|Year : 2015 | Volume
| Issue : 2 | Page : 53-60
Factors related to blood donors that may affect the quality of platelet concentrates
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
|Date of Web Publication||30-Apr-2015|
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh
This review is intended to summarize the literature in regard to blood donor-related platelet defects that might affect the quality of platelet concentrates (PCs). Donor-related platelet defects can be defined as all platelet defects, transient or permanent in nature, which may undermine the effectiveness of platelet therapy that are caused by factors related to the donor, and not due to collection, processing or storage. Although it seems that those factors might affect the quality of PCs, there is still significant work that needs to be done to understand their impact on the efficacy of platelet transfusion.
Keywords: Platelet concentrate, platelet function, platelet transfusion
|How to cite this article:|
Albanyan A. Factors related to blood donors that may affect the quality of platelet concentrates. J Health Spec 2015;3:53-60
| Introduction|| |
Platelets are small discoid enucleated cells with a diameter of 2.0 - 4.0 μm. They circulate for 7 - 10 days before being cleared, mainly by the reticuloendothelial system. Nearly 100 billion platelets are produced from megakaryocytes every day to maintain a normal count of 150 - 400 × 10 9 /L. Platelet transfusion is indicated to treat (therapeutic) or prevent (prophylaxis) bleeding in patients with thrombocytopenia or less commonly thrombocytopathy. However, the accurate diagnosis of the underlying abnormality is important as platelet transfusion in some thrombocytopenic conditions may be contraindicated (e.g., thrombotic thrombocytopenic purpura).
Millions of platelet concentrates (PCs) are transfused around the world every year.  A significant percentage of these PCs are used in the management of patients undergoing chemo-or radiotherapy where it has become an essential part of their therapy. However, this procedure can trigger serious side-effects. It also significantly adds to the cost of the patients' therapy, particularly those who require frequent platelet transfusions.
Currently, platelet function is generally not assessed prior to donation in blood donors, prior to transfusion in PCs, nor after transfusion in the recipients' blood.  Platelet transfusion effectiveness is monitored by measuring the corrected count increments, which is a rough measure of platelet survival, but provides little information on platelet function. Platelet function and survival are two different aspects, and the results of one cannot necessarily be extrapolated to the other. It is possible that the unexplained variation in the effectiveness of transfused PCs and the controversy over the optimal platelet dose and dosing interval are partly caused by the variation in the functional potential of PCs. This review aims at reviewing the literature in regards to factors affecting the function of platelets prior to donation. As for platelet function testing, there are several excellent reviews available in the literature on this subject. ,
The PCs are increasingly being sourced from single donors (SD) via aphaeresis (SD - PC) in many countries around the world. In the USA, the use of SD - PC has exceeded that of the pooled PC since 1994.  Unlike pooled PCs, where the donor platelets' quality is potentially less important as pooling may mask the defect from one donor, the donor quality is very important in the case of SD - PC. 
Donor-related platelet defects can be defined as all platelet defects, transient or permanent in nature, that may undermine the effectiveness of platelet therapy which are caused by factors related to the donor, and not due to collection, processing, or storage. Unlike some storage-induced defects, where they are reversible after transfusion, donor-related defects are unlikely to be reversible.  Those defects are particularly important when the platelet dose is largely derived from one donor, as in SD - PC, or when the recipient is an infant, receiving one platelet unit produced from the whole blood of one donor.
Theoretically, any donor with defective platelets should be deferred from the donation as transfusion of defective platelets would undermine the efficacy of platelet therapy. Currently, there is no routine testing of the donor platelets, and the quality of the donor platelets is largely assumed based on detailed questionnaires and physical examination. The questionnaires include questions about family history of bleeding and recent drug intake. Although this practice may exclude donors with severe defects, it might not detect those with mild or transient defects. Therefore, some donors, particularly with acquired platelet defects may not be identified. 
Due to the wide use of SD - PC, the donor variable in the equation of PC quality is becoming increasingly important. Donor-related platelet defects can be classified into defects associated with frequency of donation and influence of the apheresis procedure, and acquired defects caused by diet or drugs.
| The Short- And Long-Term Effects of The Platelet-Pheresis Procedure and The Effect of The Frequency Of Donation on The Donors' Platelet Function|| |
There are many factors that should be taken into consideration when studying the effect of platelet-pheresis on the donor platelets. These include: length of the interval between donations, the total number of donations, the number of units donated per session and the technology of the separator. Platelet-pheresis is generally considered as a safe procedure with minimum adverse effects.  However, the short- and long-term effects of this procedure on platelet function are not clear.
