The effect of iron balance on platelet counts in blood donors

The effect of iron balance on platelet counts in blood donors

Anne F Eder 1, Yu Ying Yau 1, Kamille West 1
Affiliations expand
PMID: 27900761
DOI: 10.1111/trf.13881

Abstract

Background: Thrombocytosis (or, less commonly, thrombocytopenia) is associated with iron-deficiency anemia and resolves with iron therapy. Many volunteer blood donors have low iron stores, with or without anemia. Iron balance could affect platelet counts in blood donors.

Study design and methods: Whole blood donors deferred for finger-stick hemoglobin levels less than 12.5 g/dL were evaluated by complete blood count and serum iron panel before and after oral iron treatment. Group assignment for iron depletion was based on serum ferritin cutoffs of less than 20 µg/L for women and less than 30 µg/L for men or was based on changes in serum ferritin levels after iron replacement.

Results: Among 1273 Hb-deferred whole blood donors, 55% (619 of 1128) of the women and 70% (102 of 145) of the men were iron depleted. Iron-depleted donors had higher platelet counts compared with donors who had normal ferritin levels (women: 286 vs. 268 × 103 /µL; p < 0.0001; men: 246 vs. 222 × 103 /µL; p = 0.0454). Only 4.4% of iron-depleted donors had thrombocytosis (> 400 × 103 /µL) compared with 2.0% of donors who had normal ferritin levels (p = 0.017). Iron replacement decreased platelet counts in iron-depleted female donors (mean, -19,800/µL; interquartile range, 8000 to -45,000/μL), but not in donors who had normal or stable ferritin levels. The same trends were observed in male donors.

Conclusion: Iron-depleted donors had higher platelet counts than donors who had adequate iron stores. Oral iron replacement decreased platelet counts on average by about 20,000/µL in iron-depleted donors but had no effect on platelet counts in donors who had normal or stable ferritin levels.

Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Ruxolitinib

Ruxolitinib (Oral Route)


Description and Brand Names
Before Using
Proper Use
Precautions
Side Effects

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IBM Micromedex

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of ruxolitinib in children to treat myelofibrosis or polycythemia vera or in children younger than 12 years of age to treat steroid-refractory acute graft-versus-host disease. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ruxolitinib in the elderly.
Breastfeeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Abatacept
Boceprevir
Clarithromycin
Cobicistat
Conivaptan
Fluconazole
Idelalisib
Indinavir
Itraconazole
Ketoconazole
Lopinavir
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Anemia (low number of red blood cells) or
Dyslipidemia (high cholesterol or fats in the blood) or
Neutropenia (low number of white blood cells) or
Skin cancer, history of or
Thrombocytopenia (low number of platelets) or
Tuberculosis, or history of—Use with caution. May make these conditions worse.
Infection—May decrease your body's ability to fight infection.
Kidney disease, moderate or severe or
Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
Kidney disease, requiring dialysis—This medicine should be taken after your dialysis treatment.

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy

Adam S. Fisch, Christina G. Perry, Sarah H. Stephens, Richard B. Horenstein, and Alan R. Shuldiner
Author information Copyright and License information Disclaimer

The publisher's final edited version of this article is available at Curr Cardiol Rep
See other articles in PMC that cite the published article.

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Abstract

Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with the new diagnostic targets and therapeutic strategies on the horizon hold promise for more effective individualized anti-coagulation and anti-platelet therapy.

Keywords: Pharmacogenomics, Personalized medicine, Anti-platelet therapy, Clopidogrel, Plavix, Warfarin, Coumadin, CYP2C19, CYP2C9, VKORC1, Platelet function, Cardiovascular disease, Thrombosis, Coronary artery disease, Percutaneous coronary intervention, Anti-coagulation
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Introduction

Anti-coagulant and anti-platelet medications are widely prescribed drugs used for the primary and secondary treatment of a variety of pathological thrombotic processes such as thrombotic cerebrovascular and cardiovascular diseases, atrial fibrillation, pulmonary embolism, deep vein thrombosis and genetic or acquired hypercoagulability. Warfarin is the most commonly used oral anti-coagulant, whereas the most commonly used anti-platelet medications include aspirin and clopidogrel, each of which influences blood hemostasis through different mechanisms. Marked inter-individual variation in response to these commonly prescribed medications have been well-documented and represent a significant challenge to medical practice [1•]. Warfarin has a relatively narrow therapeutic index around which under-dosing may result in recurrent thrombosis and over-dosing may result in severe and life-threatening bleeding. While newer agents such as dabigatran and rivaroxaban are now available, physicians’ familiarity with warfarin, its effectiveness when dosed properly, and its low cost continue to make it the anti-coagulant treatment of choice. Likewise, clopidogrel continues to be widely prescribed due to its efficacy in the majority of patients as well as its relatively low price, while newer anti-platelet medications such as prasugrel and ticagrelor often function as alternative anti-platelet agents offered to patients for whom clopidogrel is not effective.

 Understanding factors that influence response to these agents offers practical opportunities for more individualized and effective therapy.

Several gene polymorphisms have been found that reproducibly contribute to inter-individual response variability to warfarin and clopidogrel. The aim of this review is to familiarize the reader with the gene polymorphisms found thus far that most significantly contribute to a given individual’s response to either of these two medications; because of the lack of genetic polymorphisms reproducibly associated with aspirin response, aspirin pharmacogenomics will not be discussed in this review, though others have covered the issue very well [2-4]. With bona fide common polymorphisms that can predict one’s response to warfarin and clopidogrel now in hand, the next challenge and active area of investigation is the development of strategies to implement these discoveries into clinical practice.

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Warfarin

In 1948, warfarin was introduced as a pesticide against rodents. Recognizing its potent anti-coagulant action and potential efficacy for thrombotic disease, warfarin was approved for use in humans in 1954 and remains among the most commonly prescribed drugs today. It is derived from dicoumarol, a natural product initially isolated from sweet clover. Its synthetic form consists of both R and S enantiomers of which the S form is more active. Each form is metabolized through a different mechanism, with S-warfarin metabolized primarily by cytochrome P450 2C9 (CYP2C9) and R-warfarin metabolized predominantly by CYP3A4 [5]. Warfarin acts by inhibiting the vitamin K epoxide reductase complex by binding to the VKORC1 subunit, thus preventing reduced vitamin K-dependent gamma-carboxylation of clotting factors II, VII, IX and X, as well as proteins C and S, resulting in a potent anti-coagulant effect [6].

Dosing of warfarin typically involves a loading dose followed by daily maintenance therapy. Its therapeutic dosing is monitored by measuring activity of the extrinsic coagulation pathway using the standardized international normalized ratio (INR). There is wide inter-individual variation in the warfarin dose required to reach a therapeutic INR. Factors that markedly affect the anti-coagulant effect of warfarin include diet, particularly foods high in vitamin K, smoking, certain drugs and botanicals that affect warfarin metabolism, alcohol, body weight, and age [7]. Based upon knowledge of the mechanism of action and metabolism of warfarin, candidate gene studies have identified three genes whose common variation explains ~40%, and up to 54% of inter-individual response to warfarin dose, depending on the ancestry of the population studied. More recent genome-wide association studies (GWAS) have provided additional insights into warfarin pharmacogenomics.

