Ex Vivo Manufacture of Megakaryocytes and Platelets from Stem Cells: Recent Advances Toward Transfusion in Humans.

The generation of ex vivo functional megakaryocytes (MK) and platelets is an important issue in transfusion medicine as donor dependence implies in limitations, such as shortage of eligible volunteers. Indeed, platelet transfusion is still a procedure that saves the lives of patients with defective platelet production. Recent technological development has enabled the isolation and expansion of stem cells that can be used as a source for the production of functional platelets for transfusion. In this review, we discuss recent approaches of in vitro or ex vivo production of MK and platelets, suggesting that, in the near future, donor-independent sources may become a possibility. The feasibility of using these cells in the clinic may be safer, and in vitro manipulation could generate universally compatible products, solving problems related to platelet refractoriness. However, functionality and survival testing of these products in human beings are scarce; therefore, additional studies are needed to consolidate this purpose.

Thrombocytopenia and the effect of platelet transfusions on the occurrence of intracranial hemorrhage in patients with acute leukemia - a nested case-control study.

We designed a study to describe the incidence of intracranial hemorrhage according to severity and duration of thrombocytopenia and to quantify the associations of platelet transfusions with intracranial hemorrhage in patients with acute leukemia. In this case-control study nested in a cohort of 859 leukemia patients, cases (n = 17) were patients diagnosed with intracranial hemorrhage who were matched with control patients (n = 55). We documented platelet counts and transfusions for seven days before the intracranial hemorrhage in cases and in a "matched" week for control patients. Three measures of platelet count exposure were assessed in four potentially important time periods before hemorrhage. Among these leukemia patients, we observed the cumulative incidence of intracranial hemorrhage of 3.5%. Low platelet counts were, especially in the three to seven days preceding intracranial hemorrhage, associated with the incidence of intracranial hemorrhage, although with wide confidence intervals. Platelet transfusions during the week preceding the hemorrhage were associated with higher incidences of intracranial hemorrhage; rate ratios (95% confidence interval) for one or two platelet transfusions and for more than two transfusions compared with none were 4.04 (0.73 to 22.27) and 8.91 (1.53 to 51.73) respectively. Thus, among acute leukemia patients, the risk of intracranial hemorrhage was higher among patients with low platelet counts and after receiving more platelet transfusions. Especially, the latter is likely due to clinical factors leading to increased transfusion needs.

Frozen Platelets-Development and Future Directions.

Storage requirements and outdating of platelets represent a continued challenge for blood banks. These hurdles are confounded for rural area hospitals or in military deployments. Over 60 years of research and development into frozen platelets have generated a stable and reproducible product. Valeri's method to freeze platelets in 6% dimethyl sulfoxide (DMSO) and storage at -80°C allows for long-term storage alleviating burdens placed on blood banks. Clinical studies show that frozen platelet transfusions are safe with no related thrombotic or other serious adverse events. There are ongoing efforts to demonstrate cryopreserved platelet (CPP) superiority in efficacy studies designed in trauma or cardiac surgery patients. Technical advances in CPP manufacturing including closed system manufacturing, applications of pathogen reduction technology and potency standard characterization add to the appeal of CPP as an alternative to traditional liquid-stored platelets (LP) in settings of supply shortages, mass casualty, active bleeding, rapid provision of HLA-compatible platelets, and remote care.

Evolution of perioperative blood transfusion practice after coronary artery bypass grafting in the past two decades.

