Thrombosis Research

Editorial Board

2012-02-01

Elevated plasma factor VIII levels in patients with venous thrombosis – Constitutional risk factor or secondary epiphenomenon?

Kevin Ryan, James S. O'Donnell — 2011-10-28

Whilst elevated plasma factor VIII (FVIII) levels has long been associated with increased risk of arterial disease, its potential importance as a risk factor for venous thromboembolism (VTE) only emerged more recently in the Leiden Thrombophilia Study (LETS) . In that case control study of 301 patients with first objectively confirmed VTE, elevated plasma FVIII:C levels (>150IU/dL) were shown to be a common finding (25% of patients versus 11% of controls). Importantly, the median time interval between occurrence of VTE and blood sampling for FVIII:C measurement was 18months, with a minimum of 6months. Moreover, in multivariate analysis, thrombotic risk increased with increasing levels of FVIII:C. Following adjustment for ABO blood group, an odds ratio of 4.8 (95% CI 2.3-10.0) for thrombosis was determined in those individuals with elevated FVIII:C >150IU/dL, when compared to subjects with FVIII:C levels less than 100IU/dL.

Use of anticoagulants in elderly patients

Rupert M. Bauersachs — 2011-10-20

Abstract: Thromboembolic disorders are a major cause of morbidity and mortality, and the risk of thromboembolism increases with age. Anticoagulants are recommended for indications including the prevention of venous thromboembolism in surgical and medical patients, treatment of venous thromboembolism and stroke prevention in patients with atrial fibrillation. Traditional anticoagulants that have been used include unfractionated heparin, low molecular weight heparin, fondaparinux and vitamin K antagonists. However, these agents are all associated with drawbacks (i.e. parenteral administration or frequent coagulation monitoring/dose titration), and it has been particularly challenging to treat elderly patients with anticoagulants. Some specific characteristics of elderly patients may influence the safety of anticoagulant therapy, such as decreased renal function, co-morbidities and the use of multiple medications. The complexity of anticoagulation therapy and the increased risk of bleeding complications in elderly patients may prevent some physicians from prescribing anticoagulants to these patients, which leaves them at risk of thromboembolic events. Thus, safer and more convenient anticoagulants are needed, particularly for elderly patients. New oral anticoagulants have been developed in recent years and have shown promise in clinical studies that included elderly patients. These agents could simplify the management of thromboembolic disorders and improve the safety of anticoagulation.

Platelet dysfunction in vascular pathologies and how can it be treated

Nicoleta Alexandru, Doina Popov, Adriana Georgescu — 2011-10-31

Abstract: Cardiovascular diseases are one of the leading causes of morbidity and mortality in industrialized countries, and although many processes play a role in the development of vascular disease, thrombosis is the primary event that precipitates stroke and acute coronary syndromes. The blood platelets are of significant importance in medicine. These cells are involved in many physiological processes, particularly haemostasis through their ability to aggregate and form clots in response to activation. In addition, these dynamic cells display activities that extend beyond thrombosis, including an important role in initiating and sustaining vascular inflammation. The expansion of knowledge from basic and clinical research has highlighted the critical position of platelets in several inflammatory diseases such as arthritis and atherosclerosis. Platelets are emerging as important mediators of inflammation and provide important signals to mediate phenotype of other blood and vascular cells. The important role of platelets in arterial thrombosis and the onset of acute myocardial infarction after atherosclerotic plaque rupture make inhibition of platelet aggregation a critical step in preventing thrombotic events associated with stroke, heart attack, and peripheral arterial thrombosis. However, the use of platelet inhibitors for thrombosis prevention must seek a delicate balance between inhibiting platelet activation and an associated increased bleeding risk. The aim of this review is to up-date the knowledge on platelets physiology and dysfunction in pathologies, such as diabetes mellitus, hypercholesterolemia, and hypertension, emphasizing the link between platelets and the inflammation-related atherosclerosis. The review evaluates the opportunities offered by the novel platelet inhibitors to efficiently alleviate the thrombotic events.