CYP2C9

The CYP2C9*1 allele encodes a fully active enzyme, has the highest frequency of the 30 different alleles discovered to date, and is considered the wild-type allele. Although frequencies vary across ethnic populations, the most common decreased function alleles are CYP2C9*2 (C430T; rs1799853) and *3 (A1075C; rs1057910) alleles, which encode enzymes with 70% and 20% of wild-type enzyme activity, respectively. Multiple studies now show that patients with CYP2C9*2 and *3 alleles have greater sensitivity to warfarin, requiring lower doses to achieve a therapeutic INR [8, 9]. Among the initial important studies, Higashi and colleagues performed a retrospective study of 185 largely Caucasian patients followed in two Seattle area anticoagulation clinics, and found that compared to the *1/*1 genotype, patients with one or two copies of the *2 or *3 variant required significantly lower daily doses of warfarin [8]. Gage and colleagues examined the effect of the CYP2C9 variants in 369 patients who were taking maintenance doses of warfarin and found that the presence of the *2 or *3 variant was strongly associated with lower warfarin dose necessity; the maintenance dose was decreased by 19% per *2 allele and by 30% per *3 allele [9]. From these and other studies, it has become clear that about 13% of the variability in warfarin dose can be explained by CYP2C9 polymorphisms.

As might be expected of patients who have increased sensitivity to warfarin, several studies indicate that CYP2C9 decreased function allele carriers are at increased risk of over-anti-coagulation and bleeding events [10-12]. Higashi found that patients carrying *2 or *3 alleles experienced a bleeding rate of 10.92 per 100 patient-years, which was significantly higher than the 4.89 per 100 patient-years experienced in the *1/*1 homozygotes [8].

Some uncommon CYP2C9 decreased function alleles include *5, *6, *8, and *11. These alleles have not been studied as thoroughly but would be predicted to have similar effects as the more common CYP2C9 decreased functional alleles [13]. The allele frequencies vary noticeably among ethnic groups; for example, the frequencies of CYP2C9*2 and *3 are higher in Asian populations than Caucasian populations, which have higher frequencies of the alleles than African-American populations [12, 13]. Importantly, the allele frequency of CYP2C9*8 among African-Americans is approximately 9%, suggesting that this allele should be measured and considered in warfarin dosing algorithms [14].

VKORC1

The VKORC1 G-1639A (rs9923231) variant is located in the promoter region and results in decreased transcription as well as lower levels of VKORC1 messenger RNA (mRNA) [1•, 15]. Another VKORC1 variant, C1173T (rs9934438), is in complete linkage disequilibrium with G-1639A [16]. Decreased VKORC1 expression is associated with increased warfarin sensitivity and thus patients heterozygous (G/A) and homozygous (A/A) for the VKORC1 G-1639A variant require lower doses of warfarin compared to individuals homozygous for the wild-type VKORC1 genotype (G/G) [17]. The early important study demonstrating the potent effect of VKORC1 variants on warfarin dose was carried out by Rieder and colleagues with the same Seattle area cohort discussed above. They found that compared to those patients homozygous for the wild-type VKORC1 allele, having one of five highly correlated variants predicted an approximately 25% variance in warfarin dose. The effect of the VKORC1 variants on warfarin dose in this study was more potent than the CYP2C9 variants and accounted for 10% of the variance in warfarin dose. With respect to Rieder’s findings, it is currently estimated that the VKORC1 G-1639A variant accounts for 24% of the variation in warfarin dose [16]. The frequency of the VKORC1 -1639A allele is approximately 40% in Caucasians, 20% in African-Americans, and 85% in Asians [16, 18]. As might be expected, the VKORC1 -1639A allele has been shown to be associated with increased bleeding events and over-anti-coagulation [18, 19]. In a randomized trial of genotype-guided versus standard warfarin dosing, Anderson et al. [19] found that patients who carry variants in both CYP2C9 and VKORC1 were at a significantly increased risk of an elevated INR (INR>4) compared to all other patients.

CYP4F2

After vitamin K is reduced by the vitamin K epoxide reductase complex, the reduced form of vitamin K can used in the synthesis of coagulation factors or it can be converted into hydroxyl-vitamin K1 by the enzyme CYP4F2, encoded by the CYP4F2 gene [20]. The rs2108622 variant in CYP4F2 is a C>T nucleotide substitution that introduces a V433M missense mutation resulting in a CYP4F2 enzyme with decreased function [21]. Patients with the CYP4F2 decreased function T allele require 4-12% more warfarin per allele compared to CC homozygotes [22], accounting for approximately 1.1-7% of the inter-patient variability in warfarin dose requirement [23, 24]. The frequency of rs2108622 T alleles is approximately 25% among Caucasians and Asians, with a lower frequency of 7% observed among African-Americans [22]. Moreover, dosing models designed to include rs2108622 along with CYP2C9 and VKORC1 variants resulted in improved overall warfarin dose predictability [25]. Two GWAS identified the same three variants as being significantly associated with warfarin response [26, 27]; other genome-wide significant associations were not detected, suggesting that it is unlikely that there are other common variants that exert as large an effect.



Translation of Warfarin Pharmacogenomics into Patient Care

CYP2C9, VKORC1, and CYP4F2 genotyping is likely to have clinical utility, allowing clinicians to better individualize warfarin dosing to enhance efficacy and decrease adverse events such as bleeding. In 2007, the FDA modified the package insert of warfarin to reflect the clinical utility of VKORC1 and CYP2C9 genotype to include the statement, “lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes” [28]. The package insert was later modified in 2010 to include a table containing recommended daily warfarin doses for patients with various CYP2C9 and VKORC1 haplotypes [7]. There are currently several trials examining application of genetics in warfarin therapy, including the Warfarin Adverse Event Reduction For Adults Receiving Genetic Testing at Therapy Initiation (WARFARIN, 2011-2014) Trial, and the Clarification of Optimal Anticoagulation Through Genetics (COAG, 2009-2013) Trial. Both of these are NIH-funded prospective randomized clinical trials designed to determine if a dosing algorithm that includes genotypes for warfarin-response genes, such as CYP2C9 and VKORC1, can result in a greater proportion of time within the therapeutic INR range, as well as decreased warfarin-related clinical events, compared to standard dosing practices that do not include genotypes. A number of warfarin dosing algorithms and tables, such as those found at http://www.warfarindosing.org [29], have been developed that incorporate genotype to estimate warfarin dose. In addition, the Pharmacogenomics Research Network Clinical Pharmacology Implementation Committee recently published guidelines for warfarin dosing recommending that pharmacogenetic algorithm-based dosing be used when possible, and if electronic means for dosing are not available, the table-based dosing approaches are suggested [7].
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Clopidogrel

Clopidogrel is an oral second-generation thienopyridine that prevents platelet activation and aggregation by irreversibly inhibiting the P2Y12 ADP receptors on the surfaces of platelets [30]. Upon ingestion, clopidogrel is absorbed by duodenal enterocytes and moves through these cells into the bloodstream. Once in circulation, approximately 85% of the clopidogrel is hydrolyzed into inactive metabolites by carboxylesterases, primarily carboxylesterase 1 (CES1), in the liver during first-pass metabolism [31]. The remainder of the drug undergoes biotransformation from an inactive pro-drug into the unstable active metabolite. This process requires two steps that involve several CYP enzymes also found in the liver. Two important CYP enzymes involved in this activation step include CYP2C19 and CYP2B6, as well as other potential enzymes including CYP1A2, CYP2C9, CYP3A4/5, and PON1 [32-34]. The active metabolite then circulates through the bloodstream, oxidizing cysteine residues and irreversibly blocking platelet P2Y12 ADP receptors. Without functional P2Y12 receptors, the Gi proteins associated with the receptors are unable to inhibit adenylyl cyclase. This causes an increase in cAMP, followed by the lack of activation of phosphoinositide 3-kinase (PI3K) and decreased expression of glycoprotein IIb/IIIa (GpIIb/IIIa). The ultimate result of this pathway is a slow-starting, long-term activation and aggregation of platelets, which clopidogrel effectively blocks [35].