BACKGROUND AND AIM OF THE STUDY: Transfusion of blood products after coronary artery bypass grafting (CABG) is associated with increased morbidity and mortality. We evaluated the perioperative use of blood products in patients undergoing CABG in our institution over the past two decades. METHODS: The study included 18 992 patients who underwent isolated CABG at our hospital between 1998 and 2017. Baseline characteristics of patients and the number of perioperative transfusions during their hospital stay (including red blood cells [RBCs], platelets, and fresh frozen plasma [FFP]) were assessed. Logistic regression models were used to identify risk factors for perioperative transfusion. RESULTS: The rates of perioperative RBC transfusion decreased for all patients undergoing isolated CABG (52.1% in 1998 vs 18.6% in 2017) in our institution. The mean number of transfused RBC units was significantly higher in women than in men (1.57 ± 2.2 vs 0.68 ± 1.84; P < .005); this difference remained significant over the years. After adjusting the results for other risk factors, female sex was a significant independent risk factor for perioperative RBC transfusion. The platelet transfusion rate increased over the past two decades (1.4% in 1998 vs 9.7% in 2017). The number of FFP transfusions remained unchanged. CONCLUSIONS: Over the past two decades, we observed a decrease in the incidence of perioperative RBC transfusions in patients undergoing isolated CABG, whereas platelet transfusions increased. Female sex was an independent predictor of perioperative RBC transfusion.

Transfusion Medicine Equations Made Internet Accessible.

Multiple mathematical equations inform the practice of transfusion medicine. These equations apply to a wide range of topics: dosage of blood products, calculation of fluid volumes, and even specific treatment decisions (e.g. corrected count increment for determination of platelet refractoriness). The calculation of these equations can be complicated, prone to error, and time-consuming. A trusted source is needed to accurately perform these calculations 24 hours a day without error and without monetary cost. We sought to build internet-enabled calculators relevant to the practice of transfusion medicine. We partnered with MDCalc, an online host of medical calculators with 1 million monthly users in 196 countries, to design and host the calculators. The calculators guide users in the application of transfusion medicine equations by providing indications for use, inputs for the equations variables, error-checking, warnings for bad inputs, and interpretive guidance of the result. The following calculators were built: blood volume, corrected count increment (CCI), plasma dosage, cryoprecipitated antihemophilic factor dosage, approximate number of units for compatibility testing, maternal-fetal hemorrhage Rh(D) immune globulin dosage, intrauterine RBC transfusion dosage, neonatal polycythemia partial exchange, theoretical removal of a substance by plasmapheresis, sickle cell RBC exchange volume, peripheral blood stem cell collection, and a calculator relevant to donor lymphocyte infusion. Clinicians can now utilize this reputable and highly visible online source to access these common transfusion medicine equations at any time with an internet-enabled device (https://www.mdcalc.com/search?filter=transfusion+medicine).

Future of platelet formulations with improved clotting profile: a short review on human safety and efficacy data.

BACKGROUND: Platelet (PLT) transfusion is a widely used therapy in treating or preventing bleeding and hemorrhage in patients with thrombocytopenia or trauma. Compared to the relative ease of PLT transfusion, current practice for PLT storage at room temperature (RT) for up to 5 to 7 days is inefficient, costly, wasteful, and relatively unsafe. STUDY DESIGN AND METHODS: This study was a review of major advances in PLT derivative products with improved hemostatic potential and safety feature. RESULTS: Recent progress in understanding the PLT activation and host clearance mechanisms has led to reassessments of current and new storage conditions that employ refrigeration and/or cryopreservation to overcome storage lesions and significantly extend shelf life of PLTs with reduced risk of pathogen contamination. DISCUSSION: It is anticipated that future PLT preservation involving cold, frozen, and/or pathogen reduction strategies in proper PLT additive solutions will enable longer term and safer PLT storage.

Trends in transfusion practice over 20 years in paediatric liver transplant programme.

