Observational Study of Transfusion Support and Hemorrhagic Tendencies in Newly Diagnosed Patients of AML Undergoing Chemotherapy

  

    
Variables
      
(total    days of exposure) 
    
Days of    transfusion
      
with    Bleeding 
    
Days of    transfusion
      
without    bleeding 
    
P value 
  
  

    
Fever    (n=166) 
    
104 
    
62 
    
0.00 
  
  

    
Infection/sepsis    (n=151) 
    
85 
    
66 
    
0.048 
  
  

    
Splenomegaly    (n=76) 
    
37 
    
39 
    
0.89 
  
  

    
Daunorubicin    (n=24) 
    
14 
    
10 
    
0.37 
  
  

    
Cytarabine    (n=82) 
    
39 
    
43 
    
0.69 
  
  

    
Amphotericin    B (n=307) 
    
183 
    
124 
    
0.00 
  
  

    
G-CSF    (n=316) 
    
154 
    
162 
    
0.69 
  
  

    
Tranexamic    acid (n=343) 
    
193 
    
150 
    
0.00 
  

Table 5:  Factors associated with risk of bleeding.

Discussion

Understanding transfusion needs of AML patients is crucial for the appropriate management and planning of health care strategies. Our study sheds light on transfusion requirements for newly diagnosed AML patients undergoing chemotherapy. The mean LRBC usage per patient was 14 units (range 3-25) throughout the hospital stay. Favre et al. evaluated transfusion requirements in patients undergoing initial induction consolidation chemotherapy for newly diagnosed AML. The group reported a median usage of 18 RBC units (range 3-44) during the course of chemotherapy [7]. In the present study the mean RBC requirement during the induction phase was higher than during the subsequent consolidation phase (9.8 vs. 8). The same pattern of RBC usage was also found in studies by Dawson et al. and Favre et al. who reported that the mean RBC requirement was higher during initial phase of induction chemotherapy [7,8].

During the chemotherapy, mean no of RDP units (55.3 units during induction vs. 50 during consolidation) and thus the dose of transfused platelets was not significantly different during the induction and consolidation phases. The usage pattern as reported by Dawson et al. [8] reported, 12 platelet units being transfused during induction 7 and 9 platelet units during subsequent consolidation phases for 111 AML patients undergoing chemotherapy while Favre et al. [7] reported median usage of 6 platelet units during first induction and 4 platelet units in the second induction and during consolidation the median usage was 2 and 4 platelet units in subsequent consolidation phase of chemotherapy. In current study mean dosage of 3.6 RDP units (1.6 x 10¹¹ platelets) per transfusion episode was administered, while in studies by Dawson et al.[8] and Favre et al.[7] dosage of the platelet being used was 2 x1011 platelets per transfusion derived form 4-5 pools of whole blood derived platelets or a single apheresis units.

The mean platelet dose transfused in our study was (~1.6 x 10¹¹ platelets) which was equivalent to the low dose category as reported by Slichter et al. [9] (1.1 x 10¹¹ platelets/m2) and Tinmouth et al [10] (3 whole blood derived platelets, WBDP). Tinmouth et al. studied the safety and effectiveness of low dose (3 WBDP) vs. high dose platelets (WBDP) in acute leukemics and recipients of autologous stem cell transplant. He reported that the patients who were transfused with low dose prophylactic platelets received 25% fewer platelets thus, favoring the use low dose platelet transfusion which appeared to be safe and effective [10]. Slichter et al. compared three different platelet doses in hypoproliferative thrombocytopenia and reported that the use of low dose (1.1 x 10¹¹ platelets/m2) platelet transfusion led to decreased usage of platelets. The low dose platelet transfusions were also found to be effective without any adverse events [9]. Recently another large randomized multicentre trial comparing the traditional prophylactic platelet transfusion strategy with a therapeutic transfusion strategy in patients with acute myeloid leukaemia or autologous haematopoietic stem-cell transplantation investigators recommended restrictive platelet transfusion strategy than is presently used worldwide in non-bleeding and clinically stable patients despite a morning platelet count of less than 10x10⁹/L [11].

The response to platelet transfusion was inadequate in 60% episodes. Friedberg et al. [12] evaluated clinical and

blood bank factors or management of platelet refractoriness and alloimmunization in haemato-oncology patients. They reported CCI <5000 in 50.2% of platelet transfusions. In the current study, presence of fever, infection/sepsis, splenomegaly, and use of Daunorubicin, cytarabine and Amphotericin B were significantly associated with poor CCI both at 1 hour and 24 hours. Bishop et al. [13] has reported significant correlation between splenomegaly, administration of AMB and poor CCI at both 1 hour and 24 hour, with other factors marginally affecting the CCI. Similar findings have also been reported by Friedmann et al. [14] where he found clinical factors such as fever, bleeding, DIC, sepsis, splenomegaly, neutropenia to affect the response to platelet transfusions. Slichter et al. [15] has also reported that the presence of palpable spleen, bleeding, fever, infection and use of amphotericin B negatively affects the platelet increment at 1 hour and 24 hour.

