number of platelet transfusions to about 50% compared with the prophylactic strategy (Wandt et al, BMT2006, 37, 387–392). To confirm these results, we started a randomised multicenter study in 2005 and present the results of the first planned interim analysis. In the prophylactic platelet transfusion arm (p) transfusions were given to patients if the morning platelet count was < 10/nl, while in the therapeutic transfusion arm (t) clinically stable patients (no sepsis or systemic inflammatory response syndrome II° or III° (SIRS), no invasive Aspergillosis or infection with Stenotrophomonas maltophilia) received platelet transfusions only in the case of clinically relevant bleeding. Apheresis platelets were recommended, but pooled platelet units were allowed as well. We now analysed the first 92 patients, 45 patients with a prophylactic and 47 patients with a therapeutic transfusion strategy. Both groups were well balanced according to age, gender, diagnosis and conditioning regimens. Median days of thrombocytopenia < 20/nl were 4 (0–14) in the prophylactic and 4 (0–20) in the therapeutic arm. The corresponding days regarding platelets below 10/nl were 1(p) (0–5) and 2(t) (0–14), respectively. The total number of days with thrombocytopenia <20/nl was 185 in the prophylactic arm and 239 in the therapeutic arm, resp. The number of days with a platelet count below 10/nl was 63 (p) vs. 110 (t). The number of days in hospital was 15 (p) (6–29) and 14 (t) (9–29), resp. Minor hemorrhages were observed in only 13 patients: 4 out of 45 patients in the prophylactic arm (8,9%) and 9 out of 47 patients in the therapeutic arm (19,2%). This difference was due to the protocol strategy and not significant. We observed no major clinically relevant bleedings. There was a significant difference in the number of transfused platelet units: 68 (p) vs 37 (t), (p=0,005). The median number of platelet units was 1(0–6) in the prophylactic arm and 0(0–5) in the therapeutic arm. More than 95% of the transfusions were single apheresis units. So the primary objective of the study, a reduction of platelet transfusions by 25% was reached, without significant difference in the number of major bleeding complications (secondary objective). 9 out of the 37 platelet transfusions (24%) in the therapeutic strategy arm were given because of sepsis or SIRS and in 4 out of the 37 (11%) transfusions there was no indication according to the protocol. There was a non-significant difference in the number of red blood cell transfusions: 59 (median 0, range 0–8) in the prophylactic arm versus 87 (median 2, range 0–12) in the therapeutic arm. With these first results of the randomised study we could confirm that a therapeutic platelet transfusion strategy is safe and can reduce the number of platelet transfusions by about 50%. The study will continue until 200 patients are included.

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A Therapeutic Platelet Transfusion Strategy without Routine Prophylactic Transfusion Is Feasible and Safe and Reduces Platelet Transfusion Numbers Significantly: Preliminary Analysis of a Randomized Study in Patients after High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation

Blood ◽

10.1182/blood.v112.11.286.286 ◽

2008 ◽

Vol 112 (11) ◽

pp. 286-286 ◽

Cited By ~ 5

Author(s):

Hannes Wandt ◽

Knut Wendelin ◽

Kerstin Schaefer-Eckart ◽

Markus Thalheimer ◽

Mario Stephan Schubert ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Factor ◽