BACKGROUND: We investigated changes to transfusion practices over time in paediatric liver transplant centre and evaluated the effect of transfusion practice to mortality. METHODS: A pilot retrospective study included two cohorts each with 101 sequential paediatric LT recipients: an Early group (1994-1998) and a Recent group (2009-2013). Demographic characteristics and data on the intraoperative transfusion of red blood cells (RBC), fresh-frozen plasma (FFP), platelets and cryoprecipitate were collected. Postoperative laboratory results were also obtained, together with donor and data regarding 1- and 5-year survival. Appropriate intergroup comparisons, univariate and multivariate analysis were made and P ≤ 0·05 was considered statistically significant. RESULTS: There were no significant group differences in demographic data (except patient height). Despite the fact that median total blood loss did not differ between groups (111 ml/kg in both groups), the Early group had greater levels of intraoperative RBC transfusion (75 vs. 59 ml/kg, respectively, P = 0·04) and less use of FFP (53 vs. 62 ml/kg, respectively, P = 0·01). Overall we noted a lower 1- and 5-year survival in the Early group (88·2% vs. 96%, P = 0·04 and 82·4% vs. 89·1%, P = 0·01, respectively). Univariate, but not multivariate regression analyses demonstrated that higher PELD score, RBC and FFP transfusion, and inclusion in the Early group were contributing factors to 1-year higher mortality. CONCLUSIONS: This retrospective analysis of blood loss and replacement in paediatric LT patients demonstrates that the majority of our patients suffer major haemorrhage and require large-volume RBC and FFP replacements. In our pilot study, large volume of RBC and FFP replacement did not contribute to mortality. Paediatric LT involves a number of multidisciplinary teams. Thus, all care-related factors and combinations thereof that may contribute to outcome and should be evaluated in the future.

Variation in Platelet Transfusion Practices in Cardiac Surgery.

OBJECTIVE: Although the morbidity associated with red blood cell transfusion in cardiac surgery has been well described, the impacts of platelet transfusion are less clearly understood. Given the conflicting results of prior studies, we sought to investigate the impact of platelet transfusion on outcomes after cardiac surgery across institutions in Maryland. METHODS: Using a multiinstitutional statewide database created by the Maryland Cardiac Surgery Quality Initiative, we retrospectively analyzed data from 10,478 patients undergoing isolated coronary artery bypass across 10 centers. Platelet transfusion practices were compared between institutions. Multivariate logistic regression model was used to analyze the association between platelet transfusion and 30-day mortality and postoperative complications. RESULTS: Rates of platelet transfusion varied between institutions from 4.4% to 24.7% ( P < 0.001), a difference that remained statistically significant in propensity score-matched cohorts. Among patients on preoperative antiplatelet therapy, transfusion rates varied from 8.5% to 46.4% ( P < 0.001). There was no statistically significant relationship between case volume and transfusion rates ( P = 0.815). In multivariate logistic regression, platelet transfusion was associated with increased risk of 30-day mortality (OR 2.43, P = 0.008), postoperative pneumonia (OR 2.21, P = 0.004), prolonged intubation (OR 2.05, P < 0.001), and readmission (OR 1.43, P = 0.039). CONCLUSIONS: Significant variation existed in platelet transfusion rates between institutions, even after controlling for various risk factors. This variation may be associated with increased mortality and length of stay. Further study is warranted to better understand risks associated with platelet transfusion. Standardizing practice may help reduce risk and conserve resources.

Prophylactic Platelet Transfusions for Critically Ill Patients With Thrombocytopenia: A Single-Institution Propensity-Matched Cohort Study.