Clopidogrel response variability is well established [36-41]. Patients treated with clopidogrel who demonstrate higher ex vivo platelet reactivity are at increased risk of ischemic events [42-48]. For example, Matezky and coworkers [49] found that up to 25% of subjects who received PCI with stenting for acute MI and who were placed on aspirin and clopidogrel were resistant to clopidogrel when ADP-induced platelet aggregation was assessed at day 6 of therapy. Recurrence rates for a cardiovascular event were 40% in the lowest quartile of clopidogrel response compared to only 6.7% in the upper quartile of responders. Factors that may influence variation in platelet function in response to clopidogrel include use of lipophilic statins, calcium channel blockers, proton pump inhibitors, St. John’s Wort, and smoking [50-52]. However, these factors account for only a small fraction of the variation in response.

Genetic factors have also been found to play a role in clopidogrel resistance. The Amish Pharmacogenomics of Anti-Platelet (PAPI) Study found that in healthy subjects the heritability of clopidogrel response, as measured by post-exposure ADP-stimulated platelet aggregation, was 70%. In search of specific genetic variants that influence clopidogrel response, a number of candidate gene studies and, to date, one GWAS has been performed. Following is a summary of the most salient findings.

CYP2C19

Common loss-of-function (LOF) variants in CYP2C19 are the most well-established genetic determinants of clopidogrel responsiveness. Its most common LOF variant is *2 (rs4244285), with allele frequencies of 29% in Asians, and 15% in Caucasians and Africans. Other LOF alleles include *3-*8, which are all considered rare. Those with one and two CYP2C19 LOF alleles are considered intermediate metabolizers (IM) and poor metabolizers (PM), respectively. Multiple studies have demonstrated that CYP2C19 LOF variants are associated with lower clopidogrel active metabolite concentrations [53-55], greater on-treatment residual platelet function [54-57] and poorer cardiovascular outcomes in PCI patients treated with clopidogrel [53, 58-63]; other excellent reviews have also covered much of the literature surrounding CYP2C19 [1•, 64-69]. Other studies in coronary artery disease populations with lower rates of stent placement or in patient populations with other indications for anti-platelet therapy have not shown significant effects of CYP2C19 LOF variants on clopidogrel response [70, 71]. Meta-analyses provide supporting evidence for a clinically important role of CYP2C19 LOF variants [72, 73]. For example, Jang et al. [72] estimated that carriers of one or more CYP2C19 LOF alleles had an increased risk of cardiovascular death (OR 2.18, 95% CI 1.37 to 3.47), MI (OR 1.42, 95% CI 1.12 to 1.81), and stent thrombosis (OR 2.41, 95% CI 1.76 to 3.30). These effects appear to be qualitatively consistent across ethnic populations [74-76]. By contrast, a recent meta-analysis by Holmes and coworkers [77] concluded that CYP2C19 LOF variants are not clinically significant contributors to clopidogrel response, citing issues with “treatment only” study designs and small study bias as the reasons for positive findings of other meta-analyses. We [78] and others [79, 80] suggest that a more likely explanation is that CYP2C19 genotype is an important determinant of patients’ responses to clopidogrel after receiving PCI, but possibly not in patients treated with clopidogrel for other indications [78, 81].

The burden of evidence led the FDA in March 2010 to mandate the addition of a boxed warning to clopidogrel’s label informing physicians that patients carrying CYP2C19 LOF variants may be less responsive to clopidogrel, that tests are available to assess CYP2C19*2 status, and that alternative drugs or doses are recommended in poor metabolizers [82]. The label was silent regarding CYP2C19 intermediate metabolizers and fell short of stronger language regarding use of alternative therapy. A consensus report by the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association (ACCF/AHA) published in June 2010 recommends against routine testing for CYP2C19 LOF variants, citing that these variants only explain approximately 12% of the variation in clopidogrel response and have low positive predictive value [83]. Furthermore, at the time of its writing, prospective randomized clinical trials showing that genotype-directed therapy improves clinical outcomes had not been performed. Subsequently, in the RAPID GENE Study, 200 PCI patients were randomized to standard treatment with clopidogrel versus genotype-directed therapy in which CYP2C19*2 carriers received prasugrel. None of the 23 CYP2C19*2 carriers in the genotype-directed group had high on-treatment platelet reactivity while 7 of the 23 CYP2C19*2 carriers in the standard care group, a significantly higher number of individuals, had high on-treatment platelet reactivity [84].

At the time of this writing, no prospective randomized trials of genotype-directed therapy and clinical outcomes have been reported. The ACCF/AHA consensus statement stressed the importance of clinical judgment in choice of anti-platelet therapy, and we and others have suggested that CYP2C19 genotype may be useful in context with clinical and other factors in choosing anti-platelet therapy [85]. The Pharmacogenomics Research Network (PGRN) Clinical Pharmacogenomics Implementation Consortium (CPIC) published guidelines for CYP2C19 testing and interpretation, and a suggested algorithm for treatment (Fig. 1) [86••]. These guidelines may be useful in select patients, at least until results of properly designed and powered randomized clinical trials are available.

Fig. 1


A suggested algorithm for genotype-guided anti-platelet therapy [86••]. (Adapted with permission from: Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328-32. doi:10.1038/clpt.2011.132) [86••]

In addition to LOF variants in CYP2C19, there is a gain-of-function (GOF) variant, CYP2C19*17 (rs12248560), residing in the 5’ regulatory region of the gene. This common variant, with minor allele frequencies of 21% and 16% in individuals of European and African ancestry, respectively, [87] is associated with increased transcriptional activity [63, 88]. The underlying mechanism of increased transcriptional activity likely involves hepatocyte nuclear binding to the *17 variant as evidenced by electrophoretic mobility shift assays [88].

