Patients with hematologic malignancies frequently become thrombocytopenic as a result of their underlying malignancy or treatments, including cytotoxic chemotherapy and hematopoietic stem cell transplantation and are at increased risk of hemorrhage. Prophylactic platelet transfusions are aimed at preventing severe or life-threatening hemorrhage. This review summarizes recent evidence, including the need for prophylactic platelet transfusions, the optimal dose, platelet transfusion triggers, and risk factors for bleeding. It also discusses controversies surrounding platelet transfusions in this population.
Key points
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A uniform prophylactic platelet transfusion strategy for all patients with thrombocytopenia is not appropriate.
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Patients may have significant bleeding at platelet counts of greater than 10 × 10 9 /L and should be assessed and managed on clinical grounds, not platelet count alone.
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Platelet count is not the only factor that contributes to a patient’s propensity to bleed.
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Patients with acute leukemia should receive prophylactic platelet transfusions when their platelet count is less than 10 × 10 9 /L to prevent clinical bleeding.
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Greater consistency in the assessment and documentation of bleeding across transfusion trials is essential to support comparisons of outcomes between studies.
Introduction
Duke reported the first description of bleeding in the setting of thrombocytopenia, which improved after blood transfusion and recurred when the platelet count decreased. Up to 70% of patients with hematologic malignancy will have clinically significant bleeding (World Health Organization [WHO] grade 2 or higher) and up to 10% will have severe or life-threatening bleeding.
Patients have a tendency to develop bleeding symptoms as their platelet counts decrease, and major bleeding occurs more frequently at platelet counts of less than 10 × 10 9 /L. However, many patients with severe thrombocytopenia do not develop clinically significant bleeding. Conversely, major and even fatal bleeding is well-recognized to occur at platelet counts of greater than 10 × 10 9 /L.
In early leukemia studies, bleeding as a result of thrombocytopenia was a major contributing factor to mortality rates. Platelet transfusions helped to decrease the incidence of death attributable to bleeding and today mortality as a result of thrombocytopenia-related bleeding is exceedingly rare ( Table 1 ). Platelet transfusions have become an important adjunctive therapy and led to improved patient survival. They have also supported delivery of more intensive chemotherapy regimens.
| Trial | Total Patients (n) | Bleeding Scale | Bleeding Assessment and Rates of Bleeding | Deaths from Hemorrhage (n) | ||
|---|---|---|---|---|---|---|
| Therapeutic only vs prophylactic platelet transfusions | ||||||
| Solomon et al, 1978 | 31 | Not defined | Not reported | 0 | ||
| Sintnicolaas et al, 1982 | 12 | Not defined | Not reported | 0 | ||
| Grossman et al, 1980 | 100 | Study specific Mild (not requiring active intervention) vs severe | Mild | Severe | 14 e | |
| 86 (86%) | 74 (74%) | |||||
| Murphy et al, 1982 | 56 | Study specific | Clinically significant bleeding event | 3 | ||
| 21 bleeds from study enrollment until study closure (37.5%) | ||||||
| 15 bleeds in the first 10 mo of the study (27%) | ||||||
| Wandt et al, 2012 | 396 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 2 |
| Reported per treatment cycle | 10 (2.5%) | 18 (4.5%) | ||||
| Stanworth et al, 2013 | 600 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 0 |
| 272 (45%) | 5 (0.8%) | 2 (0.3%) | ||||
| Platelet dose | ||||||
| Roy et al, 1973 | 62 | Study specific | Minor a | Major b | NR | |
| 18 (29%) | 7 (11%) | |||||
| Steffens et al, 2002 | 54 | Not reported | NR | NR | ||
| Sensebé et al, 2005 | 101 | WHO 1979 | Hemorrhaging | WHO grades 2–3 | Grade 4 | 0 |
| 14 (14%) | 5 (5%) | NR | ||||
| Tinmouth et al, 2004 | 111 | Modified GIMEMA | Minor | Major | 0 | |
| 33 (30%) | 10 (9%) | |||||
| Heddle et al, 2009 | 129 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 0 |
| 56 (43%) | 11 (8.5%) | 3 (2.3%) | ||||
| Slichter et al, 2010 | 1351 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 1 |
| 177 (13%) | 24 (1.8%) | 7 (0.5%) | ||||
| Platelet trigger | ||||||
| Heckman et al, 1997 | 78 | Ajani 1990 | Any bleeding event | Significant bleeding event | 0 | |
| 72 (92%) | 24 (31%) | |||||
| Rebulla et al, 1997 | 255 | Study specific GIMEMA scale | Major | 1 | ||
| 53 (21%) | ||||||
| Zumberg et al, 2002 | 159 | Modified GIMEMA | Minor c | Major d | 0 | |
| 128 (8%) | 25 (16%) | |||||
| Diedrich et al, 2005 | 166 | WHO 1979 | WHO grade 2 | Grades 3–4 | 1 | |
| 19 (11%) | 8 (4.8%) | |||||
| Platelets vs other product | ||||||
| Higby et al, 1974 | 21 | Study specific | Hemorrhage | Serious bleeding | 0 | |
| 13 (6%) | 9 (4%) | |||||
a Skin, mucous membranes of mouth, lips, gums, epistaxis.
b Genitourinary and Gastrointestinal tracts.
c Minor bleeding events (petechial, mucosal, and microscopic bleeding) as well as melena and hematemesis not requiring red blood cell (RBC) transfusion.
d Major bleeding events (gross hematuria, any bleed requiring RBC), retinal bleeding, or central nervous system bleeding.
e Bacterial and/or fungal sepsis were a contributing factor in 8 of these deaths.