BACKGROUND: Thrombocytopenia is frequently encountered in critically ill patients, often resulting in prophylactic transfusion of platelets for the prevention of bleeding complications. However, the efficacy of this practice remains unclear. The objective of this study was to determine the relationship between prophylactic platelet transfusion and bleeding complications in critically ill patients. METHODS: This is a retrospective cohort study of adults admitted to surgical, medical, or combined medical-surgical intensive care units (ICUs) at a single academic institution between January 1, 2009, and December 31, 2013. Inclusion criteria included age ≥18 years and a platelet count measured during ICU admission. Propensity-matched analyses were used to evaluate associations between prophylactic platelet transfusions and the outcomes of interest with a primary outcome of red blood cell transfusion in the ensuing 24 hours and secondary outcomes of ICU and hospital-free days and changes in sequential organ failure assessment scores. RESULTS: A total of 40,693 patients were included in the investigation with 3227 (7.9%) receiving a platelet transfusion and 1065 (33.0%) for which platelet transfusion was prophylactic in nature. In propensity-matched analyses, 994 patients with prophylactic platelet transfusion were matched to those without a transfusion. Patients receiving prophylactic platelets had significantly higher red blood cell transfusion rates (odds ratio 7.5 [5.9-9.5]; P < .001), fewer ICU-free days (mean [standard deviation] 20.8 [9.1] vs 22.7 [8.3] days; P = .004), fewer hospital-free days (13.0 [9.7] vs 15.8 [9.4] days; P < .001), and less improvement in sequential organ failure assessment scores (mean decrease of 0.2 [3.6] vs 1.8 [3.3]; P < .001) in the subsequent 24 hours. These findings appeared robust, persisting in multiple predefined sensitivity analyses. CONCLUSIONS: Prophylactic administration of platelets in the critically ill was not associated with improved clinical outcomes, though residual confounding may exist. Further investigation of platelet transfusion strategies in this population is warranted.

Hemorrhagic Complications of External Ventriculostomy in the Aspirin and P2Y12 Response Assay Era.

OBJECTIVE: Hemorrhagic complications reported from external ventricular drain (EVD) placement range from 10% to 44%. There remains limited literature investigating the incidence, risk factors, and mechanisms to prevent its occurrence, especially in the setting of antiplatelet agent use. We investigated EVD-related hemorrhagic complications after the implementation of VerifyNow platelet inhibition assays at our institution. METHODS: Medical records from 445 patients requiring EVD placement during a 2-year period during which our institution used the assays were reviewed. In total 345 patients were included, and 208 of them underwent assay testing. Indications for EVD included complications of cerebrovascular disease (n = 215), traumatic brain injury (n = 74), primary hydrocephalus (n = 23), and tumor (n = 33). Hemorrhage was defined as any new area of hyperdensity adjacent to or immediately along the catheter trajectory on computed tomography. RESULTS: There was no significant decrease in catheter-induced hemorrhage (CIH) between patients who underwent the VerifyNow assay and those who did not. Platelet transfusion did not significantly decrease the risk of CIH. CIH occurred in 17.7% of patients, significantly decreased when compared with our previously published incidence of 33% before platelet inhibition assay use (P < 0.05). Patients with cerebrovascular disease complications exhibited a significant decrease in CIH, 20% versus 39%, before assay use (P < 0.01). CONCLUSIONS: The incidence of hemorrhage is lower in our new cohort when compared with that of our previously published cohort. Despite the overall decreased rate of hemorrhage, there was no significant difference in hemorrhage rates between patients who did or did not undergo the assay. Platelet transfusion did not decrease the incidence of hemorrhage in patients with inhibited platelet function.

Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures.

BACKGROUND & AIMS: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. METHODS: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/µL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/µL or more with an increase of 20,000/µL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. RESULTS: The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/µL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/µL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/µL or more). CONCLUSION: In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

Long-term audit of platelet consumption in a university hospital.

OBJECTIVES: To determine the long-term trend in platelet consumption in a university hospital. MATERIALS AND METHODS: The annual consumption of platelets concentrate (PC) was analyzed over 23 years (1985-2007) in King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. RESULTS: The total 23 years consumption was 100,466 units of PC. Consumption went through 3 phases: the first, 1985-1994: the annual consumption increased from 1706 to 5912 which coincided with the increase in the number of patient admissions; the second, 1994-2003:featured a remarkable drop (48.9%) in annual consumption while patient admission remained stable. There was a concurrent decline in platelet consumption and all-cause mortality/patient. Third phase: 2003-2007, the consumption increased to reach 5642 units/year in 2007. The Department of Medicine consumed (52%), followed by Pediatrics (21%), and General Surgery (16%). CONCLUSION: This audit uncovered evidence of inappropriate platelet consumption that reached 48.9% in the period 1994 to 2003, which coincided with widely publicized HIV scare that dominated blood transfusion during that period. We also found evidence suggesting that reducing platelet transfusion could improve patient outcome.

