Analysis of Donor Safety in High Yield Plateletpheresis Procedures: An Experience from Tertiary Care Hospital in South India

Abstract

The apheresis platelets are the preferred blood components for the thrombocytopenic hemato-oncology patients. The one of the important factors for post transfusion increment is the dose of the platelet product infused. The minimum platelet product yield is defined but the amount of maximum possible platelets collection from a single donor is not universally defined. There is lots of apprehension in our country for apheresis procedures harvesting more than a standard unit. This retrospective observational study was conducted to determine safety of high yield plateletapheresis collection among Indian donors This retrospective observational study was conducted for a period of 15 months including all consecutive plateletapheresis procedures. The informed consent had been obtained from all donors including high yield plateletapheresis (Yield ≥ 5 × 10¹¹). The apheresis product was subjected to platelet count. The donor adverse reactions were recorded along with procedural details. Post procedure complete blood count was done for the donors who consented for post procedure blood sample draw A total 569 procedures were performed during this period including 174 high yield procedure. The 526 procedures were analyzed for adverse donor reactions. The 43 were excluded for adverse donor reaction analysis due to yield less than 3 × 10¹¹ (n = 43). The adverse reactions rate between high yield procedures (18/174, 10.34%) and normal yield (20/352, 5.68%) were not statistically different (p = 0.052). The phlebotomy related complication (3.23%) followed by citrate toxicity (2.28%) were the two most common adverse reaction observed. The adverse reactions associated with high yield plateletapheresis procedures are comparable to normal yield procedures in term of overall adverse reactions observed and post procedural platelet counts. This can be beneficial to patients by providing products of greater yield.

Introduction

Single donor apheresis platelet (SDAP) units provide large amount of the platelets to patients, its usage gradually increasing in haematological, oncological and surgical patients. During 2015 in United States of America, the whole blood derived platelets accounted for only 8.6% of total platelets utilized rest 91.4% platelets were SDAP [1]. While in India few studies before 2010 depicted that more than 95% platelets were whole blood derived platelets and only < 5% platelet transfusion utilised the apheresis platelets but now a days there is gradual increase in utilization of apheresis platelets also [2, 3]. The minimum platelet count should be > 1.5 × 10⁵/µl to keep post donation platelet count in donor more than 1.0 × 10⁵/µl after collection of 3x10¹¹platelets from a plateletpheresis donor [4, 5]. The recent advances in apheresis equipment has allowed to process larger amount of donor whole blood in a single procedure to get a yield more than 3 × 10¹¹ per product [6]. The patients with thrombocytopenia majorly haemato-oncology patients undergoing chemotherapy and bone marrow transplant (BMT) require higher amount of platelet transfusion support. The use of high yield apheresis components can result in higher platelet count increments and longer interval between two transfusions that in turn may benefit patients by reducing number of days of thrombocytopenia and less number of overall platelet component requirement [7, 8]. The posttransfusion platelet increment was significantly high with the number of platelets transfused (P = 0.01) and the mean posttransfusion counts increments were 33, 51, and 62 × 10³/μl respectively after transfusion of 4.6, 6.5, and 8.9 × 10¹¹ platelet dose [7]. The Klumpp TR et al. reported a statistically significant (p < 0.0001) difference between mean posttransfusion platelet count increment, (17010 v/s 31057 per μL) with low dose platelet and high dose platelet component respectively [8]. The daily fixed physiological loss of platelets (approximately 7100/µl per day) from circulation for maintenance of normal haemostasis leads to need for transfusion even after good increment achieved [9].

Till now there is no universal definition of high yield plateletpheresis procedure and it varies in different countries. Previous researchers like Klumpp TR et al. [8] defined platelet yield of ≥ 5 × 10¹¹, while Makroo RN et al. [10] defined a target yield of 6 × 10¹¹ as high yield plateletpheresis. The high yield platelets are being split into two or three units of platelet components and transfuse to patient to reduce the donor exposure in other countries [11–13] but in India split products are not licensed by regulatory authorities [14]. The eligibility criteria of donors for high yield plateletpheresis procedure also varies in previous studies and its mainly based on donor weights and pre-procedure donor platelet counts. The reported cut-off of preprocedural platelet counts varies from 2.25 × 10⁵ to 2.70 x 10⁵/µl [10, 13, 15, 16].