Platelet concentrates are the second most commonly prescribed blood product after red blood cells (RBC) and hematooncology patients are the largest users of platelet concentrates. Platelet transfusion rates are increasing; in the United States, more than 2 million platelet units were transfused in 2011, a 7.3% increase compared with 2008. Platelet transfusions may be given therapeutically, to treat bleeding when thrombocytopenia or abnormal platelet function are contributing factors, but are more frequently given prophylactically, in efforts to avert bleeding before a procedure or when the platelet count falls below a certain threshold. Many patients with platelet counts of less than 10 × 10 9 /L will not have clinically significant bleeding, and therefore many platelet transfusions may be being given unnecessarily.
Introduction
Duke reported the first description of bleeding in the setting of thrombocytopenia, which improved after blood transfusion and recurred when the platelet count decreased. Up to 70% of patients with hematologic malignancy will have clinically significant bleeding (World Health Organization [WHO] grade 2 or higher) and up to 10% will have severe or life-threatening bleeding.
Patients have a tendency to develop bleeding symptoms as their platelet counts decrease, and major bleeding occurs more frequently at platelet counts of less than 10 × 10 9 /L. However, many patients with severe thrombocytopenia do not develop clinically significant bleeding. Conversely, major and even fatal bleeding is well-recognized to occur at platelet counts of greater than 10 × 10 9 /L.
In early leukemia studies, bleeding as a result of thrombocytopenia was a major contributing factor to mortality rates. Platelet transfusions helped to decrease the incidence of death attributable to bleeding and today mortality as a result of thrombocytopenia-related bleeding is exceedingly rare ( Table 1 ). Platelet transfusions have become an important adjunctive therapy and led to improved patient survival. They have also supported delivery of more intensive chemotherapy regimens.
| Trial | Total Patients (n) | Bleeding Scale | Bleeding Assessment and Rates of Bleeding | Deaths from Hemorrhage (n) | ||
|---|---|---|---|---|---|---|
| Therapeutic only vs prophylactic platelet transfusions | ||||||
| Solomon et al, 1978 | 31 | Not defined | Not reported | 0 | ||
| Sintnicolaas et al, 1982 | 12 | Not defined | Not reported | 0 | ||
| Grossman et al, 1980 | 100 | Study specific Mild (not requiring active intervention) vs severe | Mild | Severe | 14 e | |
| 86 (86%) | 74 (74%) | |||||
| Murphy et al, 1982 | 56 | Study specific | Clinically significant bleeding event | 3 | ||
| 21 bleeds from study enrollment until study closure (37.5%) | ||||||
| 15 bleeds in the first 10 mo of the study (27%) | ||||||
| Wandt et al, 2012 | 396 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 2 |
| Reported per treatment cycle | 10 (2.5%) | 18 (4.5%) | ||||
| Stanworth et al, 2013 | 600 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 0 |
| 272 (45%) | 5 (0.8%) | 2 (0.3%) | ||||
| Platelet dose | ||||||
| Roy et al, 1973 | 62 | Study specific | Minor a | Major b | NR | |
| 18 (29%) | 7 (11%) | |||||
| Steffens et al, 2002 | 54 | Not reported | NR | NR | ||
| Sensebé et al, 2005 | 101 | WHO 1979 | Hemorrhaging | WHO grades 2–3 | Grade 4 | 0 |
| 14 (14%) | 5 (5%) | NR | ||||
| Tinmouth et al, 2004 | 111 | Modified GIMEMA | Minor | Major | 0 | |
| 33 (30%) | 10 (9%) | |||||
| Heddle et al, 2009 | 129 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 0 |
| 56 (43%) | 11 (8.5%) | 3 (2.3%) | ||||
| Slichter et al, 2010 | 1351 | Modified WHO | WHO grade 2 | Grade 3 | Grade 4 | 1 |
| 177 (13%) | 24 (1.8%) | 7 (0.5%) | ||||
| Platelet trigger | ||||||
| Heckman et al, 1997 | 78 | Ajani 1990 | Any bleeding event | Significant bleeding event | 0 | |
| 72 (92%) | 24 (31%) | |||||
| Rebulla et al, 1997 | 255 | Study specific GIMEMA scale | Major | 1 | ||
| 53 (21%) | ||||||
| Zumberg et al, 2002 | 159 | Modified GIMEMA | Minor c | Major d | 0 | |
| 128 (8%) | 25 (16%) | |||||
| Diedrich et al, 2005 | 166 | WHO 1979 | WHO grade 2 | Grades 3–4 | 1 | |
| 19 (11%) | 8 (4.8%) | |||||
| Platelets vs other product | ||||||
| Higby et al, 1974 | 21 | Study specific | Hemorrhage | Serious bleeding | 0 | |
| 13 (6%) | 9 (4%) | |||||
a Skin, mucous membranes of mouth, lips, gums, epistaxis.