All 19 patients in our study were refractory to platelet transfusions at some point of time during the treatment, the increased rate of refractoriness in our study could be largely due to the use of ABO incompatible and non leukofiltered platelets. Fever, infection/sepsis, splenomegaly, and use of Daunorubicin, cytarabine and Amphotericin B also have contributed to refractoriness. Unfortunately, the humoral causes of platelet refractoriness e.g. HLA or HPA antibodies were not evaluated.

Mean FFP units transfused per patient was 10 (range 0-68). Majority of which were (92.6%) transfused during the induction phase while cryoprecipitate was required only on two instances. We could not find any study quantifying FFP/Cryoprecipitate usage in patients of AML (excluding APML).

We observed clinically significant bleeding (grade >2) on 141 days (10.8%) and severe bleeding on 55 days (4.2%). Webert et al. has also reported total of 743 (10.13%) days of bleeding over 7335 patientdays. They found 560 days (75.4%) days with grade 1, 108 (14.5%) days with grade 2, 51 (6.9%) with grade 3 and 24 (3.2%) with grade 4 bleeding severity [16]. Heddle et al. [17] reported clinically significant bleeding on 12.1% patient days and fatal bleed on 0.5 % days of observation with low dose prophylactic transfusion (corresponding to a dose of 1.5-3x10¹¹ platelet per transfusion). Similarly in an another multicentre trial, Heddle et al. [18] observed 6% days with clinically significant bleed (> Grade 2) of the total patient days observed when platelets were transfused prophylactically at a trigger of 10 x10⁹/L (centre: Italy). Thus, severity of the bleeding observed in our study was concordant to other studies. Bleeding from gastrointestinal tract was most frequent in our study present on 28.5% of bleeding days. This was closely followed by oropharyngeal bleeding which was seen on 19.1% bleeding days. Rebulla et al evaluated the sites of major of major bleeding (≥WHO grade 2) and observed that most common site of bleeding was gastrointestinal tract (23.6%) [19].

Sixty-three (24.6%) bleeding episodes were observed with platelet count <10 x10⁹/L and 133 (52%) when the platelet count was 10- 20 x109/L while 52 (20.3 %) episodes of bleeding occurred when platelet count was 20- 50x10³/μl, and 8 (3.1 %) when platelet count was >50 x10⁹/L. We noted that majority of bleeding episodes (76.6%) occurred when the platelet count was less than 20 x10⁹/L. This is in corroboration of study by Lawrence et al. [20] who while studying relationship between platelet count and presence of major or minor bleed, observed close correlation between lower platelet counts (<10x10⁹/L) and minor bleeding. A similar relation was also observed for major bleeding. However, majority of their bleeding episodes (50%) were reported when the counts were <5 x10⁹/L. This is in contrast to our study where majority of bleeding episodes occurred at 10-20x10⁹/L (52%) This could be attributed to the fact that our patients received prophylactic platelet transfusions at counts ≤10 x10⁹/L. The difference in the platelet counts at which bleeding occurred was also influenced by the presence of other associated risk factors that led to bleeding. In our study, presence of fever, infection/sepsis and use of Amphotericin B and Tranexamic acid were found to be significantly associated with bleeding. Presence of various factors associated with bleeding has also been investigated in a study by Friedmann et al. [14] where he found that neither the first morning platelet count nor the lowest platelet count of the day were significantly related to the risk of bleeding. He also reported a correlation between bleeding and presence of fever (OR-1.21), bacteraemia (OR-1.06) and use of Amphotericin B (OR-1.62). Tranexamic acid is mainly used as a supportive therapy in bleeding patients thus; its use was associated with presence of bleeding [21].

Blood transfusion support remains an indispensable part of the patient undergoing chemotherapy as substantial number of RBC, platelets and FFP are required during course of treatment. Our findings indicate that the threshold of 10x10⁹/L for prophylactic platelet transfusion is safe for AML patients who are not actively bleeding or not high risk. In cases where additional risk factors are present the threshold should be increased up to 20 x10⁹/L and in the presence of major bleeding complications the platelets count should be maintained greater than 20x109/L. In conclusion the study provided insights into the complex issues of transfusion requirement of AML patients. We emphasize individualizing transfusion management of these patients as clinical factors are the major determinants of transfusion requirements. We also recommend that bleeding grades should be used as an outcome measure when determining the efficacy of platelet transfusions.

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