Platelet Count ◽

Platelet Transfusion ◽

Additional Risk Factor ◽

Transfusion Strategy ◽

Bleeding Events ◽

Additional Risk ◽

Mucosal Bleeding ◽

Platelet Transfusions

Abstract We performed a multicenter randomized trial comparing the traditional prophylactic platelet transfusion strategy -arm P- (trigger: morning platelet count ≤ 10/nL) with an experimental therapeutic transfusion strategy -arm T- where patients (pts) received platelet transfusions only if they experienced clinically relevant bleeding (more than petechias or minimal mucosal bleeding). The morning platelet count was no trigger in arm T for transfusion as well as fever per se. Fever was no additional risk factor for bleeding in thrombocytopenic pts treated with our therapeutic transfusion strategy as published recently. (Wandt, H et al. Bone Marrow Transplant2006; 37:387–392) For safety reasons prophylactic transfusion was recommended in arm T, however, for pts with invasive aspergillosis, sepsis syndrome and unexpected headache. Randomisation was stratified according to age (<50 years), sex and center. Different diagnoses (multiple myeloma, non Hodgkin’s lymphoma, Hodgkin’s disease, acute leukemia) were well balanced between both arms. One hundred seventy one consecutive pts with a median of 56 years (19–68) who signed informed consent were included in the study. Primary objective was a reduction of platelet transfusions of 15–25%; secondary objectives were safety, duration of leuko- and thrombocytopenia, hospitalisation, and numbers of red blood cell transfusion. Red blood cells should be transfused when hemoglobin level dropped below 8 g/dL or as clinically indicated. Results: Platelet transfusions could be reduced significantly by 27% in arm T compared with arm P (p0.004). In arm T 46% of pts did not need any platelet transfusion and this was more than the double compared to arm P (0.001). Between younger and older pts there was no difference in numbers of platelet transfusions needed. Overall, adherence to the protocol was good. Since clinically relevant bleeding (more than petechias and minimal mucosal bleeding) was the trigger for platelet transfusion in arm T consequently more such hemorrhages occured in arm T (28.7% vs 9.5%). No life threatening or fatal bleeding was registered. Hemorrhages were mainly (21.8%) epistaxis or mucosal, 6.9% were minor bleedings (e.g. vaginal, hematochezia, hemoptysis, hematuria). One pt with sudden headache had a minor cerebral hemorrhage (subarachnoid) documented by ct-scan without any clinical sequelae. Days with hemorrhage overall were rare but significantly increased in arm T (0.69 vs 0.17 days per pt). Age was no risk factor for bleeding. As already expected by our former experience we could show that fever and infection were no additional risk factor for bleeding in arm T compared with arm P despite the very stringent platelet transfusion strategy in the experimental transfusion arm. In pts with multiple myeloma bleeding events were very rare compared to other diagnoses (p <0.0001). Numbers of red blood cell units were not significantly different between the two arms, as well as the duration of leukocytopenia and hospitalisation. In contrast duration of thrombocytopenia <20/nL was significantly longer in arm T (median 5 vs 3 days; p 0.004) as expected. We conclude that our therapeutic platelet transfusion strategy is cost effective and safe in pts after autologous stem cell transplantation. Despite more minor hemorrhages in the experimental arm compared with the traditional prophylactic strategy all bleeding events could be safely controlled by consecutive platelet transfusion. Development of major bleeding could be prevented by the therapeutic transfusion strategy according to our protocol.

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Perioperative Coagulation Management and Control of Platelet Transfusion by Point-of-Care Platelet Function Analysis

Transfusion Medicine and Hemotherapy ◽

10.1159/000109642 ◽

2007 ◽

Vol 34 (6) ◽

pp. 396-411 ◽

Cited By ~ 58

Author(s):

Klaus Görlinger ◽

Csilla Jambor ◽

Alexander A. Hanke ◽

Daniel Dirkmann ◽

Michael Adamzik ◽

...

Keyword(s):

Platelet Function ◽

Platelet Transfusion ◽

Function Analysis ◽

Point Of Care ◽

Coagulation Management ◽

And Control

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Routine Prophylactic Platelet Transfusions Are Not Necessary in Patients with Acute Myeloid Leukemia - A Therapeutic Transfusion Strategy Is Safe and Cost Effective.

Blood ◽

10.1182/blood.v106.11.428.428 ◽

2005 ◽

Vol 106 (11) ◽

pp. 428-428 ◽

Cited By ~ 6

Author(s):

Hannes Wandt ◽

Markus Frank ◽

Kerstin Schaefer-Eckart ◽

Martin Wilhelm

Keyword(s):