Results of genetic association studies evaluating the effect of the CYP2C19*17 variant on clopidogrel response traits have been inconsistent. While some studies investigating patients during clopidogrel treatment have observed a decrease in cardiovascular event rates in individuals carrying the CYP2C19*17 variant [71, 89-92], others have not [53, 60, 63, 71, 93-97]. Similarly, bleeding was increased in subjects with CYP2C19*17 in some reports [91-95, 98, 99] and not associated in others [53, 71]. Although meta-analyses [91, 92] with CYP2C19*17 provide support for both a decrease in cardiovascular events and an increased risk of bleeding post treatment, CYP2C19*2 and CYP2C19*17 genotypes are in linkage disequilibrium and not independent of one another. Individuals with one or two CYP2C19*17 variant alleles are less likely to possess a copy of the CYP2C19*2 allele, and those with no copies of the CYP2C19*17 variant are more likely to have CYP2C19*2 variant alleles. Due to the linked nature of these variants, it has been suggested that enhanced response to clopidogrel in persons with one or more copies of the CYP2C19*17 variant may be due, at least in part, to the lack of CYP2C19*2 alleles in those individuals [100••]. Therefore, results reported for CYP2C19*17 should be considered cautiously unless it is clear the authors have statistically adjusted for the CYP2C19*2 variant in their association model.

ABCB1

As clopidogrel is absorbed from the intestinal lumen into the bloodstream, it must pass through intestinal enterocytes where a portion of the drug is immediately transported back into the lumen by the P-glycoprotein ATP-dependent efflux pump (ABCB1), also known as multidrug resistant 1 (MDR1). A common genetic variation in ABCB1, C3435T (rs1045642), affects gene transcription. The T allele of this polymorphism causes overexpression, which would be expected to result in greater extrusion of the drug into the intestinal lumen, less net absorption, decreased drug level in the bloodstream, and decreased response [94]. The frequency of the T allele is 57% in Caucasian, 41% in Asians (Chinese), and 11% in African descent.

Several studies have shown a modest association between the ABCB1 3435T allele and decreased clopidogrel active metabolite [101], increased on-treatment platelet reactivity [102] and cardiovascular events [103]. In addition, while determining which genes to include in a novel clopidogrel resistance risk score, which incorporates genotype and phenotype data, one group found a significant association between ABCB1 genotype and platelet reactivity as well as cardiovascular event risk [95].

Other studies have not found such an association between this ABCB1 variant and clopidogrel response, which may be due to inadequate power to discern a modest effect on clopidogrel response, specific characteristics of the patient populations, or false positive results of other studies. A recent meta-analysis examined 12 previously published studies of ABCB1 C3435T genotype. In the combined dataset, they found no association between ABCB1 genotype and on-treatment platelet reactivity, MI, ischemic stroke, all-cause mortality, stent thrombosis, or long-term major cardiovascular events. However, when stratified by loading dose, they found evidence for association between ABCB1 genotype and long-term cardiovascular events in the 300 mg loading dose group, early major adverse cardiovascular events, and bleeding; no such associations were observed in patients given the 600 mg loading dose [103]. These findings suggest that increased clopidogrel dose may be able to overcome higher efflux rates in T allele carriers.

PON1

Paraoxonase 1 (PON1) was named for its ability to metabolize paraoxon, a product of the detoxification of the insecticide parathion. PON1 is expressed in liver and is associated with HDL-cholesterol in the bloodstream. Two common variants in PON1 are A575G (rs662; Gln192Arg) and T163A (rs854560; Leu55Met), with the Gln and Met variants being associated with lower paraoxonase activity [104, 105]. Bouman and coworkers reported a significant association between PON1 Gln192Arg genotype and active clopidogrel metabolite concentration, level of platelet inhibition, and stent thrombosis [106]. These findings were remarkable since PON1 was not previously recognized to be involved in clopidogrel bioactivation. Curiously, this same study showed no effect of CYP2C19 genotype on on-treatment platelet reactivity or stent thrombosis. Subsequently, several studies failed to replicate association of Gln192Arg PON1 with a variety of endpoints including clopidogrel active metabolite levels [107], platelet function [62, 104, 107, 108], cardiovascular outcomes [104, 107, 109, 110], and stent thrombosis [107]. The reason underlying these discrepant findings are unclear. One study involving 300 patients undergoing PCI for ischemic heart disease showed a significant association between PON1 Gln192Arg genotype and on-treatment platelet reactivity at 1 and 6 months post-PCI, though with much smaller effect size than CYP2C19*2, *17, and ABCB1 genotypes [111]. These findings suggest that Bouman’s original study may have benefited from “the winner’s curse” and that PON1 genotype might have a smaller effect on clopidogrel response than initially reported, and that subsequent negative studies were not adequately powered, at least not for the stent thrombosis endpoint. Another study showed that PON1 may form a different thiol metabolite that is scarcer than clopi-H4 called Endo, which is not associated with anti-platelet response [112]. A recent analysis of PON1 Gln192Arg genotype in 424 Chinese with acute coronary syndrome found significant association with on-treatment platelet reactivity in CYP2C19*1 homozygotes but not in CYP2C19*2 carriers, suggesting interaction between clopidogrel metabolic pathways [113].

Also clouding the picture are several studies that have demonstrated that PON1 genotype may be related more to underlying cardiovascular disease risk than to clopidogrel response. A substudy of the CURE trial showed an association between PON1 genotype and cardiovascular event rates in the placebo group when the results were stratified by treatment arm [114]. These findings suggest a non-pharmacogenomic effect of PON1 genotype on cardiovascular outcome, which fits well with prior data showing PON1 to be associated with HDL particles, and that PON1 genotype is associated with enzymatic activity and the ability of HDL to prevent oxidation of LDL particles [115]. Planned large scale GWAS using an ultra-dense selection of SNPs will help resolve questions regarding associations of PON1 genetic variants with coronary events and HDL. Overall, the burden of evidence does not support a role for PON1 genotype in clopidogrel response, meaning further study will be required [116, 117].

P2RY12

The gene P2RY12 encodes the P2Y12 ADP receptor, the target for inactivation by clopidogrel on the surface of platelets. Two common linked genetic variants in this gene, G52T (rs2046934) and T744C (rs2046934), distinguish two major haplotypes, denoted H1 and H2, respectively. The H2 allele is believed to be associated with increased expression of P2RY12 [118]. A study in 225 healthy Caucasian volunteers exposed to clopidogrel showed that the H2/H2 genotype is associated with a significant decrease in inhibition of platelet aggregation in comparison to H1/H1 and H1/H2 individuals [119]. Similarly, another study in 557 clopidogrel-treated PCI patients showed H2/H2 homozygote individuals had significantly higher platelet aggregation and lower clopidogrel response [120]. In contrast, other studies, including several that examined clinical outcomes, have failed to show such associations [60, 121, 122] leading to the conclusion that if common variants in P2RY12 have an effect on clopidogrel response, this effect is small and not likely to be clinically important.

CES1

CES1 converts clopidogrel into an inactive carboxylic acid metabolite from its prodrug and thiolactone intermediate states [31]. An uncommon G/A variant (rs71647871) encodes a nonsynonymous substitution Gly143Gln resulting in marked decrease in catalytic function [123]. The frequency of the decreased function 143Gln allele is ~1%. A decreased function allele would be expected to be associated with decreased metabolism of clopidogrel into its inactive metabolite and conversely increased active metabolite levels and clopidogrel response. Indeed, in 566 healthy participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) study, the seven 143Gln carriers had significantly higher active metabolite levels and more effective inhibition of ADP-simulated platelet aggregation. Although the variant is uncommon in the population, the effect size was found to be approximately two-fold greater than CYP2C19*2. In 330 PCI patients treated with clopidogrel, the six 143Gln carriers similarly showed more effective inhibition of platelet reactivity. In this same sample, there was a trend toward lower cardiovascular event rates in 143Gln carriers, not statistically significant perhaps due to the small sample size. Although these observations will require replication in larger studies, these data suggest that this relatively uncommon variant, present in its heterozygous form in approximately 2% of the population, may be a clinically important determinant of clopidogrel efficacy [124].