b Genitourinary and Gastrointestinal tracts.
c Minor bleeding events (petechial, mucosal, and microscopic bleeding) as well as melena and hematemesis not requiring red blood cell (RBC) transfusion.
d Major bleeding events (gross hematuria, any bleed requiring RBC), retinal bleeding, or central nervous system bleeding.
e Bacterial and/or fungal sepsis were a contributing factor in 8 of these deaths.
Platelet concentrates are the second most commonly prescribed blood product after red blood cells (RBC) and hematooncology patients are the largest users of platelet concentrates. Platelet transfusion rates are increasing; in the United States, more than 2 million platelet units were transfused in 2011, a 7.3% increase compared with 2008. Platelet transfusions may be given therapeutically, to treat bleeding when thrombocytopenia or abnormal platelet function are contributing factors, but are more frequently given prophylactically, in efforts to avert bleeding before a procedure or when the platelet count falls below a certain threshold. Many patients with platelet counts of less than 10 × 10 9 /L will not have clinically significant bleeding, and therefore many platelet transfusions may be being given unnecessarily.
Methods
This review provides an update of the literature and some of the challenges raised by a very recent update of a Cochrane systematic review. The methodology of this update has been described elsewhere; in brief, searching for platelet transfusion trials multiple datasets was undertaken. Eligible trials were identified and data abstracted, alongside an assessment of risk of bias. The update of an earlier Cochrane review aimed to determine whether therapeutic-only platelet transfusions were as effective and safe as prophylactic platelet transfusions in patients with hematologic disorders undergoing cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). Seven randomized controlled trials (RCTs) met the predefined selection criteria (one is still ongoing), leaving a total of 6 eligible trials and a total of 1195 participants. These trials were conducted over a 35-year time period. Five studies contained separate data for each arm and were able to be critically appraised. Only 1 study was deemed to be at low risk of bias.
Main findings for review
For the systematic review’s primary outcome (number of patients with ≥1 bleeding episode within 30 days) significant heterogeneity was noted ( I 2 = 88%). This heterogeneity may reflect in part the different methodology and grading systems used to analyze and categorize bleeding in the individual studies. Four studies in the review reported clinically significant bleeding events and all showed a similar effect: higher rates of bleeding in participants receiving therapeutic-only platelet transfusions. Major differences were noted between studies, including platelet transfusion indications, RBC transfusion policy, and study endpoints, as well as classification of bleeding events. Individual studies also reported bleeding outcomes over different time periods and used different units of analysis. For these reasons a metaanalysis was unable to be performed.
Time to first bleeding episode was reported by 2 studies and again metaanalysis was unable to be performed because of heterogeneity ( I 2 = 90%). Individually, both studies showed that time to first bleeding episode was shorter in patients receiving therapeutic-only platelet transfusions. One study reported the number of days with clinically significant bleeding events per patient and this was statistically higher in the therapeutic-only transfusion group.
Owing to low mortality rates and rates of WHO grade 3 and 4 bleeding, there was insufficient evidence to determine whether there was any difference between platelet transfusion strategies for these outcomes. Three studies reported higher numbers of patients with WHO grade 3 or 4 bleeding events in the therapeutic-only transfusion group; however, a significant difference was not demonstrated, reflecting the rarity of this outcome.
Recent trials
The systematic review included the results of 2 recent, large, multicenter RCTs; the Trial of Prophylactic versus No-Prophylactic Platelet Transfusions (TOPPS) and the trial by Wandt and colleagues. Bleeding events were graded and reported differently in the trials; each trial used their own modification of the WHO bleeding scale and the same bleeding event would have been classified differently between studies ( Table 2 ). TOPPS reported that WHO grade 2 to 4 bleeding events occurred in 50% of patients in the therapeutic-only platelet transfusion group compared with 43% in the prophylaxis group; P = .06 for noninferiority, indicating that a therapeutic-only strategy was noninferior to prophylactic platelet transfusions. Analysis of TOPPS data by the systematic review found that although there seemed to be an increased risk of bleeding events with a therapeutic-only transfusion policy, the 95% CI crossed 1.0 (relative risk [RR], 1.17; 95% CI, 0.99–1.39). In the study by Wandt and colleagues, therapeutic-only transfusions were associated with an increased risk of WHO grade 2 to 4 bleeding events per treatment cycle ( P <.0001).
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