The apheresis donation with modern instruments is considered as low risk activity [17]. The basic principle to collect platelets through various equipment is invariably same but the technical differences may lead to different component quality parameters and varying donor safety profile [18]. The commonly available devices in India are from the manufacturer Haemonetic corporation, Braintree, MA, USA (MCS plus), Fresenius Kabi, Bad Homburg, Germany (Amicus, Com.Tec) and Terumo penpol, Lakewood, Colorado, USA (Trima accel, Cobe spectra, Optia).

The donor safety concerns in high yield plateletpheresis have been evaluated previously [6, 19]. A wide range of plateletpheresis donor adverse events have been reported in India ranging from 4.36 to 18% [20–22]. The donor adverse events associated with apheresis procedures are similar to whole blood donation like vasovagal, hypotension and phlebotomy related complications except few specific adverse events like citrate toxicity, allergic reactions to kit sterilizing agent and adverse events due to equipment malfunction [21, 23]. The citrate toxicity can range from mild as tingling and numbness to moderate as paraesthesia, chills, cramp and hypotension to severe as double vision, loss of consciousness, seizures and cardiac arrythmias [23].

We planned a retrospective observational study to evaluate the safety profile of high yield platelet apheresis procedures on donors. Along with that we also compared the pre and post donation haematological parameters of platelet apheresis donors and evaluated the collection efficiency of various apheresis equipment.

Materials and Methods

The retrospective observation study was planned in a tertiary care haemato-oncology hospital with bone marrow transplant unit from February 2016 to April 2017. The hospital ethics committee approved this study. The plateletpheresis donor selection was based on Transfusion Medicine Technical Manual of Director General of Health Services, Ministry of health and family welfare, Government of India [4].

1. Selection of high yield plateletpheresis donor

The high yield plateletpheresis procedures were defined with a product yield of ≥ 5 × 10¹¹ as defined by Klumpp TR et al. [8] while normal yield was considered from 3 to 4.9999 × 10¹¹.

The apheresis donors were selected based on standard operating procedure (SOP) of the department. The selection criteria for high yield plateletpheresis donors was as follows

• Pre-procedure Hb ≥ 12.5 gm/dl,

• Platelet count of ≥ 2.7 × 10⁵/µl based on the mean platelet reduction of 0.6 × 10⁵/µl as reported by Simon et al. [24] with mean 3.3 × 10¹¹ yield collection

• Calculated blood volume of ≥ 4.5 l keeping maximum volume collection 500 ml per procedure based on maximum withdrawal of 10.5 ml/kg [25] with a minimum acceptable weight of 50 kg. and

• Those who consented for high yield product were selected for high yield platelet collection.

• The blood volume of plateletpheresis donor was calculated by Nadler’s formula [26].

The baseline data of donor (age, weight, height, blood volume, blood pressure, Pulse, Temperature) were recorded in plateletpheresis consent & procedure monitoring form.

The procedural data was recorded from procedural details at the end of the procedure from apheresis equipment display. The donor haematology values were obtained from pre and post-procedure complete blood count.

• (b)Blood sample collection

The pre-donation peripheral blood samples were collected for all donors who presented for donation of apheresis platelet. Two ml EDTA for complete blood count and 3 ml sample in clot activator tube for mandatory infectious marker screening were collected. The post donation samples of the donors who consented verbally during counselling of the plateletpheresis procedure were drawn as per SOP. It was incorporated in SOP after seeing enthusiasm and/or anxiety especially first-time apheresis donors to know the effect of plateletpheresis on their platelet count. A 2 ml EDTA blood sample within 30 min of procedure completion was collected. The quality control for product yield was done for each unit of plateletapheresis unit as per departmental SOP and hospital policy to provide exact dose of the product to clinical departments. The all products were allowed to rest for one hour on flat surface before sampling as reported previously in literature including for products collected by Trima cell separator [27, 28]. The flat surface resting may improve some in vitro parameters of platelet quality during storage [29]. The one hour resting period was also kept for all platelet products collected to maintain uniformity in procedure. The apheresis product samples were collected in EDTA vials (1–2 ml) to avoid incorrect platelet count due to microaggregates as reported by McShine RL et al. previously [30]. The complete blood count was performed on Beckman- coulter 5-part hematology analyzer (Beckman coulter Inc., USA) within 30 min of sample collection.