Other CYPs

As described above, other cytochrome P450 enzymes likely play roles in in vivo metabolism of clopidogrel [125-127]. Although functional variants in several of these enzymes exist and would be predicted to affect clopidogrel efficacy, to date the literature is mixed. It is likely that there are redundant mechanisms for clopidogrel metabolism rendering the effect of any single functional variant in these other CYPs small or non-existent. For example, some studies suggest a role for LOF variants in CYP2C9 in clopidogrel response [128, 129], while others do not [53, 122, 130].

Perhaps variants in other CYP genes play a role in clopidogrel response in subjects with LOF variants in CYP2C19, for whom alternate pathways may be more important. A study by Kassimis et al. showed that the *5 variant of CYP2B6 is associated with significantly higher platelet reactivity during clopidogrel treatment, but only in non-CYP2C19*2 carriers, thus showing both CYP2B6’s importance in and the profound impact of CYP2C19*2 on on-treatment platelet reactivity [130]. It is also possible that factors that affect activity of these CYPs, such as smoking or concurrent use of drugs that induce expression or inhibit action, may influence clopidogrel response in a genotype-dependent manner. A study suggests that CYP1A2 may explain in part the apparent increased clopidogrel response in smokers – the so-called smokers’ paradox – because CYP1A2 is induced by polycyclic aromatic hydrocarbons found in cigarette smoke [131]. A study by Zhou and coworkers demonstrated in Koreans that smokers carrying the CYP1A2*1F variant (rs762551) had reduced on-treatment platelet reactivity, an effect that was not apparent in non-smokers [132]. In some patients, variants in CYP3A5, a “back-up” pathway for CYP3A4, may explain interaction between clopidogrel and amlodipine, a potent CYP3A4 inhibitor. In subjects homozygous for the loss of function CYP3A5*3 variant, amlodipine causes a significant increase in on-clopidogrel platelet reactivity while no such effect was observed in carriers of at least one functional allele [133]. Another study showed that the CYP3A5*3 variant is only associated with clopidogrel response when clopidogrel is co-administered with itraconazole, a known CYP3A inhibitor [134].



Translation of Clopidogrel Pharmacogenomics into Patient Care

While approximately 12% of variation in clopidogrel response may be explained by CYP2C19 LOF variants, data suggest that a large amount of the heritability of response remains unknown. Future studies in search of genetic determinants of clopidogrel response will require much larger sample sizes of clopidogrel-treated patients and the application of genome-wide and NextGen sequencing approaches. The International Clopidogrel Pharmacogenomics Consortium (ICPC) seeks to perform a large GWAS in order to identify novel common variants for clopidogrel response [135]. The PGRN has developed a sequencing panel of 84 “pharmacogenes” (PGRN-Seq) [136]. Early data suggest the existence of much more rare variation in these genes than was previously thought [137]. As additional genetic determinants of clopidogrel response are uncovered, it is anticipated that their addition to already available CYP2C19 genetic testing will increase the clinical utility of genetic testing toward more effective individualized anti-platelet therapy.
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Conclusions

In recent years, there has been much progress in our understanding of the genetic basis of variation in clopidogrel and warfarin response. Solid data now supports findings that common variants in CYP2C9 and VKORC1 alter warfarin maintenance dose requirements and prospective trials are now underway to learn whether genotype-guided therapy can increase the percent of time in the therapeutic INR range and lower adverse bleeding and thrombotic events. A large body of data now also supports a role of common LOF variants in CYP2C19 on clopidogrel response, including studies that have examined active drug levels, platelet reactivity, and clinical outcomes. There is a likely a real but smaller effect of variants in ABCB1 as determinants of clopidogrel response. At the current time, the aggregate of literature does not support a major effect by PON1, P2RY12, or other CYP genes on clopidogrel response, although variation in these genes may contribute in other ways to the complex architecture of clopidogrel response.
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Acknowledgments


Adam S. Fisch has received grant support from NIH.
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Footnotes




Conflict of Interest

Adam S. Fisch declares that he has no conflict of interest.

Christina G. Perry declares that she has no conflict of interest.

Sarah H. Stephens declares that she has no conflict of interest.

Richard B. Horenstein declares that he has no conflict of interest.

Alan R. Shuldiner declares that he has no conflict of interest.

A Study of Patterns of Platelet Counts in Alcohol Withdrawal

A Study of Patterns of Platelet Counts in Alcohol Withdrawal

Devavrat G. Harshe, Harshal Thadasare,1 Sagar B. Karia,1 Avinash De Sousa,1 Rashmin M. Cholera,2 Sanjiv S. Kale,2 Omkar S. Mate,2 and Nilesh Shah1
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Abstract

Aims:

This study aimed to evaluate the patterns of platelet counts during the course of alcohol withdrawal and its relationship if any with liver enzymes.

Methodology:

Forty consecutive patients, with alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-fourth edition, Text Revision criteria, willing for a 10-day inpatient detoxification program and presenting within 12 h of the last consumption of alcohol were recruited in the study. Details about the diagnosis and alcohol consumption patterns were assessed with a detailed psychiatric interview. After admission, routine investigations (complete blood counts [CBCs] and liver function tests) were sent and records were kept. CBC was sent for platelet counts on the 2nd, 4th, 6th, 8th, and the 10th day of alcohol withdrawal.

Results:

Nearly 40% of the patients developed delirium tremens (DT group) and rest had an uncomplicated alcohol withdrawal (ND group). Platelet counts at baseline and all the 4 days of collection were significantly lower in DT group than the ND group. Platelet counts increased gradually from baseline till 10th day of alcohol withdrawal, mean increase in platelet counts being 88.61 ± 11.60% (median: 61.11%, range [23.41–391.23%]). Platelet counts in 63% of the patients showed a drop on the 4th day of withdrawal before rising till the 10th day of alcohol withdrawal. Platelet counts were not affected by liver enzymes or other alcohol consumption patterns.

Conclusions:

Transient thrombocytopenia and reverse thrombocytosis during alcohol withdrawal are associated with an initial drop in platelet counts. The synchrony between the drop and the onset of DT needs to be evaluated.

Keywords: Delirium, reverse, thrombocytopenia, transient
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INTRODUCTION

Alcohol withdrawal syndrome (AWS) is a clinical entity which ensues after a sudden cessation of or reduction in quantity of absolute alcohol consumed daily in those who are dependent on alcohol. AWS has a self-limiting course in most cases, 5%–20% of patients however develop a complicated AWS[1] with alcohol withdrawal seizures or delirium tremens (DT).