Risk assessment models for thromboprophylaxis of medical patients

Meyer M. Samama, Sophie Combe, Jacqueline Conard, Marie-Helene Horellou — 2011-11-02

In spite of epidemiologic studies and updated international guidelines, more than 50% of hospitalised patients for an acute medical condition do not receive prophylactic treatment for venous thrombo-embolic (VTE) disease. A systematic identification combined with a stratification of risk factors at entry might help in improving this situation. Some risk assessment models (RAMs) have been proposed, sometimes using mathematical methods or scoring scales. Their implementation and regular use requires ease of use, fast evaluation, and validation through a prospective study. Very few RAMs comply with all these pre-requisites.

Interaction between homocysteine and lipoprotein(a) increases the prevalence of coronary artery disease/myocardial infarction in women: A case-control study

2011-08-01

Abstract: Introduction: Our aim was to investigate the association of elevated homocysteine (Hcy) and lipoprotein(a) Lp(a) with the prevalence of coronary artery disease (CAD) and myocardial infarction (MI) and to investigate their interaction in both genders.Materials and methods: 955 (male/female: 578/377) consecutive patients admitted for coronary angiography were enrolled in the study. Lp(a), Hcy, vitamin B12, folic acid, MTHFR C677T polymorphism and traditional risk factors were determined.Results: 619 patients had significant (≥50%) stenosis (CAD+) and 341 had MI (MI+). CAD-MI- cases (n=302) were considered as controls. Adjusted Hcy levels were significantly elevated only in the female CAD+MI+group that was related to decreased vitamin B12 levels. Lp(a) was elevated in the CAD+MI+group of both genders. Folic acid levels and MTHFR T677 allele frequency did not show significant difference. Moderate hyperhomocysteinemia (Hcy >15μmol/L) or elevated Lp(a) (>300mg/L) increased the risk of CAD (OR 2.27, CI 1.36-3.80 and OR 1.64, CI 1.03-2.61, respectively) and MI (OR 2.52, CI 1.36-4.67 and OR 1.89, CI 1.06-3.38, respectively) only in women. Only simultaneous but not isolated elevation of Hcy and Lp(a) conferred a significant, 3.6-fold risk of CAD in females and even higher (11-fold) risk in young females, which suggested an interactive effect.Conclusions: Moderate hyperhomocysteinemia or elevated Lp(a) level associated with a risk of CAD and MI only in women. While isolated elevation of one of the two parameters represented a mild risk of CAD, their combined elevation highly increased the risk in females. No such effect was observed in males.

Physician and patient perceptions of the route of administration of venous thromboembolism prophylaxis: Results from an international survey

Claudio Cimminiello, Frederick A. Anderson — 2011-08-04

Abstract: Introduction: Acceptability of a prescribed treatment regimen is crucial to its clinical success, and the route of drug administration can play an important role in determining acceptability. This international survey explored physician and patient perceptions of injectable and oral treatments, and how these perceptions affect acceptability of treatments. Findings are discussed in the context of patient acceptance of treatments for venous thromboembolism (VTE) management.Methods: Physicians who are regular prescribers of VTE prophylaxis and a randomly selected patient population were recruited to take part in a questionnaire. Patients had to answer 23 questions and physicians gave their predictions of patients’ responses.Results: In total, 568 physicians and 825 patients from 5 countries took part in the survey. More patients considered injectable treatments effective than considered oral treatments effective (87% versus 76%, respectively). This trend was well predicted by the physicians (98% and 61%, respectively). Additionally, 46% of patients would accept an injectable treatment program lasting >2months (rising to 67% for life-threatening diseases), a figure underestimated by physicians (11% and 46%, respectively). Overall, 73% of patients stated they would never miss an injection, where as 54% of physicians expected patients to miss one injection in a month of therapy.Conclusions: Physicians who are regular prescribers of VTE prophylaxis underestimate patients’ ability to accept injectable treatments as an alternative to oral therapy. This survey suggests that injectable treatments may be an acceptable, and often preferred, option over oral administration of therapeutic and preventive medicines.

Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy

Ammar Majeed, Anna Eelde, Anna Ågren, Sam Schulman, Margareta Holmström — 2011-08-02

Abstract: Background: There is uncertainty regarding the efficacy and incidence of thromboembolic events in patients treated with prothrombin complex concentrates (PCC) for the emergency reversal of warfarin effect.Methods: During 2002 to 2010 we prospectively included 160 patients treated with PCC for emergency reversal of warfarin either for bleeding or because of the need of emergency surgery. A possible relationship to PCC was considered if objectively verified thromboembolism occurred within 7days of PCC administration. Efficacy was adjudicated as good if the bleeding was controlled promptly or if the surgeon did not report excessive perioperative bleeding.Results: We included 160 patients; 72% received PCC for bleeding. The median international normalized ratio (INR) before and after treatment with PCC was 3.5 (interquartile range [IQR] 2.6-5.4) and 1.4 (IQR 1.2-1.6). The mean dose of PCC was 1800IU (IQR 1200–2000). In addition to PCC, 74% of the patients received vitamin K and 34% received plasma. Six patients (3.8%; 95% confidence interval [CI], 1.4-8.0%) developed thromboembolic events (3 strokes, 1 myocardial infarction, 1 deep vein thrombosis, 1 splenic infarction), possibly related to PCC. The clinical efficacy was good in 146 (91%), moderate in 6 (4%), poor in 4 (2.5%) and non-evaluable in 4 patients.Conclusion: The administration of PCC for the emergency reversal of warfarin may be associated with a low risk of thromboembolism. The contribution of an unmasked thrombotic process by cessation of anticoagulation or of activation of coagulation by the hemorrhagic event should also be considered.

Elevated soluble endothelial cell protein C receptor (sEPCR) levels in women with preeclampsia: A marker of endothelial activation/damage?

2011-08-09

Abstract: The endothelial protein C receptor (EPCR) plays a crucial role in the anticoagulant and anti-inflammatory effects of the protein C pathway, whereas its soluble form (sEPCR) exhibits opposite properties. High plasma levels of sEPCR have been observed in subjects carrying the A3 haplotype of PROCR, the EPCR gene. Elevated plasma levels of sEPCR were also recently reported in women with preeclampsia (PE), a multisystemic syndrome involving inflammation, endothelial dysfunction and thrombosis. To determine whether this increase is genetically mediated or acquired, we analyzed sEPCR levels and the A3 haplotype distribution in 145 preeclamptic women and 145 age- and term-matched women with normal pregnancies enrolled in a case-control study. Plasma sEPCR levels were higher in the women with PE than in the controls, and this difference was not due to A3 haplotype over-representation. We observed a positive correlation between sEPCR levels and two markers of endothelium activation/damage (von Willebrand factor and soluble thrombomodulin), and a trend towards a third (sVCAM1). We also found an association between sEPCR levels in the highest quartile and the PE risk. The modest increase of sEPCR levels, together with the correlation with other endothelium activation/damage markers, suggest that it is more an innocent bystander of the endothelium activation/damage than an actor in PE.

Impact of altered venous hemodynamic conditions on the formation of platelet layers in thromboemboli

2011-10-03

Abstract: Although it is generally believed that the structure of venous thromboemboli is a homogeneous red blood cell-fibrin clot, their structure may be heterogeneous, with non-uniformly distributed platelet layers, known as the lines of Zahn. We tested (a) whether venous thromboemboli ex vivo contained platelet layers, i.e. the lines of Zahn, and (b) whether, according to mathematical modeling, eddies can arise in the venous system, possibly contributing to platelet aggregation. The structure of venous thromboemboli ex vivo was determined by high-resolution magnetic resonance imaging (MRI) and by immunohistochemistry (IHC). High-resolution ultrasound (US) imaging was employed to determine the popliteal vein geometry and hemodynamics in healthy subjects and in subjects with previous venous thrombosis. The US data were then used as input for numerical simulations of venous hemodynamics. MRI and IHC confirmed that 42 of 49 ex vivo venous thromboemboli were structurally heterogeneous with platelet layers. The peak venous flow velocity was higher in patients with partly recanalized deep vein thrombosis than in healthy subjects in the prone position (46±4cm/s vs. 16±3cm/s). Our numerical simulation showed that partial venous obstruction with stenosis or malfunctioning venous valves creates the conditions for eddy blood flow. Our experimental results and computer simulation confirmed that the heterogeneous structure of venous thromboemboli with twisted platelet layers may be associated with eddy flow at the sites of their formation.