• (c)Apheresis equipment

The plateletaphersis procedures were performed on three apheresis equipment i.e. Amicus (3.2 version, Fresenius Kabi, Bad Homburg, Germany), Trima Accel (5.1 version, Terumo BCT, Lakewood, Colorado, USA) and COM.TEC (Fresenius Kabi, Bad Homburg, Germany). All these equipment uses closed system plateletapheresis kit of respective manufacturer. The procedures including kit installation were performed as per manufacturer instructions and standard operating procedure (SOP) of department.

• (d)Donor monitoring during procedure and adverse event reporting

The plateletpheresis donors were monitored throughout the procedure as per SOP. The donor vitals (blood pressure, pulse, temperature) were recorded twice before procedure initiation and after completion of procedure. Any adverse event reported by donor or observed by staff during the procedure or within 30 min of procedure completion was recorded. Donors were not offered prophylactic calcium supplementation; the calcium tablets were offered after donor complained of symptoms suggestive of hypocalcaemia.

• (e)Calculation
  • Adjusted values were calculated as described by Fontana S et al. [28] to account for changes in circulatory blood volume, dilutional effect of ACD while assuming conservation of red cell mass. The formula used for adjusted values is

    $$\begin{array}{cc}\hfill \text{Value}\left(\text{adjusted}\right)=& \left[\text{Hematocrit}\left(\text{pre-procedure}\right)÷\text{Hematocrit}\left(\text{Post-procedure}\right)\right]\hfill \\ \hfill & \times \text{value}\left(\text{non-adjusted}\right).\hfill \\ \hfill \end{array}$$
    All post procedural parameters of donors were adjusted for result calculation.
  • Platelet recruitment: A recruitment was defined, if the ratio of the total PLT yield and the reduction of circulating PLT in the donor was more than 1 based on donor blood volume and pre-procedure and post-procedure platelet count [28, 31]. The formula used was

    $$\begin{array}{cc}\hfill \text{Platelet recruitment}& =\text{Platelet yield}÷\left(\text{Platelet pre}-\text{Platelet post}\right)\hfill \\ \hfill & \times \text{Donor blood volume}\hfill \\ \hfill \end{array}$$
  • Collection rate is yield collected per hour by a cell separator

    $$\text{Collection rate}=\text{Platelet yield}÷\text{procedure duration}\left(\text{hours}\right)$$
  • Collection efficiency was calculated by this formula as described earlier [27, 31]

    $$\text{Collection efficiency}=\text{Platelet yield}÷\left(\text{Platelet average}\times \text{Processed blood volume}\right)$$

    $$\text{Platelet average}=\left(\text{pre-procedure platelet count}+\text{adjusted post-procedure platelet count}\right)÷2$$

• (f)Statistical analysis

Statistical analysis was done using the SPSS statistical package (version 23, IBM corporation, USA). All results were calculated as mean ± SD and a ‘p’ value of < 0.05 was considered statistically significant. The numerical variables are represented by mean ± 1 standard deviation (SD). For comparison of pre and post value of the procedures we used “paired t test” while for comparison of same parameter in different cell separators we used “unpaired t test”.

Results

A total of 569 apheresis procedures were performed during study period. All the plateletapheresis donors were male including first time donor (n = 118), repeat whole blood donor (n = 328) and repeat plateletapheresis donor (n = 123). The baseline characteristics of donors and apheresis procedure parameters are given in Table 1.

Table 1.