Research Progress of Platelet Transfusion in China.

Platelet products have been increasingly used for more than 50 years. Platelet transfusion is effective for correcting bleeding caused by thrombocytopenia and platelet function defects. In this review, we will outline research on platelet transfusion in China including platelet biosafety, cryopreservation of platelets, the assessment of the effectiveness of platelet transfusion, the causes of platelet transfusion refractoriness including immunization against CD36, and neonatal alloimmune thrombocytopenia.

Red cell and platelet transfusions in neonates: a population-based study.

OBJECTIVES: This study aimed to describe the use of red cells, platelets and exchange transfusions among all neonates in a population cohort, to examine trends in transfusion over time and to determine transfusion rates in at-risk neonates. DESIGN: Linked population-based birth and hospital data from New South Wales (NSW), Australia, were used to determine rates of blood product transfusion in the first 28 days of life. The study included all live births ≥23 weeks' gestation in NSW between 2001 and 2011. RESULTS: Between 2001 and 2011, 5326 of 989 491 live born neonates received a red cell, platelet or exchange transfusion (5.4/1000 births). Transfusion rates were 4.8 per 1000 for red cells, 1.3 per 1000 for platelets and 0.3 per 1000 for exchange transfusion. Overall transfusion rate remained constant from 2001 to 2011 (p=0.27). Among transfused neonates, 60% were <32 weeks' gestation (n=3210, 331/1000 births), 40% were ≥32 weeks' gestation (n= 2116, 2/1000 births) and 7% received transfusions in a hospital without a neonatal intensive care unit (NICU). Factors other than prematurity associated with higher transfusion rates were prior in utero transfusion (631/1000), congenital anomaly requiring surgery (440/1000) and haemolytic disorder (106/1000). CONCLUSIONS: In this population-based study, preterm neonates had a higher rate of transfusion than term neonates; however, 40% of those who received a transfusion were born ≥32 weeks' gestation and 7% were transfused in hospitals without an NICU. These findings need to be considered by transfusion services and personnel developing neonatal transfusion guidelines.

Risk of bleeding and use of platelet transfusions in patients with hematologic malignancies: recurrent event analysis.

A recent randomized trial (TOPPS) compared prophylactic platelet transfusions (for counts <10×10(9)/L) with a strategy of no-prophylaxis in adults with hematologic malignancies. Seventy percent of enrolled patients received an autologous hematopoietic stem cell transplant. Statistical models were developed to explore which patient factors or clinical characteristics are important prognostic factors for bleeding. These models were presented for baseline characteristics and for recurrent analysis of bleeding to assess the risks of World Health Organization grade 2-4 bleeding on any given day. Additional analyses explored the importance of fever. Treatment plan (chemotherapy/allogeneic hematopoietic stem cell transplant), female sex, and treatment arm (no-prophylaxis) were significantly associated with an increased number of days of bleeding. The number of days with a platelet count <10×109/L was significantly associated with a grade 2-4 bleed (P<0.0001). Patients with a temperature of at least 38°C had the highest hazard of a grade 2-4 bleed (hazard ratio: 1.7, 95% confidence interval: 1.3 to 2.4, compared with the risk in patients with a temperature <37.5°C). There was no evidence that minor bleeding predicted a grade 2-4 bleed. The results highlighted the limited role of correction of thrombocytopenia by platelet transfusion in reducing the risk of bleeding. Clinically stable patients undergoing autologous hematopoietic stem cell transplantation had the lowest risk of bleeding and benefited least from prophylactic platelet transfusions. Prospective studies are required to address the usefulness of risk factors to support better targeted platelet transfusions. TOPPS Controlled-Trials.com number ISRCTN08758735.