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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 1  |  Page : 10-14

Preponderant use of fresh-frozen plasma in children despite weaker evidence


Department of Immunohematology and Blood Transfusion, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India

Date of Web Publication30-Apr-2019

Correspondence Address:
Dr. Manish Raturi
Assistant Professor, Department of Immunohematology and Blood Transfusion, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Swami Ram Nagar, Jolly Grant, Dehradun - 248016 Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_37_18

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  Abstract 

BACKGROUND: Considering the higher use of fresh-frozen plasma (FFP) in our hospital, we desired to determine the pattern, prevalence, and potential complications of its utilization in new-born and children with the primary aim to observe its effect on the conventional coagulation screening (CCS) parameters.
SUBJECTS AND METHODS: Patients' demographics, clinical indications, and pre- and posttransfusion CCS parameters such as the prothrombin time, the international normalized ratio (INR), and partial thromboplastin time were observed over a period of 10 months. Any improvement observed in the laboratory parameters after FFP transfusion was noted.
RESULTS: We studied 433 episodes, where 499 FFP units were utilized in 184 patients. Mean age in years was 6 ± 0.16 (new-born to 17). Diagnoses-wise majority had diffuse intravascular coagulation with sepsis 25% (46/184) followed by febrile illness 23% (42/184). Around 46% (84/184) patients had bleeding episodes of which four had known family history of bleeding (three factors IX and one factor XI deficiency). Mean doses of FFP utilized (mL/kg) in children and infants were 12.6 ± 6.3 (n = 297 episodes) and 14.4 ± 6.3 (n = 136 episodes), respectively (P = 0.006). Mean change in INR in the cohort with deranged coagulation parameters against the overtly bleeding cohort was 0.85 versus 0.40 (P = 0.006).
CONCLUSION: The study elicits minimal evidence in correcting the coagulation parameters, especially in the infants, whenever FFP was transfused prophylactically. Joint-decision making of the pediatricians and transfusion medicine physician would promote judicious use in children.

Keywords: Children, conventional coagulation parameters, fresh-frozen plasma, international normalized ratio, transfusion therapy


How to cite this article:
Raturi M, Shastry S, Baliga PB. Preponderant use of fresh-frozen plasma in children despite weaker evidence. J Appl Hematol 2019;10:10-4

How to cite this URL:
Raturi M, Shastry S, Baliga PB. Preponderant use of fresh-frozen plasma in children despite weaker evidence. J Appl Hematol [serial online] 2019 [cited 2019 May 20];10:10-4. Available from: http://www.jahjournal.org/text.asp?2019/10/1/10/257468


  Introduction Top


One of the common challenges faced by the pediatric hematology/oncology services is referral for coagulopathy. Prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), and platelet counts are commonly used for the conventional coagulation screening (CCS) tests used to assess hemostasis. Several factors may influence the results of these CCS tests such as patients may present with little or no significant history of bleeding, and the initial screening coagulation studies might have been performed untimely or with inherent preanalytic process problems.[1] Other reasons such as patients may not be at baseline health conditions and or different storage conditions of samples, may alter the reproducibility of these tests.[2],[3] Furthermore, neither PT nor PTT reflect in vivo hemostasis because the test systems do not include platelets or red cells, but contain nonphysiological substances. They only measure fibrin generation as an endpoint and do not assess the sensitivity of the fibrinolytic proteins. Therefore, the use of these tests to routinely assess hemostasis in nonbleeding patients is not only questionable but also often unjustified. Further, many laboratories report their CCS test results for neonates and children based on the adult reference ranges. This makes it difficult for the clinicians to base the transfusion triggers in them and caution is always needed while interpreting such results. In addition, the studies of fresh-frozen plasma (FFP) use in the pediatric intensive care units (PICU) demonstrate more frequent use to support the volume expansion, massive bleeds, liver disease, disseminated intravascular coagulation, and correction of deranged coagulation (DC) parameters, among other clinical indications.[4] Our institution is a multi-specialty tertiary care center. Considering the increasing demand and utilization of FFP at our hospital, we aimed to conduct this study to determine the pattern, prevalence, and potential complications of FFP use in newborns and children with the primary goal to observe its effect on the CCS test results.