Evidence suggests that low platelet count has a good predictive power in predicting the development of DT[2,3,4,5,6] in cases of AWS. Kim et al., 2015,[3] Berggren et al., 2009,[4] Eyer et al., 2011,[5] and Monte et al., 2009,[6] demonstrated that platelet count in patients with DT was in thrombocytopenia range (<150 × 109/L) whereas Huang et al., 2011,[2] showed a nonsignificantly lower platelet count in DT group as compared to ND group. A recent systematic review and meta-analysis[7] substantiated this observation. Most of the authors hypothesized that chronic alcohol consumption, heavy alcohol intake, recent binging, and comorbid liver cirrhosis may be the causative factors for thrombocytopenia during alcohol withdrawal.

Interestingly, with the exception of Berggren et al., 2009,[4] who showed a significantly higher aspartate transaminase (AST) levels in patients with DT compared to those without DT, neither any study nor the meta-analysis showed any significant difference between DT and non-DT groups for AST and alanine transaminase (ALT)! Thus, we planned this study to evaluate the stability of platelet count during the course of alcohol withdrawal and its relationship if any with serum liver enzymes.

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METHODOLOGY

Sample

The study was cleared by the Institutional Ethics Committee. Eighty consecutive patients diagnosed with alcohol dependence and presented within 12 h of their last drink were screened. Patients with (1) dependence on any other substance except nicotine, (2) a history of traumatic brain injury, peripheral vascular disease, past myocardial infarction and cerebrovascular accidents, comorbid psychosis and mood disorder, and alcohol withdrawal seizure during the past alcohol withdrawal, and (3) patients taking anti-platelet/anti-coagulation medications were excluded from the study. Patients willing for a 10-day inpatient detoxification program were recruited in the study after a written and informed consent (n = 44). Patients who developed alcohol withdrawal seizure during the course of alcohol withdrawal (n = 4) were excluded from the study.

Method

Patients (n = 40) were admitted after discussing the diagnosis and treatment strategy with a consultant (assistant professor and above). Routine investigations (complete blood count [CBC]; liver function tests; and renal function tests) were sent early morning on the 2nd day of alcohol withdrawal. Patients were started on tablet lorazepam (8–12 mg/day) in divided doses and injection thiamine 100 mg 12 hourly. Provision was made for (1) injectable lorazepam in cases of a seizure and DT, (2) tablet zolpidem (10 mg) for insomnia, and (3) tablet escitalopram for depressive symptoms during the course of AWS although they were not administered on any patient enrolled in the study. Patients were observed round the clock by on-duty residents, and an orientation chart was maintained. Dose of lorazepam was adjusted according to the clinical status, orientation, and higher functions and vital signs. CBC for platelet counts was sent on alternate days (day 2, day 4, day 6, day 8, and day 10) of alcohol withdrawal. Patients were shifted on oral multi-vitamin supplementation from day 5 of alcohol withdrawal. Lorazepam was tapered gradually from 6th day onward based on the clinical improvement and stopped completely by the time of discharge. Patients were prescribed appropriate medications for relapse prevention based on clinical status, affordability, and tolerability profile.

Data analysis

Data were pooled in a spreadsheet program and analyzed. Dichotomous variables were assessed with Chi-square test and 2 × 2 cross-tabs analysis. Quantitative variables (platelet counts on 5 days of blood collection) were compared with independent samples t-test. Pearson's correlation was used to study relationship between platelet counts, serum liver enzymes, and alcohol consumption details. Statistical significance was assumed at P < 0.05.

Demographic details

Sample of 40 was an all-male sample with a mean age of 38.47 ± 9.86 years (range: 21–56 years). Mean age at the onset of alcohol consumption was 21.27 ± 4.70 years. Nearly 63% of the patients (25/40) were consuming country liquor (CL) at the time of this study and the rest were consuming whiskey. Almost 40% of the patients developed DT during the course of AWS.

Platelet counts in AWS

Nearly 30% of the patients showed thrombocytopenia. Platelet counts were significantly lower in DT group than ND group, on all five occasions. Mean platelet count on day 4 was lower than that of baseline in both DT and ND groups. Mean platelet counts showed a gradual rise on days 6, 8, and 10 of alcohol withdrawal. Nearly 63% (25/40) of the patients showed a drop in platelet counts on the 4th day of withdrawal followed by a rise whereas the rest (15/40) showed a continuous rise from 2nd day in platelet counts till 10th day of alcohol withdrawal. Mean increase in the platelet counts on day 10 from baseline was 88.61 ± 11.60% (median: 61.11%; range [23.41–391.23%]). DT group showed a significantly higher increase in platelet counts as compared to ND group on the 8th (82.24 ± 56.54 [DT] vs. 38.29 ± 16.84 [ND]%, Z = −2.457, P = 0.013) and the 10th day (151.77 ± 101.77 [DT] vs. 61.54 ± 32.08 [ND]%, Z = −2.678, P = 0.007) of AWS. Incidence of the initial drop in platelet counts did not differ between DT and ND groups (68 [DT] vs. 59 [ND]%, χ2 = 0.444, P = 0.372).

Factors affecting platelet counts

Platelet counts [Table 1] did not differ significantly in groups (1) with and without elevated liver enzymes, (2) consuming CL and Indian-made foreign liquor (IMFL), and (3) with duration of alcohol dependence (DAD) <10 and >10 years. The incidence of the initial drop in platelet counts was not affected by (1) the alcoholic beverage (74 [CL] vs. 56% [IMFL], χ2 = 1.202, P = 0.241), (2) course of alcohol withdrawal (69 [DT] vs. 60 [ND]%, χ2 = 0.444, P = 0.372), (3) serum AST (64 [elevated] vs. 60 [normal], χ2 = 0.012, P = 0.597), and (4) serum ALT levels (60 [elevated] vs. 66 [normal], χ2 = 0.181, P = 0.465). Platelet counts did not show a significant correlation with liver enzymes, age, and DAD [Table 2].

Table 1


Platelet counts (×109/L) across various clinical and biochemical factors


Table 2


Platelet counts and various clinical variables

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DISCUSSION

This study observed that platelet counts are not stable during the course of alcohol withdrawal. Platelet counts show a gradual rise from baseline till the end of alcohol withdrawal, a phenomenon which has been described as reverse thrombocytosis (RT) in literature. We also found that, in a large proportion of patients, platelet counts show a drop below the baseline in the first half of alcohol withdrawal (day 4), followed by a gradual rise till the 10th day of withdrawal. Fink and Hutton, 1983 (n = 18),[8] and Mikhailidis et al., 1986 (n = 27),[9] demonstrated RT in patients with alcohol withdrawal. Both studies, however, estimated platelet counts on day 1, day 8, and then on day 15 of alcohol withdrawal and did not report a decline in platelet counts on the 4th day. The 3rd and 4th days in the course of alcohol withdrawal have significant clinical attributes. It is the time when usually AWs and DT set in during AWS. Only further research can report whether this synchrony is of any clinical significance or is mere an accidental finding.