Base line characteristics of plateletpheresis donors and procedure data (n = 526)

Parameters	Mean ± 1 standard deviation (range) (n = 526)	Normal yield mean ± 1 standard deviation (n = 352)	High yield mean ± 1 standard deviation (n = 174)	P value
Age (years)	29.6 ± 6.89 (18–54)	29.62 ± 7.13	28.59 ± 5.47	0.047
Weight (kg)	77.07 ± 10.89 (52–151)	76.01 ± 10.78	79.03 ± 9.67	0.009
Blood volume (ml)	4893 ± 480.13 (3083–7025)	4865.74 ± 478.73	4947 ± 442.95	0.029
Hemoglobin Pre (g/dl) *	15.31 ± 1.07 (12.4–18.9)	15.39 ± 1.08	15.21 ± 1.03	0.03
Hematocrit Pre (%)	46.64 ± 3.17 (38.3–55.7)	46.82 ± 3.18	46.41 ± 3.14	0.000
Platelet count Pre (× 103/µl)	284.2 ± 60.80 (162–498)	258.73 ± 43.85	344.35 ± 48.23	0.000
Product volume (ml)	304.03 ± 85.91 (140–500)	254.83 ± 30.94	412.25 ± 66.93	0.000
Product yield (× 1011 per bag)	4.57 ± 1.40 (3.0–8.77)	3.87 ± 0.49	6.41 ± 0.77	0.000
Blood volume processed (ml)	2628.25 ± 402.69 (1727–3856)	2470.46 ± 303.06	2952.97 ± 408.79	0.000
ACD used (ml)	313.22 ± 64.24 (204–566)	299.23 ± 60.93	337.3 ± 58.22	0.000
Run time (minutes)	58.97 ± 9.90 (38–101)	56.98 ± 9.86	62.56 ± 9.05	0.000

The 526 procedures (92.44%) yield was more than 3 × 10¹¹, 43 (7.55%) procedure yield was less than 3 × 10¹¹. The number of procedures performed with different equipment including 174 high yield (≥ 5 × 10¹¹) procedures is given at Table 2.

Table 2.

Number of plateletpheresis procedures using 3 equipment according to yield

	Total procedures (n = 569)	Less than 3 × 1011 yield (n = 43)	Normal yield (3 to 4.9999 × 1011 yield) (n = 352)	High yield (≥ 5 × 1011 yield) (n = 174)
Trima accel	463	22	282	159
Amicus	87	13	59	15
COM.TEC	19	8	11	Nil

A total of 38 (7.22%) donor reactions, 20 in normal yield and 18 among high yield group were recorded (Table 3). The combined phlebotomy related adverse events (Hematoma + Phlebotomy failure) were maximum (17, 3.23%) followed by Hypocalcaemic adverse events (2.28%). The vasovagal reactions (Giddiness and nausea/vomiting) were higher in the high yield group (p = 0.0074) and all were of mild grade. Hypocalcaemic adverse events were limited to perioral tingling and numbness at tips of hand fingers, which most of the time responded to 1000 mg oral calcium. There was no significant difference between high yield and low yield group (p = 0.54). No severe adverse donor reactions noted during study period.

Table 3.

The frequency of observed adverse reactions during plateletapheresis

Adverse reaction	Number (%)	High yield (n = 174)	Normal yield (n = 352)	Significance
Giddiness	4 (0.76)	4	Nil	0.0074a
Nausea/vomiting	5 (0.95)	3	2
Hypocalcemia	12 (2.28)	5	7	0.54
Hematoma formation	10 (1.90)	3	7	0.31€
Phlebotomy failure	7 (1.33)	3	4
Total	38 (7.22)	18	20	0.0519

^avasovagal reactions

^€ phlebotomy related complications

The difference of donor adverse reaction between normal (20/352, 5.68%) and high yield group (18/174, 10.34%) was not statistically significant (p = 0.0519). The observed donor reactions were not associated with donor weight, pre-procedure platelet count and apheresis procedure related parameters (Table 4).

Table 4.

Comparison of donor and procedural parameters for donor reactions

Parameters	Donors with adverse reactions	Donors without adverse reactions	Significance (Asym. 2 tailed)
Weight	75.2 ± 9.14	77.2 ± 11.01	0.263
Platelet count pre	286.58 ± 45.38	284.05 ± 61.90	0.801
Product volume	311.28 ± 84.24	303.52 ± 86.17	0.587
Product yield	4.65 ± 1.28	4.57 ± 1.41	0.742
Blood volume processed	2612.82 ± 437.36	2619.69 ± 424.97	0.713
ACD used	316.59 ± 59.16	312.59 ± 64.12	0.924