Some studies that investigated the effect of platelet-pheresis were mainly prompted by the results of other studies that detected the presence of in-vivo activated platelets after other forms of extracorporeal circulation. However, there is an essential difference between platelet-pheresis and other forms of extracorporeal circulation in that most platelets are collected and carried in a bag. Thus platelets, which might be activated by the procedure are not re-infused. 
| The Short-Term Effects of The Apheresis Procedure|| |
Based on flow cytometric studies, platelet-pheresis seems not to cause platelet activation in-vivo. Many of these studies did not find activated platelets in-vivo post platelet-pheresis as assessed by the expression of CD62P, CD63 and CD42b using two different separators (Spectra and AS 104)  or four different separators (Spectra LRS, MCS, Amicus-90 min and Amicus 45 min).  Moreover, no difference was found in the expression of CD62P, fibrinogen binding or PS of resting platelets or when activated with thrombin receptor activation peptide. , Further, Barnard et al., could not find differences between pre- and post-platelet-pheresis in the donors' levels of CD62P, activated granulocytes or platelet-granulocyte aggregates. 
A study by Gutensohn et al., demonstrated an increase in CD62P and CD63 mean fluorescence index (MFI) post donation for up to 5 days.  However, the percentage of platelets expressing these markers was not measured in this study. Therefore, this increase in MFI may reflect only an increase of expression in a small fraction of cells, which may be as low as 1%.
Aggregation studies, however, seems to show that responsiveness to some agonists may be reduced in some donors post platelet-pheresis. Choi found that platelet aggregability to epinephrine is markedly reduced after platelet-pheresis and also some donors show non responsiveness to epinephrine or adenosine diphosphate (ADP). The aggregability to epinephrine, however, normalized within 24 - 72 h and even improved after 3 weeks.  In another study, some donors exhibited significant but slight reduction in aggregation to ADP after platelet-pheresis, which lasted for more than 24 h.  However, many studies, but not all,  did not find reduced aggregation in response to ADP plus epinephrine, collagen, or ristocetin after platelet-pheresis. , Differences between studies may be explained, in part, by the different types of separators that had been used.
Using platelet function analyser-100 (PFA-100), a slight but significant prolongation of the closure time (CT) of collagen/epinephrine (CEPI) following platelet-pheresis was found, but the mean CEPI CT post donation (204 s) was not very different from the upper limit of the normal range (194 s) and none of the donors had CT >300 s.  Moreover, in a larger study, Boehlen and Clemetson found significant prolongation of the overall means of the CT of CEPI and collagen ADP (CADP) after platelet-pheresis, but it still remained within normal ranges. A fraction of the donors had prolonged CEPI and CADP CTs (18% and 15% respectively) and 7% had CT >300 s.  However, it is not clear for how long this effect will persist.
Taken together, these studies indicate that there is little or no in-vivo platelet activation post platelet-pheresis. However, the responsiveness to weak agonists (ADP and epinephrine) may be transiently reduced after platelet-pheresis in some donors. The significance of this transient impairment is unknown.
| Long-Term Effects of Platelet-Pheresis|| |
It has been suggested that repeated donation may lead to the production of dysfunctional platelets due to intense or exhaustion of thrombopoiesis.  It has also been reported that reticulated platelets, mean platelet volume , and thrombopoietin (TPO)  increase significantly after platelet-pheresis and this may persist for few days. The increase in TPO levels would be expected as the decrease in platelet numbers decreases the availability of TPO receptors. Nevertheless, an American retrospective study found that donors who regularly donated for 4 years had sustained and a significant decrease in platelet counts indicating a possible effect of platelet-pheresis on thrombopoiesis. Interestingly, the number of donations directly correlated with the decrease in platelet count. In contrast, Stohlawetz did not find any difference in platelet count post donation between 1 st -time platelet-pheresis donors and regular donors who donated for 18 months every 2 weeks.  The long-term effect is therefore not clear, and large prospective studies are important to determine the effect of platelet-pheresis on thrombopoiesis.