Systemic and local factors associated with coronary plaque disruption

2011-10-05

Abstract: Introduction: Yellow plaques are regarded vulnerable; and disrupted yellow plaques are the major cause of acute coronary syndrome. We examined the factors associated with the disruption of yellow plaques among patients and lesion characteristics.Materials and Methods: Consecutive 161 patients with ischemic heart diseases who received coronary angioscopic examination were analyzed. Yellow plaques in the segments to which intervention had never been performed were included, and their yellow color grade and presence/ absence of disruption were examined. Associated factors for plaque disruption were examined among patients and lesion characteristics.Results: In 161 patients, 392 yellow plaques were included for analysis and 70 of them were disrupted. Frequency of plaque disruption (=disrupted / all yellow plaques) was significantly higher at the segments of severer stenosis (stenosis≥75% vs. 75-25% vs. <25%: 34% vs. 21% vs. 14%, p=0.006). Multivariate analysis revealed angiographic stenosis (odds ratio [OR], 1.014; 95% confidence interval [CI], 1.005-1.023; p=0.003), yellow color grade (OR, 3.297; 95% CI, 2.062-5.273, p<0.001), LDL-cholesterol (OR, 1.012; 95% CI, 1.004-1.020, p=0.003), male gender (OR, 3.608; 95% CI, 1.538-8.465; p=0.003), and hypertension (OR, 2.552; 95% CI, 1.094-5.953; p=0.030) as significant associated factors for plaque disruption.Conclusion: Angiographic stenosis, yellow color grade, LDL-cholesterol, male gender, and hypertension were significantly associated with the disruption of yellow plaques.

Anopheline anti-platelet protein from a malaria vector mosquito has anti-thrombotic effects in vivo without compromising hemostasis

2011-10-11

Abstract: Introduction: The saliva of blood-feeding animals (e.g., mosquitoes, ticks, bats) has pharmacological activities that facilitate efficient blood-sucking. We previously identified a unique anti-platelet protein, anopheline anti-platelet protein (AAPP), from the salivary gland of female Anopheles stephensi (human malaria vector mosquito). AAPP specifically blocks platelet adhesion to collagen by binding directly to collagen and subsequently aggregating platelets. To examine the potential of AAPP as a therapeutic agent, we investigated the in vivo anti-thrombotic effects of AAPP.Materials and Methods: Effects of AAPP on whole blood/platelet aggregation in mice were examined. AAPP was also challenged in an established model of pulmonary thromboembolism in mice. We simultaneously investigated the side-effects of the protein (prolongation of bleeding time and coagulation time). Aspirin was used as a positive control for comparison of anti-thrombotic effects.Results and Conclusions: AAPP inhibited whole blood aggregation induced by collagen at 10mg/kg body weight. AAPP prevented pulmonary death at a lower dose (3mg/kg) without prolongation of bleeding time compared with aspirin (100mg/kg) that compromised hemostasis. AAPP and aspirin did not affect coagulation time. These results indicate that AAPP has great potential as a new anti-platelet agent with a better risk/benefit ratio than that seen with aspirin (the most widely used anti-platelet agent).