Donor Haematological Parameters and Platelet Recruitment

Post procedure hematological parameters were available for 103 donors (Trima accel = 86, Amicus = 13 and COM.TEC = 4). The comparison of pre and post procedural hematological parameters between normal yield (n = 35) and high yield (n-68) is shown in Table 5. The donor post procedure haemoglobin and haematocrit were not significantly different from pre procedure value in normal yield group but differed significantly in high yield procedures. The change of Hb and Hct for high yield group was significantly different. The post procedure platelet count dropped by 61.94 ± 26.81 and 103.49 ± 29.85/µl for normal and high yield procedures respectively. We have observed a mean recruitment of 1.37 ± 0.64 (n = 103), which was seen in both normal (1.44 ± 0.71, n = 35) and high (1.33 ± 0.60, n = 68) yield procedures and did not differ statistically.

Table 5.

Comparison of hematological and procedural parameters between normal and high yield procedures

S. No.	Parameters	Normal yield (n = 35)			High yield (n = 68)			p value
		Pre	Post	Difference (Pre to post)	Pre	Post	Difference (Pre to post)
1	Hemoglobin (g/dl)	15.52 ± 1.07	15.51 ± 0.98	0.01 ± 0.47	15.45 ± 1.06	15.88 ± 1.10	− 0.43 ± 0.59	0.48a 0.011b 0.0001c
2	Hematocrit (%)	47.17 ± 3.17	47.15 ± 2.86	0.02 ± 1.78	47.14 ± 3.05	48.56 ± 3.31	− 1.42 ± 1.99	0.48a 0.005b 0.0002c
3	Platelet count (× 103/µl)	249.26 ± 60.88	187. 31 ± 43.81	61.94 ± 26.81	340.78 ± 42.19	237.29 ± 41.91	103.49 ± 29.85	–
4	Adjusted platelet count	187.74 ± 45.86			230 ± 38.3			–
5	Yield	3.38 ± 1.01			6.55 ± 0.67			–
6	Platelet recruitment	1.44 ± 0.71			1.33 ± 0.60			p = 0.18
7	Platelet collection rate	3.62 ± 0.83			6.22 ± 1.00			p = 0.00
8	Collection efficiency	0.64 + 0.13			0.75 ± 0.06			p = 0.00

^a pre to post for normal yield

^b pre to post for high yield

^c difference normal yield and high yield

Collection Efficiency and Collection Rate

The collection efficiency for 103 procedure was 0.72 ± 0.13 (95% CI—0.69 to 0.74). The collection efficiency with Trima accel, Amicus and COM.TEC apheresis equipment was 0.74 ± 0.10, 0.61 ± 0.22 and 0.51 ± 0.024 respectively. The collection rate and collection efficiency between normal and high yield procedures were significantly different with a p value ≤ 0.00 (Table 5).

Discussion

Blood component donation by apheresis especially platelet collection has become more common in modern transfusion practices. The technical advances in automated apheresis equipment have improved the productivity and quality of the collection of apheresis platelets [32, 33]. Transfusion of apheresis platelets are associated with reduced infectious complications, transfusion reaction rate, transfusion frequency and refractoriness to platelet transfusion [34]. The newest generation of cell separators can collect high platelet yields from a single donation [31]. However, the safety of platelet donors is a concern particularly post donation counts, contrary to high yield collection and technical possibilities [6]. During study period, 92.44% apheresis platelets yield was ≥ 3 × 10¹¹qualifing AABB standards requirement of at least 90% sampled unit to have ≥ 3 × 10¹¹ yield [5]. Approximately one-third (33.07%, 174/526) of the procedure performed during study period were of high yield (≥ 5 × 10¹¹) procedures. The previous investigator from India Makroo RN et al. [10] reported 33.97% of donor acceptance for double dose platelet while donor acceptance was 19.8% in study by Chaudhary R et al. [15]. The both studies have adopted platelet yield of ≥ 6 × 10¹¹ criteria for double dose yield.