  Subjects and Methods Top


Study design

We conducted a descriptive study where we retrospectively reviewed the medical records of infants and children admitted at our 2032-bed multi-specialty teaching hospital. All the patients who received FFP for 10 months (December 2012 to September 2013), regardless of gender either with or without the receipt of other blood components were included in the study. The following data were collected from each patient's medical record when available: age, gender, body weight, location, and the indication for transfusing FFP with or without documented records of pretransfusion CCS test results. Patients were categorized into two age-related cohorts, namely, Cohort I as infants-aged (new-born up to 1) year and Cohort II as children-aged (1–17) years. We noted any bleeding information, with site specification as evident from their charts, any known family history of bleeding and history of any invasive procedure/s with or without bleeding during or following any procedure. Any adverse transfusion reactions due to FFP administration were noted. The Institutional Ethics Review Committee approved the study protocol, before its commencement. The study was conducted in accordance with the principles of good clinical practices.

Laboratory coagulation parameters and dose

We reviewed all the CCS tests-ordered relevant to an evaluation for their derangement, including INR (value >1.5), PT (range, 12–16 s), PTT (range, 26.0–36.0 s), and platelet count (range, 150–400 × 109/L). Comparative analyses such as the improvement in coagulation parameters of pre- and post-FFP in both the age-cohorts were performed. For each episode, the magnitude of correction in INR was calculated according to the formula (Pretransfusion INR – Posttransfusion INR / Number of FFP transfused). Based on their hemostatic condition, patients were further categorized into two groups, namely, bleeding and prophylaxis groups as documented by the clinicians in their charts. For transfusions, 10–15 mL/kg was considered as a standard dose, in alignment with the British Committee for Standards in Hematology (BCSH) recommendations.[5] The total number of FFP units requested and transfused to the recipients based on their body weight were noted.

Study outcomes

Our study had two endpoints, that is, primary to see any adjudicated improvement (based on their clinical judgment of treating physicians) in the clinical status of patients as evident from the discharge summaries and secondary to observe any improvement in the CCS parameters such as INR/PT/PTT post-FFP administration.

Statistical analysis

The overall analysis was descriptive with results presented as percentages for categorical data and as mean (±standard deviation, range) for the numerical data. The two-tailed t-test for paired data was used to compare the CCS test values of pre- and post-transfusion, and the Student's t-test was used to calculate the relative confidence intervals. A value of P < 0.05 was considered as statistically significant. Data were analyzed using the SPSS software version 20. (IBM Inc., Armonk, NY, USA).


  Results Top


Patient demographic characteristics

We studied 433 episodes where 499 FFP units were utilized in 184 (n = 117 children and 67 infants) patients with an average use of three units for each patient. Mean age was 6.0 years, ranging from new-born to 17 years. There was a slight preponderance of males over females, with a ratio of 1.3:1 [Table 1]. The mean (range) body weight in kg among the infants was 2.79 (0.5–5.1) and in children, it was 21 (2.5–49). Diagnoses-wise majority were diffuse intravascular coagulation with sepsis 25% (46/184) followed by febrile illness 23% (n = 42/184). A total of 46% (n = 84/184) of patients received FFP after experiencing bleeding with or without prolonged PT and/or PTT on previous evaluation. Among these 84 patients with the histories of bleeding episodes, 29 (35%) had isolated epistaxis and 20 (24%) had the upper GI bleeds followed by 13 (15%) hematuria which were the most commonly reported symptoms [Figure 1]. The family history of bleeding was reported in four patients (Three factors (f) IX and one f XI deficiency). History of bleeding episodes was found in only 70% (23/33) patients who underwent an invasive procedure or before any surgery. Of total 184 patients, 81 (44%) had a DC profile on routine preoperative coagulation screening tests. Prolonged PT was the most frequent laboratory observation, leading to a referral in 81 patients (44%), followed by a prolonged PTT in 66 patients (36%), and the presence of both prolonged PT and PTT in 61 patients (33%), respectively.
Table 1: Baseline characteristics of the patients*

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Figure 1: Categories of bleeding symptoms in patients

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Indications and dose of fresh-frozen plasma administered