Platelet Count ◽

Myeloid Leukemia ◽

Platelet Transfusion ◽

Transfusion Strategy ◽

Consolidation Chemotherapy ◽

Bleeding Events ◽

Who Grade ◽

Transfusion Protocol ◽

Acute Myeloid ◽

Platelet Transfusions

Abstract During the last three years 60 patients with newly diagnosed acute myeloid leukemia (except FAB M3) were included in a therapeutic platelet transfusion protocol for a total of 101 cycles of intensive chemotherapy. All pts. without major bleeding during induction chemotherapy were included. The start of the new platelet transfusion protocol was the day after induction or day 1 of consolidation chemotherapy. Therapeutic platelet transfusions (apheresis single donor platelets) were given in case of bleeding (more than petechial) or when retinal bleeding with deterioration of vision occured. Routine prophylactic platelet transfusions were not given regardless of the morning platelet count. Platelet transfusions should only be given prophylactically (platelet count < 10/nl) when fever > 38.5 °C, fungal pneumonia, plasmatic coagulation disorders or when major unexspected headache occured. When diagnostic biopsies were planed the platelet count should be > 20/nl. The use of Aspirin and nonsteroidal antirheumatic agents were avoided. Pts. received 74 cycles of induction chemotherapy (D 45–60 mg/m2 x 3 and AraC 100 mg/m2 c.i. x 7 or Mitoxantrone 10mg/ m2 x 5, AraC 100mg/m2 x 8, Etoposide 100mg/ m2 x 5) and 27 cycles of consolidation therapy (high dose AraC 1–3 g/m2 every 12 hours for 5–6 days in combination with Mitoxantrone or m-Amsa). Median age was 51 (17–72) years and 67% obtained a complete remission. Median duration of thrombocytopenia <20 and <10/nl was 8 and 5 (0–63) days resulting in a total of 1066 and 758 days of severe thrombocytopenia, respectively. Median platelet count before major bleeding events was 8.9/nl (4–18). Maximal bleeding WHO grade II and III was documented in 36% and 6% of all 101 chemotherapy cycles. Life threatening bleeding WHO grade IV was not observed. This incidence of bleeding events compares favorably with published data with the standard prophylactic platelet transfusion strategy. Therapeutic transfusions were mainly necessary (84%) for gastrointestinal hemorrhages (25%), epistaxis (21%), increasing hematoma (21%), stomatitis (17%). Main indications for prophylactic transfusions were fever (64%), diagnostic interventions (13%) and fungal pneumonia (12%). We did not see an increased incidence of bleeding events during fever episodes. Therefore pts. with fever who are clinically stable and without bleeding signs should not be routinely transfused when the platelet count is below 10/nl. The mean and median number of apheresis platelet transfusions per chemotherapy cycle was only 3 and 2 (range 0–21), respectively. Conclusion: The proposed therapeutic platelet transfusion strategy in this pilot study is safe in AML pts. during induction and consolidation chemotherapy. Compared with historical controls (Wandt H et al. Blood.1998; 91:3601) the number of transfusions can be reduced by about 50%. Fever per se must not be a trigger for prophylactic platelet transfusion in future studies. A prospective randomized study is therefore now in Germany in progress comparing the standard routine prophylactic with the new therapeutic platelet transfusion strategy.

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Experience with a Therapeutic Platelet Transfusion Strategy in Acute Myeloid Leukemia: Preliminary Results of a Randomized Multicenter Study After Enrolment of 175 Patients.

Blood ◽

10.1182/blood.v114.22.20.20 ◽

2009 ◽

Vol 114 (22) ◽

pp. 20-20

Author(s):

Hannes Wandt ◽

Kerstin Schaefer-Eckart ◽

Bettina Pilz ◽

Markus Thalheimer ◽

Anthony D Ho ◽

...

Keyword(s):