Purification, biochemical properties and antithrombotic effect of a novel Streptomyces enzyme on carrageenan-induced mice tail thrombosis model

Jaya Ram Simkhada, Seung Sik Cho, Poonam Mander, Yun Hee Choi, Jin Cheol Yoo — 2011-10-10

Abstract: Introduction: The prevalence of cardiovascular diseases, one of the major causes of worldwide mortality, is being increasingly reported. Safer, more effective, and less expensive thrombolytic drugs can possibly overcome the underlying problems associate with current thrombolytic drugs.Methods: A thrombolytic enzyme was purified and characterized from a Streptomyces strain. Carrageenan induced tail-thrombosis mice model was used to evaluate in vivo antithrombotic effect of the enzyme.Results: First 15N-terminal amino acids of the purified enzyme were IAGGQAIYAGGGRRS, which are significantly different from the reported fibrinolytic enzymes. The enzyme exhibited 14.3±2.3-fold stronger thrombolytic activity than that of plasmin. In carrageenan induced tail-thrombosis model, the enzyme caused reduction in frequency of thrombus. Tail-thrombus of the enzyme treated group was significantly shorter than the physiological saline treated group and the thrombus decrement was correlated with the enzyme dose.Conclusions: The enzyme purified from the Streptomyces strain can be a potential candidate for the treatment of thrombosis.

The acute phase reaction explains only a part of initially elevated factor VIII:C levels: A prospective cohort study in patients with venous thrombosis

Vladimir Tichelaar, André Mulder, Hanneke Kluin-Nelemans, Karina Meijer — 2011-10-13

Abstract: We determined in a prospective cohort of patients treated with vitamin K antagonists for venous thrombosis, the course of factor VIII (FVIII:C), C-reactive protein (CRP) and fibrinogen levels, to assess the influence of the acute phase reaction on FVIII:C levels. Second, we hypothesized that patients with preceding infectious symptoms might have higher levels of FVIII:C at baseline than patients without those.We included 75 patients. Blood was sampled at baseline, once during treatment (t=1) and at the end of treatment (t=2). Mean levels of FVIII:C were 207, 186 and 175IU/dL (p for trend 0.003) at baseline, t=1 and t=2 respectively. Eight-eight percent of patients had an elevated FVIII:C at baseline, 75% at t=1 and 72% at t=2 (p for trend 0.045). Mean levels of FVIII:C were not different in patients with or without preceding infectious symptoms (206 versus 205IU/dL respectively). A baseline CRP level below 62mg/L could best distinguish between patients who will keep an elevated FVIII:C and those who will drop below 150IU/dL.We conclude that FVIII:C levels are partially influenced by the acute phase reaction, especially in patients who keep a persistent elevated FVIII:C during treatment.Preceding infectious symptoms did not influence baseline FVIII:C levels.

Harmonization and external quality assessment of antithrombin activity assays

Anton M.H.P. van den Besselaar, Fred J.L.M. Haas, Aldy W.H.M. Kuypers — 2011-07-11

Abstract: In the framework of a Dutch project named “Calibration 2000” harmonization of antithrombin activity assays was studied. The commutability of potential calibrators for antithrombin was assessed by means of a twin-study design, which is a multicentre, split-patient sample, between-field-methods protocol. The twin-study consisted of simultaneous analysis of fresh-frozen patient plasmas and three potential calibrators for antithrombin by 30 Dutch laboratories forming 15 couples. The state-of-the-art intralaboratory standard deviation (SDSA) was used to assess the commutability of the potential calibrators. The regression line residuals for the potential calibrators were normalized by expressing them as multiples of SDSA. All residuals of the potential calibrators were within the 3×SDSA limit. One potential calibrator was used in an attempt to harmonize antithrombin assay results in a Dutch field study. The interlaboratory coefficient of variation (CV) of the antithrombin results for three test samples could be reduced from 6.9 – 13.2% (before harmonization) to 5.6 – 9.8% using the common calibrator.Conclusion: The potential calibrators were commutable. Limited harmonization was achieved by using a common calibrator for all participants.