This study also supports the existing literature in showing that low platelet count in alcohol withdrawal is not associated with elevated liver enzymes. Thus, other possible causative factors need to be explored for the transient low platelet counts in alcohol withdrawal. Not only the count, but also platelets show structural as well as functional changes during the course of alcohol withdrawal. Platelets show a (1) decrease in platelet aggregation and thromboxane A2 secretion which returns to normal within 2 weeks of abstinence from alcohol,[8,9] (2) normalization of bleeding time during 2 weeks of abstinence,[9] and (3) a rise in platelet serotonin concentration[10] during the course of AWS among many other alterations. Thus, it can be hypothesized that alcohol withdrawal is associated with an array of changes in platelet structure and function. One of these changes is a transient thrombocytopenia (TT), which reverses eventually and in some cases, reverses after an initial drop in counts below the baseline count! The TT and the RT may be attributed to an initially increased platelet agreeability as shown by Fink and Hutton, 1983.[8] Berggren et al., 2009,[4] have hinted that thrombocytopenia at the onset of alcohol withdrawal is due to the cumulative hepatotoxic effects of alcohol. We, however, could not find any correlation between liver enzymes and platelet counts at the initial and final phases of alcohol withdrawal.

Small sample size is a key limitation in this study. A significant number of patients had to be excluded from the study due to the stringent inclusion criteria such as presentation within 12 h of the last drink and willingness to stay for a 10-day inpatient detoxification program. Inpatient management was vital to ensure strict abstinence from alcohol. This study estimated platelet counts on days 2, 4, 6, 8, and 10. It is possible that there may be more changes in platelet counts on the days when platelet counts were not estimated (days 1, 3, 5, 7, and 9).
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CONCLUSIONS

Thrombocytopenia associated with alcohol withdrawal and DT is transient and is associated with RT. RT is either continuous or is associated with an initial drop, which is followed by a continuous rise in platelet counts till withdrawal subsides. Platelet counts in alcohol withdrawal are not affected by serum AST and ALT levels, type of alcoholic beverage consumed, DAD, and quantity of daily intake of absolute alcohol.

Future directions

These findings need to be validated in a larger sample size. It would also be interested to know the patterns of platelet counts in the remaining days (day 1,3,5,7,9) of alcohol withdrawal.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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REFERENCES
1. Finn DA, Crabbe JC. Exploring alcohol withdrawal syndrome. Alcohol Health Res World. 1997;21:149–56. [PMC free article] [PubMed] [Google Scholar]
2. Huang MC, Chen CH, Liu HC, Chen CC, Ho CC, Leu SJ. Differential patterns of serum brain-derived neurotrophic factor levels in alcoholic patients with and without delirium tremens during acute withdrawal. Alcohol Clin Exp Res. 2011;35:126–31. [PubMed] [Google Scholar]
3. Kim DW, Kim HK, Bae EK, Park SH, Kim KK. Clinical predictors for delirium tremens in patients with alcohol withdrawal seizures. Am J Emerg Med. 2015;33:701–4. [PubMed] [Google Scholar]
4. Berggren U, Fahlke C, Berglund KJ, Blennow K, Zetterberg H, Balldin J. Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures. Alcohol Alcohol. 2009;44:382–6. [PubMed] [Google Scholar]
5. Eyer F, Schuster T, Felgenhauer N, Pfab R, Strubel T, Saugel B, et al. Risk assessment of moderate to severe alcohol withdrawal – Predictors for seizures and delirium tremens in the course of withdrawal. Alcohol Alcohol. 2011;46:427–33. [PubMed] [Google Scholar]
6. Monte R, Rabuñal R, Casariego E, Bal M, Pértega S. Risk factors for delirium tremens in patients with alcohol withdrawal syndrome in a hospital setting. Eur J Intern Med. 2009;20:690–4. [PubMed] [Google Scholar]
7. Goodson CM, Clark BJ, Douglas IS. Predictors of severe alcohol withdrawal syndrome: A systematic review and meta-analysis. Alcohol Clin Exp Res. 2014;38:2664–77. [PubMed] [Google Scholar]
8. Fink R, Hutton RA. Changes in the blood platelets of alcoholics during alcohol withdrawal. J Clin Pathol. 1983;36:337–40. [PMC free article] [PubMed] [Google Scholar]
9. Mikhailidis DP, Jenkins WJ, Barradas MA, Jeremy JY, Dandona P. Platelet function defects in chronic alcoholism. Br Med J (Clin Res Ed) 1986;293:715–8. [PMC free article] [PubMed] [Google Scholar]
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Articles from Indian Journal of Psychological Medicine are provided here courtesy of Indian Psychiatric Society South Zonal Branch


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A Study of Patterns of Platelet Counts in Alcohol Withdrawal
A Study of Patterns of Platelet Counts in Alcohol Withdrawal
Indian Journal of Psychological Medicine. Jul-Aug 2017; 39(4)441

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy
Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy
NIHPA Author Manuscripts. 2013 Jul; 15(7)
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Review Exploring alcohol withdrawal syndrome.[Alcohol Health Res World. 1997]


Differential patterns of serum brain-derived neurotrophic factor levels in alcoholic patients with and without delirium tremens during acute withdrawal.[Alcohol Clin Exp Res. 2011]
Clinical predictors for delirium tremens in patients with alcohol withdrawal seizures.[Am J Emerg Med. 2015]
Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures.[Alcohol Alcohol. 2009]
Risk assessment of moderate to severe alcohol withdrawal--predictors for seizures and delirium tremens in the course of withdrawal.[Alcohol Alcohol. 2011]
Risk factors for delirium tremens in patients with alcohol withdrawal syndrome in a hospital setting.[Eur J Intern Med. 2009]
Review Predictors of severe alcohol withdrawal syndrome: a systematic review and meta-analysis.[Alcohol Clin Exp Res. 2014]


Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures.[Alcohol Alcohol. 2009]


Changes in the blood platelets of alcoholics during alcohol withdrawal.[J Clin Pathol. 1983]
Platelet function defects in chronic alcoholism.[Br Med J (Clin Res Ed). 1986]


Changes in the blood platelets of alcoholics during alcohol withdrawal.[J Clin Pathol. 1983]
Platelet function defects in chronic alcoholism.[Br Med J (Clin Res Ed). 1986]
Platelet serotonin concentration and clinical status in alcohol withdrawal syndrome, preliminary results.[MEDICC Rev. 2014]
Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures.[Alcohol Alcohol. 2009]




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10 Causes of High Platelet Count - THROMBOCYTE.COM

10 Causes of High Platelet Count

High Platelet Count

Platelets are small, oval/spherical component of the blood that don’t have its own nucleus. These small fragments are produced in the bone marrow and plays a very important part in blood clotting.

Normal levels of platelets in the blood is about 150-350×109 in 1 mm³ blood. Platelets life span goes for only 7-10 days.

Doctors can detect thrombocytosis during routine blood tests. A display of increased level of platelets can be helpful in determining reactive thrombocytosis or thrombocythemia, which may likely cause abnormal blood clots.

What causes high platelet count? Thrombocytosis is the medical term used to describe the display of elevated platelet count. The higher end for normal platelet count range may vary from lab to lab, but is typically around 350 to 450 × 109 / L.

With the information below, we will identify further what causes platelets to be high in comparison to normal levels. There are over 10 factors actually. Also, check out the most common platelet disorders.