Ct Scan ◽

Myeloid Leukemia ◽

Platelet Transfusion ◽

Bleeding Complications ◽

Intensive Chemotherapy ◽

Transfusion Strategy ◽

Cerebral Bleeding ◽

Experimental Strategy ◽

Red Blood Cell Transfusions ◽

Platelet Transfusions

Abstract Abstract 20 Introduction We have shown in a monocenter study (ASH 2005, abstract # 428) that routine prophylactic platelet (plt) transfusions are not necessary in patients (pts) with acute myeloid leukemia (AML). Therefore, we started a multicenter randomized study comparing the routine prophylactic (morning trigger: plts ≤ 10/nl, arm P) with a therapeutic platelet transfusion strategy (arm T). Methods Diagnosis of AML and feasability of intensive chemotherapy within standard protocols was required (M3 only in CR). In arm T transfusions were given only when clinically relevant bleeding (more than petechiae) happened regardless of the morning plt count. For safety reasons prophalyctic plts were transfused in case of invasive aspergillosis, sepsis syndrom and repeated or continous headache. In case of headache pts in arm T received a ct-scan. The experimental transfusion strategy startet at day 8 of induction and at day 1 of consolidation. Primary endpoint was the reduction of plt transfusions by 20%; secondary endpoints were bleeding complications, red blood cell transfusions, side effects, duration of thrombocytopenia and hospital stay. Results Until July 2009 175 pts have been randomized. Full data were evaluable for 161 pts (79 arm P and 82 arm T). Median age was 52 years (20-78). We registered 251 induction and 112 consolidation cycles. Mean duration of thrombocytopenia (<20/nl or <10/nl) was 17 and 8 days, respectively. Duration of thrombocytopenia was significantly longer in arm T. Depite the longer duration, the number of platelet transfusions in arm T was significantly reduced, by about 25% (p <0.001). Number of red blood cell transfusions were not different (p = 0.95). Days in hospital and side effects were not different in both groups. Bleeding complications (more than petechial) were significantly increased in arm T showing a 2.3 times higher risk compared to arm P. This is clearly correlated with bleeding being the trigger for plt transfusion in arm T. Majority of hemorrhages were of minor or moderate significance that could all be treated effectively by plt transfusion. Most important was the observation that we registered 5 minor and 2 major cerebral hemorrhages in arm T and none in arm P. Minor cerebral hemorrhages with headache were not registered in arm P since we did not perform ct-scans routinely in arm P in case of headache. Minor cerebral complications were 2 sub-/epidural bleedings after vasovagal collapses of pts at plt counts of 53 and 96/nl, respectively, and 3 spontanuous minor subarachnidal/ intracerebral hemorrhages at plt counts of between 15 and <5/nl. All 5 minor cerebral complications were detected by ct-scan performed due to headache. All pts recovered after plt transfusion without any sequelae.The two other pts died following fatal cerebral bleeding. One pt. had repeated headache since several days. At a plt count of 11/nl fatal bleeding happened. A ct-scan revealed intracerebral mass bleeding. The pt was randomized to the experimental strategy but even following standard transfusion strategy the pt would not have been transfused prophylactically. The only fatal cerebral bleeding that must be clearly attributed to the therapeutic strategy was a female pt with a pulmonary fungal infection that improved under antifungal treatment. She had a morning platelet count of <5/nl. During the following night she woke up with severe headache. Despite timely platelet transfusions she died of progressive mass bleeding. Unfortunately, we could not perform an autopsy to see whether the patient had fungal involvement of the brain. 1-2 % of fatal cerebral bleedings are reported in AML trials despite a prophylactic strategy. Whether these two complications happened by chance in arm T or were the consequence of the experimental strategy cannot be answered by our study. To give proof of this important question one would need about 2000 pts in both arms for statistical reasons. Conclusions A therapeutic platelet transfusion strategy according to our protocol is feasible in AML pts during intensive chemotherapy and can reduce the number of platelet transfusions significantly. An increased risk of fatal cerebral bleeding cannot be excluded by this study. An international collaboration would be necessary to set up a study large enough to determine the final safety. Disclosures: No relevant conflicts of interest to declare.

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The Use of Recombinant Factor VIIa (NovoSeven®) in a Patient with Bernard Soulier Syndrome and Dental Extraction.

Blood ◽

10.1182/blood.v108.11.3961.3961 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3961-3961

Author(s):

Andrea Gerhardt ◽

Rudiger E. Scharf ◽

Rainer B. Zotz

Keyword(s):

Tranexamic Acid ◽

Platelet Function ◽

Platelet Transfusion ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Dental Extraction ◽

Giant Platelets ◽

Bleeding Episodes ◽

Bernard Soulier Syndrome ◽

Platelet Transfusions

Abstract Background: Bernard Soulier syndrome is a rare autosomal recessive platelet function disorder that impairs platelet adhesion to von Willebrand factor, especially at high shear flow. The disorder results from partial to complete deficiency or dysfunction of the GP Ib-IX-V receptor. Bernard Soulier syndrome typically results in prolonged bleeding time, thrombocytopenia, and giant platelets. The main clinical symptoms, evident from early childhood, include frequent episodes of epistaxis and hemorrhage associated with mucocutaneous bleeding or trauma. Specific treatment of bleeding episodes or prophylaxis for the prevention of bleeding during surgical procedures are platelet transfusions. This treatment option is not devoid of complications. Alloimmunization by HLA antigens and antibody formation to the GPIb-IX-V complex frequently occur and, thus limit future responses to platelet transfusions. Recent patient studies have suggested that recombinant factor VIIa (rVIIa, NovoSeven®) may be an effective therapy for treatment of bleeding in patients with congenital platelet function defects and other acquired platelet disorders, including thrombocytopenia. Case Reports: We report on our experience with rFVIIa in a 21-year-old woman with Bernard Soulier syndrome and dental extraction (2 wisdom teeth). In 2000, after a first extraction of one wisdom tooth, that was covered by administration of DDAVP and platelet transfusion, a bleeding episode occurred, requiring resurgery. This time rFVIIa was used as first line therapy. An initial dose of rFVIIa (100 μg/kg/bw) was administered 15 min. prior to surgery, followed by two doses of 90 μg/kg/bw at 120 min intervals postoperatively. In the first three days after surgery, 90μg/kg/bw rFVIIa were administered every 12 hrs. Tranexamic acid (Cyklokapron® 3 x 1 g/d) was started postoperatively and continued for 10 days. There were no postoperative bleeding episodes and no platelet transfusion was required. In conclusion, rFVIIa in combination with tranexamic acid appears to be an effective and safe therapeutic alternative for prophylaxis of bleeding episodes in dental extraction in patients with Bernard Soulier syndrome.