Variable plasma levels of Factor V Leiden correlate with circulating platelet microparticles in carriers of Factor V Leiden

Lisa F. Lincz, Fiona E. Scorgie, Anoop Enjeti, Michael Seldon — 2011-07-28

Abstract: Introduction: Inheritance of Factor V Leiden (FVL) is associated with an increased but variable level of risk for thrombosis. We have previously shown that FVL heterozygotes have elevated levels of circulating pro-coagulant microparticles (MP). Here we sought to determine if these subjects differed in their plasma levels of FVL and if this was related to MP concentrations and/or history of thrombosis.Materials and Methods: The Hemoclot Quanti. V-L clotting assay was used to specifically measure FVL in plasma samples from 44 known carriers (12M, 32F; aged 46±13years). Circulating MP were quantified by flow cytometry using fluorochrome conjugated antibodies to platelet (CD41a), leukocyte (CD45), and endothelial (CD62e) surface markers, and MP prothrombinase activity was determined by ELISA.Results: The cohort was found to have a mean FVL of 49.5±5.6% and this was positively correlated to the total number of circulating CD41a+MP (R=0.31, p=0.03) but not to other MP subsets or to MP prothrombinase activity. The amount of FVL relative to normal factor V (FVL/FV clotting ratio) was calculated and found to be highly variable, ranging from 0.37 to 0.69, and significantly correlated with a history of thrombosis (n=14; p=0.04).Conclusions: This is the first study to investigate the relationship between varying levels of FVL and plasma derived MP. These results are consistent with our previous findings of an increase in MP levels in carriers of FVL as compared to controls, and suggest a role for FVL/FV ratio in predicting risk of thrombosis in carriers of FVL.

Anthracycline treatment of the human monocytic leukemia cell line THP-1 increases phosphatidylserine exposure and tissue factor activity

2011-07-15

Abstract: Introduction: Cancer associated thrombosis is a well-recognized phenomenon that results in considerable patient morbidity and mortality. Malignancy conveys an increased risk for thrombosis and chemotherapy further elevates this risk. The pathophysiological mechanisms underlying this process remain poorly defined.Materials and Methods: A human acute monocytic leukemia cell line (THP-1) was treated with commonly used anthracycline chemotherapeutics at concentrations similar to those found in the plasma of cancer patients. Cells were analyzed for tissue factor (TF) mRNA, protein, and activity. Microparticle (MP) TF activity was also measured. Phosphatidylserine (PS) exposure on cells and MPs was analyzed by flow cytometry. PS levels on MPs was also evaluated in an annexin V capture assay.Results: Anthracycline treatment of THP-1 cells resulted in a concentration-dependent increase in cellular TF activity without a change in TF protein, which was associated with increased PS exposure on the cell surface and apoptosis. The increase in TF activity was abolished by annexin V or lactadherin indicating that PS exposure was required. Anthracycline treatment of THP-1 cells also increased the number of TF-positive MPs.Conclusion: Treatment of THP-1 cells with anthracyclines induces apoptosis and increases cellular TF activity. The increased activity required an increase in exposure of PS. Additionally, anthracyclines increase the release of TF-positive MPs from THP-1 cells. We propose that the increase in cellular TF activity in circulating leukemic cells, combined with increased numbers of TF-positive MPs, may contribute to thrombosis in cancer patients receiving chemotherapy.

Obesity-related Coagulation Changes in Pregnancy

2011-09-12

Obesity, a health concern of increasing importance in developed countries, is associated with a four- to five-fold increased risk of venous thromboembolism (VTE) in pregnancy . In one study, obese pregnant women were three times more likely to suffer a pulmonary embolism (PE) than a deep vein thrombosis (DVT), placing them at greater risk for mortality than non-obese gravidas . Obesity is also associated with poor pregnancy outcomes, including a 40 percent increased risk for stillbirth compared to non-obese gravidas .

When the game demons take real lives: A call for global awareness raising for venous Thromboembolism

Behnood Bikdeli — 2011-10-31

The sad story of the death of a 20year-old man who succumbed to pulmonary embolism following prolonged immobility, due to playing computer games for several hours, was lately reported in the media. Venous thromboembolism (VTE) is the third most common vascular disorder after myocardial infarction and stroke. Nevertheless and despite all such catastrophic events, it is yet to be recognized among the priorities of international bodies such as the World Health Organization.