Most FFP transfusions were given in PICU (children 60% [n = 70/117] and infants 85% [n = 57/67]) as against operating rooms (children 40% [n = 47/117] and infants 15% [n = 10/67]). Of 184 patients, total 58% (n = 68/117) children and 30% (n = 20/67) infants received FFP transfusions for nonbleeding indications. The major reasons among these were DC parameters in the absence of bleeding [Table 2]. FFP was given either before or during an invasive procedure in 23% (n = 43/184) patients, most commonly for laparotomy (9/43), biopsy (9/43), intubation (5/43), endoscopy (5/43), and central line insertion/removal (3/43). Other recorded procedures included orthopedic surgery, urosurgery, neurosurgery, and chest drains (all <5%) each. The mean FFP dose given in children and infants during each episode was 12.6 ± 6.3 mL/kg (n = 297 episodes) and 14.4 ± 6.3 mL/kg (n = 136 episodes), respectively, with the differences being statistically significant (P = 0.006). Of the total episodes, 32% (n = 96/297) children and 14% (n = 19/136) infants received <10 mL/Kg dose of FFP during each episode. Of all, 0.4% (n = 2/499) of FFP units transfused were related with the mild allergic reactions (urticaria with pruritis).
Table 2: Various indications for giving fresh-frozen plasma to children admitted in our hospital

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Effect of fresh-frozen plasma administration on coagulation tests

Around 62% (n = 73/117) children and 42% (n = 28/67) infants did not have any documented INR or PT before transfusions with this proportion rising to 75% (n = 88/117) and 69% (n = 46/67) after transfusions. There was a wide range of INR/PT results before FFP administration in children and infants specifically in bleeding versus prophylactic conditions. During bleeding episodes, the mean (range) INR before FFP administration in children and infants were 1.8 (0.89–10.4) and 2.1 (0.77–7.58), respectively. Whereas during prophylaxis, the mean (range) INR before FFP administration in children and infants were 3.9 (1.09–8.57) and 1.5 (0.91–2.4), respectively. In nearly all cases, the effect of FFP as recorded by the difference between the first recorded pretransfusion INR or PT result and the posttransfusion values varied greatly. PTT was documented in 38% (163/433) episodes before FFP transfusions. However, up to 12 h, posttransfusion PTT was documented in 27% (117/433) episodes. The mean (range) PTT before and after FFP administration in patients were 57.7 (25.1–120) s and 46.7 (24.2–120) s, respectively (P = 0.0006). Following FFP administration collectively in both the age-cohorts (I and II), mean reduction in INR (range) during prophylaxis was 0.85 (−5.7–5.6) against bleeding episodes 0.40 (−1.3–7.6), with the differences being highly statistically significant (P = 0.009). Based on the indications, mean change in INR per unit of FFP transfused during every episode was highest for the prophylaxis cohort with “DC” (0.85) against the bleeding cohort (0.40). By conventional criteria, this difference was statistically significant (P = 0.0001). Mean change in INR per unit of FFP in infants against children was 0.53 and 0.25, respectively (P = 0.005).

Study outcomes

Adjudicated improvement in clinical status of patients overall was 92.3% (n = 170/184) being higher among children (94% [n = 110/117]) than infants (90% [n = 60/67]). Further, the laboratory efficacy after FFP transfusions was seen in 75% (n = 88/117) recipients.


  Discussion Top


Both PT and PTT results are dependent on several factors such as biological variables, reagents, laboratory quality controls, and processes and they can be prolonged for various reasons not associated with bleeding risk.[6] FFP transfusions given to patients at our hospital over 10 months were studied which indicated its widespread use in a high proportion of neonates and children without any bleeding symptoms. In fact, majority reported only minor abnormalities in INR or PTT. The category of patients receiving FFP in this study appears similar to other studies, although variations exist in its use from the center-to-center for group of patients, such as cardiac surgery or critical care.[7]

The effect of FFP on laboratory coagulation parameters as recorded by the difference between the first-recorded pretransfusion INR/PT or PTT result and the posttransfusion result, despite varying in bleeding versus prophylaxis cases, were, however, of not much clinical significance as predicted by other studies.[8] The mean reduction in INR among the two age-cohorts (children and infants) was minimal ranging from 0.25 to 0.53, respectively, demonstrating little laboratory evidence for FFP transfusion efficacy. However, clinically, all the bleeding episodes could be resolved on FFP administration. Laboratory evidence of any reductions in INR/PT was more marked in patients with higher pretransfusion parameters as anticipated.

In this study, the “prophylaxis” cohort of patients had the highest change in INR per unit of FFP administered (0.85) against the “bleeding” cohort (0.40). The biologic rationale for this differential response to FFP transfusion in these two cohorts can most logically be explained as the “dilutional” effects present in the latter. We also observed that 55% (n = 101/184) recipients did not have INR/PT documented before FFP administration. Hence, we selectively excluded this cohort of recipients during the data analysis. Further, FFP was often transfused to nonbleeding patients to correct DC parameters in an assumption that it would limit the risk of bleeding.