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Subcutaneous Preadipocytes Are Ideal Candidate To Produce A Large Number Of Functional Platelets In a Culture System

Blood ◽

10.1182/blood.v122.21.3271.3271 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3271-3271

Author(s):

Yukako Ono-Uruga ◽

Tatsuya Tanaka ◽

Atsuko Igari ◽

Takanori Moriki ◽

Kenji Yokoyama ◽

...

Keyword(s):

Stem Cells ◽

Platelet Function ◽

Platelet Transfusion ◽

Thrombus Formation ◽

Severe Thrombocytopenia ◽

Hematopoietic Stem ◽

Ideal Candidate ◽

Pai 1 ◽

Platelet Transfusions

Abstract Platelet transfusions are widely used for patients with severe thrombocytopenia. There are, however, practical problems in the current donor-dependent platelet transfusions, such as the limited supply and risk of serious immune reactions. Thus, the development of new strategies for generating platelets for transfusion is crucial. Platelets have been differentiated from hematopoietic stem cells, fetal liver cells, embryonic stem cells, induced pluripotent stem cells, NF-E2-transduced fibroblasts, and preadipocytes. Here, among these cells preadipocytes, especially in the subcutaneous adipose tissue, could be ideal candidate cells for manufacturing megakaryocytes (MKs) and platelets, because (1) they are relatively easy to obtain large quantities and have ability to proliferate in vitro, (2) their differentiation does not require gene transfer, as they possess genes in relation to megakaryopoiesis and thrombopoiesis, such as p45NF-E2 and c-mpl, and (3) they differentiate into MKs and platelets using an endogenous thrombopoietin. Thus, to clarify the usefulness of preadipocytes as a donor-independent source for platelet transfusion, we compared both number and function between platelets derived from mouse subcutaneous preadipocytes and those from bone marrow mononuclear cells (BMMNCs), the established cell source for manufacturing platelets. First, BMMNCs were not feasible for their expansion in vitro and therefore the cells were directly seeded in MK lineage induction media. In contrast, preadipocytes were to be passaged 6 times without any morphological changes, and then cultured in MK lineage induction media for their differentiation into platelets. Thus, as assessed by CD41-positive platelet-sized cells, 106.2±5.0 ×105 or 3.9±1.0 ×105 platelets were obtained from 106 preadipocytes or 106 BMMNCs, respectively (p<0.01). To next analyze platelet function, the binding of Alexa Fluor 488-labaled fibrinogen to CD41-positive platelet-sized cells, as assessed by mean fluorescence, was analyzed in the presence of ADP/PAR4-activating peptide, and the binding was higher in preadipocyte-derived platelets (14.0±1.5) than in BMMNC-derived platelets (7.0±1.3, p=0.017). Furthermore, to examine the incorporation of these platelets into a thrombus under flow conditions, we performed the quantitative evaluation of the cells in the thrombus formation process using the Total Thrombus-formation Analysis System (T-TAS®) (Blood 2012; 120: 3812). We used platelets released from each preadipocyte- and BMMNC-derived MKs in vivo. Briefly, MK-sized cells were obtained by a 2-step BSA gradient, labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE) and then infused into irradiated thrombocytopenic mice (7 days after exposure to 2.0 Gy). After 90 min of infusion, whole blood samples were obtained from these mice and were shown to contain similar number of CFSE+/CD41+ platelet-sized cells; 1.8±0.4 ×104 for preadipocyte-derived cells and 1.9±0.2 ×104 for BMMNC-derived cells (p=0.9135). Subsequently, the samples were perfused on a collagen-coated chip, followed by assessment using T-TAS®, and the result showed that the frequency of incorporation of the cells into the thrombus formation was higher for preadipocyte-derived cells (77.8±5.1%) than for BMMNC-derived cells (52.5±5.3%, p=0.0257). And we also found that the frequencies were similar when 3-fold amounts of BMMNC-derived cells were used in this perfusion study. Here our microarray analyses showed that plasminogen activator inhibitor-1 (PAI-1), a well-known enhancer for platelet function, was secreted into the supernatant during MK differentiation process. Therefore, to elucidate the possibility that PAI-1 is associated with the findings as described above, the levels of PAI-1 in the supernatant were measured on Day 4 during MK differentiation, and were shown to be 3.3±0.1 ng/mL or 0.09±0.01 ng/mL for preadipocyte- or BMMNC-derived cells, respectively. Together, our findings provided the first evidence showing that preadipocytes produce a greater number of platelets than BMMNCs and their derived platelets also have more useful physiological function than BMMNC-derived platelets, allowing for the usage of fewer platelets in platelet transfusion. Disclosures: No relevant conflicts of interest to declare.

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