| The Effect of The Frequency of Donation|| |
According to the UK blood transfusion guidelines, the minimum interval between platelet-pheresis donation is 48 h with a maximum of 2 procedures per week and 24 procedures per year. Repeat platelet-pheresis procedures on less than 2-week basis for 1 year have been found, in remunerated donors, to significantly correlate, though weakly, with prolonged CEPI CTs values.  This however should be interpreted with caution as remunerated donors are more likely to withhold some information (e.g., aspirin intake) that may lead to their deferral, particularly if we know that short donation intervals also correlated with low TXB2 levels in this study. In a more recent study in volunteer donors, no correlation was found between decreasing donation frequency (>60% donated on 4 - 10 week basis) and long CEPI or CADP. 
| Acquired Platelet Defects Due to Drugs or Diet|| |
More than 100 components of foods, drugs or vitamins have been shown to cause potential platelet defects. , In addition, exercise,  smoking,  and major depression  have been shown to alter platelet function. Among all of these factors that may affect platelet function, the effect of diet and drug on platelets and particularly in relation to platelet donors will be discussed next.
| Diet-Induced Platelet Function Defects|| |
Many components of commonly consumed foods have been suggested to alter platelet function, mainly based on ex-vivo or in-vitro studies.  However, the clinical significance of many of the diet-induced platelet defects is not clear. Further, the effect of these defects on the effectiveness of platelets transfusion or how it influences the classical platelet storage lesion is largely unexplored. The duration of the effect on platelets is also not clear for many of these components. Some components, however, seem to affect platelets transiently. Blood donors are advised to eat before donation and even though the effect of these components disappears within hours some donors may donate ex vivo functionally defective platelets. For example, in a study  2 of 24 whole blood donors had CEPI CT of ≥300s, which they suggested to be due to chocolate consumption 6 h before donation. In here, some examples of food components that affect platelet function and their mechanism of action will be discussed briefly.
Several epidemiological studies have shown correlation between consumption of certain foods, flavonoid-containing food and reduced cardiovascular disease risk and mortality rate,  which is thought to be partly due to the ability of these components to inhibit platelet function, in addition to improving endothelial function. 
Therefore, flavonoids, which can be found in tea and grape juice, have been extensively studied to determine their effect on platelets. An important in-vivo study by Demrow et al. demonstrated the ability of flavonoids to inhibit platelet aggregation in dogs, after acute intragastric injection of red wine or grape juice.  Similarly, it has been shown that ex-vivo aggregation in response to collagen decreased significantly (77%) after drinking purple grape juice for 1 week. 
Inhibition of TXA 2 -induced platelet activation seems to be a common target for many food components. For example, production of TXA 2 was reduced ex-vivo and in-vitro by ginger and oil of cloves, respectively. Recently, a number of mechanisms for this inhibition have been suggested such as blockade of the thromboxane receptor by some types of flavonoids  and interference with the TXA 2 production pathway (by inhibiting both AA liberation and TXA 2 synthesis).  Components acting via the former mechanism may produce an aspirin-like defect when stimulated with AA; however, those acting via the latter mechanism may produce a similar aspirin defect when stimulated with AA or tested for TXB 2 generation.
Further, a similar aspirin pattern on the PFA-100 test has also been reported 2 - 6 h after consumption of cocoa , and chocolate. , How these in-vitro results, which resemble some aspects of aspirin, translate to the hemostatic function of platelets in-vivo is not fully clear.
Other mechanisms of platelet function inhibition by dietary components may include blocking the vWF binding site on GPIba as suggested for flavone-8-acetic acid (flavonoid). This component, which inhibits ristocetin induced platelet agglutination in-vitro, has been shown to reduce platelet deposition on the site of injury in-vivo.  Since the PFA-100 is a high shear system, the inability of vWF to bind GPIba might prolong the CT on both cartridges. In contrast, a component of garlic has been found to inhibit thrombus formation at low and high shear rate, but it did not impair ristocetin-induced agglutination.  Moreover, many flavonoids have been shown to inhibit dense granule release in response to AA, collagen or the thromboxane analog (U46619).  Furthermore, CADP CT has been shown to be prolonged 2 and 6 h following consumption of chocolate  or caffeine beverages.  Finally, the effect of food components is not only inhibitory, but may also induce platelet activation. 