Urinary excretion of iPF2α-III predicts the risk of future thrombotic events. A 10-year follow-up

2011-10-31

Oxidative modifications of cell membrane lipids and of circulating lipoproteins induced by oxygen reactive species play a key role in thrombogenesis and atherogenesis. F2-isoprostanes are prostaglandins (PG) derived from a non-enzymatic process of lipid peroxidation catalysed by oxygen free radicals. In addition to its generation by free radical catalyzed mechanisms, 8-iso-PGF2α (known as iPF2α-III) may be formed by and activate human platelets, an observation linking in vivo oxidative stress to the risk of thrombosis. An abnormally high iPF2α-III urinary excretion has been reported in subjects at high cardiovascular risk and in a variety of disease settings . A link between hyperhomocysteinemia (HHcy), F2-isoprostanes and premature arteriothrombosis has been documented .

CYP2C19 gene variants cut-off levels for on-clopidogrel platelet aggregation

Viroj Wiwanitkit — 2011-10-28

Sir, a recent report on CYP2C19 gene variants cut-off levels for on-clopidogrel platelet aggregation is very interesting . Ono et al. concluded that “the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentiallyuseful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI .” There is little doubt that the VerifyNow could help discriminate between the carriers and no carriers. However, the exact clinical usefulness of such discrimination needs to be discussed. There are some reports suggesting a for low usefulness of monitoring of PRU and % inhibition. In a recent study by Varenhorst et al., questions on regarding "the clinical use of PRU testing to identify patients at high risk for thrombosis" were raised . In addition, the trend tendency of the VerifyNow tool to detectof detected higher on-treatment platelet reactivity using the VerifyNow tool when compared comparing to other tools should be mentioned . Moreover, this study concerns japanese patients, a population characterized by a high prevalence of the 2C19*2 allele, hence, the results cannot be generalized to the Western populations. It is also important to note that the cut-off suggested in this paper only concerns post-loading dose clopidogrel. Another important argumenton the uncertain clinical usefulness of any test used to discriminatecarriers and non carriers of loss-of-function CYP alleles should be raised. It should clear that the carriage of 2C19*2 does not imply a high on clopidogrel platelet reactivity (as about one third of Caucasian carriers are "good" responders) and 2C19 variants only account for less than 20% of variation in clopidogrel response. Finally,the authors did not report the biological profile of *2*2 carriers (10% of the population studied). The present left questions are “was there a gene-dose effect?” and “did they report the behavior of *2*17 carriers?”

Tamibarotene-induced low-grade reversible intravascular coagulation in a patient with acute promyelocytic leukemia

Kinya Ohata, Hirohito Yamazaki, Hidesaku Asakura, Shigeru Shimadoi, Shinji Nakao — 2011-08-08

All-trans retinoic acid (ATRA) has proven to be a major advance in the management of patients with acute promyelocytic leukemia (APL). Several studies show that treatment regimens containing ATRA for remission induction followed by several cycles of cytotoxic chemotherapy for consolidation yield overall survival rates superior to those produced by chemotherapy alone . However, when APL relapses in patients who have received ATRA-containing regimens, few of them respond to ATRA alone .

Clinical usefulness of a high-concentration calcium chloride solution method to correct the activated partial thromboplastin time in a high hematocrit model with heparin therapy

2011-09-26

Dear Editors, Pseudoprolongation of activated partial thromboplastin time (APTT) occurs in high hematocrit (HCT) samples. In order to correct this problem, a method of Clinical and Laboratory Standards Institute (CLSI) where the amount of anticoagulant (sodium citrate solution) is adjusted according to the HCT of the patient has been reported . However, the CLSI assay needs repeated blood sampling, resulting in time-consuming and complicated procedures. Moreover, there have been serious problems related to blood collection using vacuum blood sample tubes. We previously reported on the usefulness of highly concentrated CaCl2 solution as an APTT assay reagent for high HCT patients using conventional vacuum blood sample tubes . The aim of this study is therefore to investigate whether the APTT assay using highly concentrated CaCl2 solution has efficacy in high HCT patients with heparin therapy.