In our study the high yield procedures were associated with higher platelet yield (6.41 ± 0.77 vs 3.87 ± 0.49), higher product volume (412.25 ± 66.93 vs 254.83 ± 30.94), higher processed blood volume of donor (2952.97 ± 408.79 vs 2470.46 ± 303.06), higher ACD used (337.3 ± 58.22 vs 299.23 ± 60.93) and higher run time (62.56 ± 9.05 vs 56.98 ± 9.86) than normal yield procedures and it was statistically significant.

The adverse donor reaction rate of 7.22% was observed which is comparable to 5.86% reported by Dogra K et al. [22] and 10.2% by Chaudhary R et al. [18] but much lower than reported by Patidar GK et al. [21] from India. The adverse reaction rate in total was almost similar between normal and high yield group (p = 0.52) establishing the safety of high yield procedures as reported by Heuft HG et al. [6] and Picker SM et al. [19] previously. The subgroup analysis of adverse reaction showed, no difference of hypocalcaemic reactions but vasovagal reactions (giddiness and nausea/vomiting) were significantly higher in high yield group (p = 0.0074). The vasovagal reaction observed in both groups was 1.71% which is higher than earlier investigators from India [21, 22] but all the vasovagal reaction reported were mild, no moderate to severe reaction observed.

The safety of high yield procedures was also addressed in term of changes in haematological values after donation. The safety concerns with regards to low Hb (< 12gms/dl) and platelet count less than 1 × 10⁵/μl after donation have been reported by Das SS et al. [35]. In present study, no difference was observed for donor haemoglobin and haematocrit before and after donation for normal yield collections but there was significant high haemoglobin (p = 0.011) and haematocrit (0.005) after donation among high yield group. A rise as well as drop in haemoglobin and haematocrit values have been reported previously [35–37]. The adjusted post platelet count as described by Fontana S et al. [31] were calculated for both groups but were not significantly different for both normal (p = 0.48) and high (p = 0.145) yield groups. The observed platelet loss per 1 × 10¹¹ platelet collection for normal and high yield group was 17.54 ± 7.41 and 15.94 ± 4.80 respectively which was less than reported by Simon et al. [24]. This can be explained by recruitment of platelets during apheresis procedure. Approximately 1/3 of body platelets are in splenic pool which are in equilibrium with platelets in peripheral blood [38] which can be released into circulation during apheresis as documented by previous workers [31, 39, 40]. The recruitment of platelet was present in ¾ of the plateletapheresis procedures (77/103, 74.76%). The 1/4 of donors didn’t showed platelet recruitment possibly due to individualized variation in splenic sequestration and donor related factors. The platelets pooled in spleen varies among normal individuals and splenic sequestration is affected by many factors including donor hematocrit, adrenergic state and blood flow to spleen [41, 42].

The collection rate (3.62 ± 0.83 vs 6.22 ± 1.00 per hour, p = 0.000) and collection efficiency (0.64 + 0.13 vs 0.75 ± 0.06, p = 0.000) differed significantly for both normal and high yield group. The observed collection efficiency for Trima accel and Amicus was 0.74 ± 0.10 and 0.61 ± 0.22 respectively. The comparison of these two equipment and equipment-based subgroup analysis between normal and high yield procedure was not feasible due to a smaller number of procedures performed on Amicus apheresis equipment. Both Trima and Amicus equipment has been reported efficacious in collection of high yield plateletpheresis [13, 16]. The comparison of reported collection efficiency for both equipment by various investigators with our findings is provided in Table 6 [11, 19, 43, 44].

Table 6.

Comparison of collection efficiency with published literature

	CE (Trima accel)	CE (Amicus)
Present study	0.74 ± 0.10	0.61 ± 0.22
Picker SM [11]	74.5 ± 3.9	71.1 ± 3.9
Keklik M [19]	74.99 ± 14.4	–
Keklik M [43]	83.57 ± 17.19	66.71 ± 3.47
Burgstaler EA [44]	76	86

Conclusion

The high yield platelet collection by apheresis is safe to be performed for Indian donors as adverse effects are somewhat similar to normal yield collection. All the recent equipment are capable of collecting high yield products with their inherent differences. The recruitment of platelets may help in accepting donors with low platelet count (< 250 × 10³/µl) for high yield procedure safely at region which have concerns for donor safety due to prevalence of low platelet counts [45].

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest relevant to the manuscript submitted to journal.