| Drug-Induced Platelet Function Defects|| |
There are many drugs that can affect platelet function; however, the intention here will be mainly devoted to nonsteroidal anti-inflammatory drugs (NSAIDs). This is because platelet donors are not likely to be on drugs for chronic or serious diseases. Some NSAIDs, including aspirin, are over-the-counter drugs (without prescription) that are commonly used and not considered as a drug by some donors. Therefore, such drug intake may not be declared before donation.
| Nonsteroidal Anti-Inflammatory Drugs|| |
Nonsteroidal anti-inflammatory drugs are heterogenous group of drugs that share a common mechanism of action, inhibition of prostaglandin synthesis. NSAIDs are among the most commonly used drugs and aspirin, in particular, is considered the most commonly used drug in the world.  NSAIDs are mainly used for their antipyretic, anti-inflammatory and analgesic effects. A commonly used analgesic drug, acetaminophen, is not considered as a member of the NSAIDs; however, it has a very weak anti-inflammatory effect and has been recently suggested to inhibit platelet function.
The half-life (t½) of NSAIDs in plasma varies, but they generally fall into two groups, short with t½ between 1 and 5 h and long with t½ between 10 and 60 h. Although their effect on platelets was thought to last for as long as 1-week, recent evidence suggests that the effect of ibuprofen, a common NSAID, on platelet function, as assessed by the PFA-100, normalizes within 24 h after the cessation of the drug. 
| Aspirin (Acetylsalicylic Acid)|| |
Since platelets are enucleated cells and aspirin irreversibly inhibit COX, the effect of aspirin on platelets lasts for their entire lifespan. Aspirin inhibits COX activity thereby blocking the synthesis of TXA 2 in platelets. Although TXA 2 is an important platelet-feedback agonist, other pathways can bypass it and induce full platelet activation and aggregation. Therefore, aspirin is considered a weak antiplatelet drug.
To completely abrogate the production of TXA 2 , a single dose of 100 mg is sufficient in normal individuals. As a function of platelet turnover, COX activity recovers by about 10% per day after a single dose.  After aspirin ingestion is stopped, normal hemostasis may be restored even before all the platelet population is renewed. It has been suggested that as low as 5 - 10% of platelets with normal COX can suffice for the aspirin effect and restores normal hemostasis. Platelet donors are deferred if they have ingested aspirin within the last 48 h as the AABB requires, or 5 days as the UK guidelines require. Other blood components can be taken from a donor who has ingested aspirin within these limits.
After oral administration, aspirin blocks COX activity within 1 h and results in measurable platelet inhibition.  The plasma t½ of aspirin is 20 min and it is almost completely hydrolyzed to salicylate, which also has an anti-inflammatory action. Salicylate is inactivated by conjugation with glycine.
This reaction t½ is 4 h. However, at high therapeutic doses, this process is saturated leaving salicylate without inactivation. The side-effects of aspirin mainly result from its effect on the normal function of protective prostaglandins. This might lead to serious complications such as gastric ulcers, the risk of bleeding and renal failure. Some individuals, who usually suffer from preexisting urticaria or asthma, may be aspirin-sensitive or intolerant.  Therefore, concerns over the presence of American Society of Anesthesiologists (ASA) in blood units should not be dismissed. Sharon et al. have reported a case who was transfused a blood component and developed urticaria which was found, after further investigation, to be due to the presence of 20 mg/L aspirin in the blood. The recipient was also found to be allergic to aspirin indicating that the donor might have taken aspirin very shortly before the donation. 
| Acetaminophen (Paracetamol)|| |
Acetaminophen (t½ 2 h), which is a very weak anti-inflammatory drug,  was thought to have no antiplatelet effect; however, a number of recent reports have shown that it has a weak COX inhibitory effect. , This effect appears to be dose-dependent in-vitro as assessed by aggregation and TXB2 production; however, the PFA-100 CTs were prolonged at high concentrations only. Paracetamol also appears to synergize with a traditional NSAID, diclofenac, by inhibiting platelets. , Of note, currently, platelet donors are not deferred for acetaminophen ingestion. However, the accumulating evidence that suggests it can impair platelet function indicates that this issue should be re-evaluated. The incidence of paracetamol ingestion among blood donors has been reported to be between 2.5% and 6.12%. ,
| Drugs Other Than Nonsteroidal Anti-Inflammatory Drugs|| |
Although there is a wide range of drugs that have been shown to affect platelet function in-vitro, the clinical relevance of this inhibition is still not clear.  These drugs include antibiotics (penicillin), cardiovascular drugs, thrombolytic agents and chemotherapeutic agents. In the case of blood donation, donors must be healthy, and those taking drugs for chronic illnesses are unlikely to donate blood. However, the presence of certain drugs in some donors' blood has been reported. Penicillin, which has been found to inhibit platelet aggregation and prolong the BT  has been detected in the sera of blood donors.