The causes of high platelet count or thrombocytosis can be classified as follows:

• Physiological thrombocytosis
• Reactive (secondary) thrombocytosis
• Clonal (primary) thrombocytosis

I. THE PHYSIOLOGICAL THROMBOCYTOSIS CAN BE A RESULT OF:

• Exercise (workload)
• Stress
• Adrenaline

II. THE REACTIVE (SECONDARY) THROMBOCYTOSIS MAY RESULT FROM:

• Acute blood loss
• Hemolytic anemia
• Infection
• Inflammatory diseases
• Iron deficiency anemia
• Malignant disease
• Surgery
• Post splenectomy / hypospleenism
• Drug reactions (vincristine, all trans retinoic acid, cytokines, growth factors)
• Feedback (“reactive”) thrombocytosis
• Trauma

Infection

A series of acute and chronic infections has been associated with reactive thrombocytosis. Megakaryopoiesis is inhibited during the presence of an acute infection which may be due to a virus or bacteria. This identifies what causes a high platelet count in a patient who is experiencing either a viral or bacterial infection. Bacterial infections may be pneumonia, pyelonephritis, purulent arthritis, osteomyelitis, chronic wound infections, tuberculosis, among others. Viral infections, on the other hand, rarely reflects thrombocytosis.

Inflammatory diseases

The inflammatory diseases that could cause thrombocytosis are rheumatoid arthritis, rheumatic polymyalgia, polyarteritis nodosa, inflammatory bowel disease, nephritis and liver cirrhosis. Typically, the degree of severity of the disease condition corresponds to that of thrombocytosis. With proper treatment of the involved inflammatory disease/s, platelet count is very likely to return to normal levels.

Iron deficiency anemia

Elevated platelet count is not uncommon in patients with sideropenic anemia, specifically iron deficiency anemia. Sometimes platelet count may be greater than 1000 × 109 / L. Introducing iron replacement therapy helps the platelet count to generally return to normal within 10 days.

Malignant disease

There’s also been a described association of thrombocytosis with many neoplasms, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, ovarian, bladder, mesothelioma, lung cancer, prostate and pancreatic cancer. About 90% of patients with reactive thrombocytosis due to a malignant disease displays a platelet count between 400 and 1000 × 109 / L.

Splenectomy

After splenectomy, a person may develop thrombocytosis that sometimes exceed 1000 × 109 / L. The removal of the spleen is what causes high platelets in some patients after the surgery. The platelet count usually returns to normal within a few weeks or months. Permanent thrombocytosis after splenectomy should give pause for thought about the existence of myeloproliferative disorder or any condition that may have developed like hemolysis or ineffective erythropoiesis.

Reactive thrombocytosis rarely causes symptoms.

BUT IF SYMPTOMS OCCUR, THEY MAY INCLUDE THE FOLLOWING:

• Headache
• Dizziness or lightheadedness
• Chest pain
• Weakness
• Unconsciousness
• Temporary changes in vision
• Numbness or tingling in the hands or feet

TREATMENT OF REACTIVE THROMBOCYTOSIS

Treatment of reactive thrombocytosis is directed at the cause. If the cause is due to previous surgery or injury that have resulted to a significant loss of blood, thrombocytosis will not last long. If the cause is due to chronic infection or inflammatory disease, platelet levels may remain elevated until the condition is brought into control.

In most cases, the platelet count returns to normal after treatment of the root cause. Still yet, the removal of the spleen may cause a lifetime of thrombocytosis. In this case, the doctor may prescribe a low-dose aspirin to prevent bleeding as well as blood clotting, but which rarely occur in reactive thrombocytosis.

III. THE CLONAL OR PRIMARY THROMBOCYTOSIS MAY APPEAR BECAUSE OF:

• AML (acute megakaryocytic leukemia)
• Myeloproliferative disease
• Essential thrombocytosis
• Polycythemia vera
• Agnogenic myeloid metaplasia
• Chronic myeloid leukemia
• Myelodysplastic syndrome

Chronic myeloid leukemia

Two-thirds of patients with chronic myeloid leukemia are found to have thrombocytosis.

Polycythemia vera

Increased platelet count has also been observed in approximately 66% of patients with polycythemia vera. About 5% of the patients have marked thrombocytosis (platelet count greater than 1000 x 109 / L).

Agnogenic myeloid metaplasia

Also known as idiopathic myelofibrosis, myeloid metaplasia agnogenic, is manifested by anemia and splenomegaly. A review of peripheral blood smear often detects 

Leukoerythroblastosis, described as a finding of erythrocytes in the form of tears, and immature precursors of red blood cells and leukocytes.

Thrombocytosis has been found in about 33% of patients with the condition, but in advanced stages of the disease, thrombocytopenia will usually be the significant finding.

For most myelodysplastic disorders, thrombocytosis is not typical. In fact, in most patients, it’s more often a display of normal or reduced platelet count. One form of myelodysplastic syndrome, called “5q-syndrome”, is associated with thrombocytosis in 50% of patients.

Essential thrombocytosis

Essential thrombocytosis, or primary thrombocythemia is a chronic disease characterized as a myeloproliferative neoplasm showing an enlargement in the total number of blood platelets (thrombocytes).

The exact cause of essential thrombocythemia is not fully known, but it is assumed that there is a certain degree of genetic predisposition.

Some research shows that essential thrombocythemia is diagnosed in only about 6 persons per 100,000 people in one year. Males are equally affected as females, however with the younger population, a higher percentage goes to females. This disease is more common among members of the older population, although one in five patients is younger than 40 years.

SYMPTOMS OF ESSENTIAL THROMBOCYTOSIS

Nearly every third patient at the time of diagnosis are without any signs.

Among the signs and symptoms, one of the most known insight to look for is that high platelets causes thrombosis of blood vessels. Read about the common high platelet count symptoms.

The most frequently occurring symptoms:

• Headache is the most common neurological symptom. Others include problems with speech, dizziness, fainting, loss of vision and seizures.

High platelet count causes the fingers to likely develop pain and become affected with gangrene

• Thrombosis of large blood vessels affect the blood vessels that supply the extremities (deep vein thrombosis)
• It can also affect the blood vessels of the heart (coronary syndrome)
• The gastrointestinal tract is also often found with forms of bleeding complications
• Bleeding can also occur under the skin, gums, joints and brain tissue
• Signs and symptoms like the occurrence of loss of appetite and body weight may also take place

DIAGNOSIS OF ESSENTIAL THROMBOCYTOSIS

Medical history, analysis of the clinical picture, and detailed overview can help in identifying reasons for high platelet count in a patient. This should come along with supplementary medical tests and examinations. The definitive diagnosis is made after laboratory procedures and measurements pertaining to platelet levels of the blood has been completed. Also, the identification of elevated platelet count causes behind the patient’s condition, comes with analysis that is carried further to associated factors like anemia and increase in leukocytes.

If the diagnostic process requires, a bone marrow sample may be necessary.

HOW TO TREAT ESSENTIAL THROMBOCYTOSIS:

The treatment of essential thrombocytosis involves administration of hydroxyurea, interferon alfa, radioactive phosphorus 32 and low-dose aspirin on a daily basis.

Furthermore, the use of Shiitake mushroom is considered as one of the best natural management options to regulate thrombocytosis. The plant’s essential oil has been known to inhibit platelet aggregation.

In emergency cases, we can use plasmapheresis.