Prematurity of the liver in the production of inadequate amounts of coagulation factors is a physiological limitation offering a huge challenge in accurate interpretation of the neonatal coagulation screening reports. Therefore, hospital-based laboratories need to ensure that they have systems in place for the issue of FFP based on criteria jointly agreed with the clinicians. This may further encourage an empirical issue of FFP in the event of major bleeds. However, the issue of FFP to nonbleeding patients where coagulation tests show minor derangements or they are unavailable still remains questionable. In this study, around 29% (n = 54/184) of patients received FFP transfusions prophylactically which is comparable to other studies showing approximately 30%–50% prophylactic FFP transfusions with or without planned surgeries.[9] Further, a large proportion of the study cohort 25% (n = 46/184) received transfusions for the indication of low-protein states and/or hypovolemia which were considered inappropriate based on the BCSH guidelines.[5] The primary reason for the usage of FFP in such cases was poor affordability of albumin by the patients. Hence, we selectively excluded this cohort of recipients during the data analysis. BCSH guidelines also mention that although pathogen-reduced FFP with Vitamin K may be considered among bleeding infants, prothrombin complex concentrates are an equally hemostatic alternative.[5] Wiener et al. subsequently studied >3000 blood transfusions and reported that allergic reactions were found in approximately 1% of transfusions.[10] In this study, 0.4% (n = 2/499) units of FFP transfusion-related adverse reactions were reported. We also observed that the adverse transfusion reactions reported from the wards were meticulous and prompt. All the adverse reactions were entered in the national hemovigilance software in accordance with our department protocol. There were several limitations in this study such as it did not address the use of point-of-care testing. This happened, especially during massive bleeds and or situations such as poly-trauma where lack of ordering pretransfusion parameters were mainly attributed to the staff overtly engaged and busy in the patient resuscitation. Another major limitation in the study was that we could not account for the change in laboratory parameters due to the use of other blood products and/or the dilution effect of crystalloids during massive transfusions and or poly-trauma resuscitations.


  Conclusion Top


This study elicits minimal evidence in correcting coagulation parameters, especially in younger infants when FFP was transfused as a prophylactic measure. It should rather be used to achieve hemostasis if no other alternative is at hand. Joint decision-making of pediatricians and transfusion medicine physician would promote judicious use in the pediatric population.

Acknowledgment

The authors gratefully acknowledge all the co-operation extended by the technical staff of our department.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Acosta M, Edwards R, Jaffee IM, Yee DL, Mahoney DH, Teruya J, et al. Apractical approach to pediatric patients referred with an abnormal coagulation profile. Arch Pathol Lab Med 2005;129:1011-6.  Back to cited text no. 1
    
2.
Plebani M, Carraro P. Mistakes in a stat laboratory: Types and frequency. Clin Chem 1997;43:1348-51.  Back to cited text no. 2
    
3.
Rao LV, Okorodudu AO, Petersen JR, Elghetany MT. Stability of prothrombin time and activated partial thromboplastin time tests under different storage conditions. Clin Chim Acta 2000;300:13-21.  Back to cited text no. 3
    
4.
Goldenberg NA, Manco-Johnson MJ. Pediatric hemostasis and use of plasma components. Best Pract Res Clin Haematol 2006;19:143-55.  Back to cited text no. 4
    
5.
O'Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126:11-28.  Back to cited text no. 5
    
6.
Burns ER, Goldberg SN, Wenz B. Paradoxic effect of multiple mild coagulation factor deficiencies on the prothrombin time and activated partial thromboplastin time. Am J Clin Pathol 1993;100:94-8.  Back to cited text no. 6
    
7.
Goodnough LT, Johnston MF, Shah T, Chernosky A. A two-institution study of transfusion practice in 78 consecutive adult elective open-heart procedures. Am J Clin Pathol 1989;91:468-72.  Back to cited text no. 7
    
8.
Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006;46:1279-85.  Back to cited text no. 8
    
9.
Stanworth SJ, Grant-Casey J, Lowe D, Laffan M, New H, Murphy MF, et al. The use of fresh-frozen plasma in england: High levels of inappropriate use in adults and children. Transfusion 2011;51:62-70.  Back to cited text no. 9
    
10.
Wiener AS, Oremland BH, Hyman MA, Samwick AA. Transfusion reactions: Experiences with more than three thousand blood transfusions. Am J Clin Pathol 1941;11:102-21.  Back to cited text no. 10
    


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