The incidence of defective platelet function among platelet donors: A few studies that evaluated the incidence of defective platelets among platelet donors have focused mainly on the occult intake of aspirin. This is not surprising as aspirin, unlike many other factors that alter platelet function, has been shown to be associated with clinical bleeding, particularly postoperatively in some types of surgical procedures.  Moreover, patients ingesting aspirin 2 days or less before an operation have increased allogenic red blood cell transfusion requirements preoperatively. Therefore, undisclosed intake of aspirin is among the most important causes of acquired platelet defects among platelet donors. Therefore, in here, the focus will be mainly on aspirin ingestion among platelet donors.
In the 1970s, there were some concerns over the incidence of donors donating potentially defective platelets due to ingestion of aspirin. Mielke and Britten described their findings as a potential "nightmare for blood bankers" when about half of the donors in their study were found to have ingested aspirin within the last week.  Aspirin is an over-the-counter drug that is commonly used, and many donors may not consider it as a drug. Therefore, some donors may not recall aspirin ingestion [Table 1].
|Table 1: List of studies that have tested the effect of donor related variables on Platelet Function|
Click here to view
Utilizing Trinder's method, which detects salicylate (a major metabolite of ASA), McCann et al. found that 11.2% of donors had ingested salicylate.  In another study and on a larger sample, Sharon et al. (1982) found a lower percentage of 6%.  However, aggregation studies showed a higher percentage of donors (ranged 14 - 47%) with abnormal platelet aggregation.  The higher percentage found with aggregation studies, maybe due to the fact that Trinder's method can detect only recent ingestion of aspirin since salicylate is cleared rapidly from the circulation.
More recently, the interest in investigating the incidence of donors with defective platelets has revived. This was mainly driven by advances in platelet function testing, particularly the development of PFA-100® . In a relatively small study, Paglieroni et al. found that 38% of all blood donors had prolonged CEPI-CT and normal CADP-CT with 17% >300s, indicative of an aspirin-like defect. This was also confirmed by reduced responsiveness to stimulation by epinephrine as assessed by low expression of CD62P and PAC-1 in donors with prolonged CEPI CT. 
In apheresis-remunerated donors, Jilma-Stohlawetz et al. found that 20% of donors had prolonged CEPI-CT with 11% >300s. Harrison et al. reported a lower percentage (16% with prolonged CEPI CT with 4% >300 s) of volunteer donors and the prolongation was largely transient upon re-testing. The difference in the reported percentages between those two studies may be attributed to the use of paid donors in the former study. Moreover, the anticoagulant concentration in the first study was higher, which is known to be associated with longer CTs. 
In these studies, aspirin is not necessarily the only reason for this CEPI CT prolongation as other factors, mainly dietary, can also give similar patterns.  For example, it has been shown that an intake of 19 g cocoa prolonged CEPI CT's by 44% and CADP by only 13%,  which indicates that cocoa might also show an aspirin like effect. Moreover, Jilma-Stohlawetz et al. found a substantial number (10/23) of donors with non-CT CEPI had levels of TXB2 not indicative of ASA consumption. 
| Conclusions|| |
Although when the prolonged CEPI CT results are coupled with a decrease in TXB2 are strongly suggestive of aspirin intake, it is not conclusive. This is because there are many dietary factors that also inhibit platelet function and lead to decreased TXB2 levels as discussed in the previous section. Therefore, for the detection of undisclosed intake of aspirin among blood donors, more specific tests should also be undertaken. A combination of more than one test such as, PFA-100® , aggregation, and TXB2 measurement would be more specific in detecting aspirin ingestion.
Nevertheless, these studies have shown that a significant number of donors may potentially donate defective platelets. Moreover, as prolongation of CEPI-CT in the PFA-100 test, in particular, has been found to predict bleeding during surgery,  it is reasonable to assume that deferring those donors from donating defective platelets should, therefore, potentially improve the efficacy of transfusion. However, this has to be proven by further studies on the effect of aspirin ingestion on the classical platelet storage lesion as well as by in-vivo studies.
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