Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial.

BACKGROUND: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM). METHODS: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s-1) and low-shear (5 s-1) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM. RESULTS: We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25). CONCLUSIONS: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

Effect of warfarin versus aspirin on blood viscosity in cardioembolic stroke with atrial fibrillation: a prospective clinical trial.

BACKGROUND: Warfarin is evidence-based therapy for the prevention of cardioembolic stroke, but has not been studied for its effects on whole blood viscosity (WBV). This study investigated the effect of warfarin versus aspirin on WBV in patients presenting with non-valvular atrial fibrillation (NVAF) and acute cardioembolic stroke. METHODS: We enrolled patients with acute cerebral infarction, aged 56-90 years who had NVAF, CHADS2 score ≥ 2, presenting with mild-to-moderate stroke (National Institute of Health Stroke Scale (NIHSS) score < 20 and modified Rankin Scale (2mRS) score < 4) in a single center. The patients were alternately assigned to warfarin or aspirin groups. Post-treatment WBV was assessed after international normalized ratio (INR) reached target range [2, 3] for patients in the warfarin group, and 5 days after baseline in the aspirin group. RESULTS: Total 67 patients were included, and 56 completed this study (33 warfarin and 23 aspirin). Compared to baseline values, warfarin reduced post-treatment BV at all shear rates. The BV reductions greater than 1 cP measured at shear rates of 300, 150, 5, and 1 s- 1 were independently and significantly associated with warfarin treatment compared to aspirin after adjusting for age, sex, CHA2DS2-VASc scores, and baseline hematocrit. CONCLUSIONS: Warfarin confers greater reductions in BV than aspirin in patients with acute cardioembolic stroke. BV could be a useful method to estimate thrombotic risk in patients receiving warfarin. TRIAL REGISTRATION: KCT0001291 , Date of Registration: 2014-12-01.

Ticagrelor and the Prevention of Microvascular Complications in Diabetes Patients with Lower Extremity Arterial Disease; Rationale and Design of the Hema-Kinesis Trial.

BACKGROUND: Lower extremity arterial disease (LEAD) occurs more common in patients with diabetes than without diabetes. Microvascular complications of diabetes contribute to higher rates of adverse limb events in patients with LEAD. Blood flow in the macrocirculation and microcirculation is reduced with increasing low-shear and high-shear blood viscosity. We hypothesize that the adenosine enhancing properties of ticagrelor will reduce low-shear blood viscosity and improve microcirculatory flow in the dorsum of the feet of patients with type 2 diabetes. Ticagrelor is a P2Y12 receptor antagonist with evidence of cardiovascular event reduction in patients with acute coronary syndromes and those with a previous myocardial infarction. In a large multicenter trial of patients with symptomatic LEAD and a history of limb revascularization, ticagrelor was no more effective than clopidogrel in reducing cardiovascular disease events; however, this trial was not designed to investigate microvascular complications of diabetes. DESIGN: Hema-kinesis will evaluate whether ticagrelor monotherapy or ticagrelor combined with aspirin as compared with aspirin monotherapy can reduce blood viscosity-dependent blood flow in the feet of type 2 diabetes patients with LEAD. Eligible study participants will be randomized into a three-arm double-dummy crossover trial design. All subjects will have baseline blood viscosity measurements and determinations of microvascular flow using laser Doppler flowmetry. If the results of Hema-kinesis are positive, ticagrelor should be considered as treatment to reduce microvascular complications of LEAD in patients with type 2 diabetes.

Endothelial shear stress and blood viscosity in peripheral arterial disease.

This review examines the emerging role of endothelial shear stress (ESS) and blood viscosity on the initiation and progression of atherosclerosis in peripheral arterial disease. Among the variables determining ESS, blood viscosity has to date been the most overlooked by clinical researchers. Blood viscosity is a laboratory assessment that is minimally invasive and modifiable using pharmacologic therapy as well as by hemodilution. Monitoring and controlling blood viscosity not only modulates ESS, but also reduces peripheral vascular resistance and increases blood flow to the lower extremities.

Association of blood viscosity and device-free days among hospitalized patients with COVID-19.

BACKGROUND: Increased estimated whole blood viscosity (eWBV) predicts higher mortality in patients hospitalized for coronavirus disease 2019 (COVID-19). This study assesses whether eWBV is an early predictor of non-fatal outcomes among patients hospitalized for acute COVID-19 infection. METHODS: This retrospective cohort study included 9278 hospitalized COVID-19 patients diagnosed within 48 h of admission between February 27, 2020 to November 20, 2021 within the Mount Sinai Health System in New York City. Patients with missing values for major covariates, discharge information, and those who failed to meet the criteria for the non-Newtonian blood model were excluded. 5621 participants were included in the main analysis. Additional analyses were performed separately for 4352 participants who had measurements of white blood cell count, C-reactive protein and D-dimer. Participants were divided into quartiles based on estimated high-shear blood viscosity (eHSBV) and estimated low-shear blood viscosity (eLSBV). Blood viscosity was calculated using the Walburn-Schneck model. The primary outcome was evaluated as an ordinal scale indicating the number of days free of respiratory organ support through day 21, and those who died in-hospital were assigned a value of -1. Multivariate cumulative logistic regression was conducted to evaluate the association between quartiles of eWBV and events. RESULTS: Among 5621 participants, 3459 (61.5%) were male with mean age of 63.2 (SD 17.1) years. The linear modeling yielded an adjusted odds ratio (aOR) of 0.68 (95% CI 0.59-0.79, p value < 0.001) per 1 centipoise increase in eHSBV. CONCLUSIONS: Among hospitalized patients with COVID-19, elevated eHSBV and eLSBV at presentation were associated with an increased need for respiratory organ support at 21 days. These findings are highly relevant, as they demonstrate the utility of eWBV in identifying hospitalized patients with acute COVID-19 infection at increased risk for non-fatal outcomes in early stages of the disease.

Importance of blood rheology in the pathophysiology of atherothrombosis.

Elevated blood viscosity is an integral component of vascular shear stress that contributes to the site specificity of atherogenesis, rapid growth of atherosclerotic lesions, and increases their propensity to rupture. Ex vivo measurements of whole blood viscosity (WBV) is a predictor of cardiovascular events in apparently healthy individuals and studies of cardiovascular disease patients. The association of an elevated WBV and incident cardiovascular events remains significant in multivariate models that adjust for major cardiovascular risk factors. These prospective data suggest that measurement of WBV may be valuable as part of routine cardiovascular profiling, thereby potentially useful data for risk stratification and therapeutic interventions. The recent development of a high throughput blood viscometer, which is capable of rapidly performing blood viscosity measurements across 10,000 shear rates using a single blood sample, enables the assessment of blood flow characteristics in different regions of the circulatory system and opens new opportunities for detecting and monitoring cardiovascular diseases.

Lipoprotein-X and Lipoprotein-Z Induced Hyperviscosity Syndrome in the Setting of Cholestatic Liver Failure.

We describe a case referred for worsening hypercholesterolemia in the setting of atorvastatin and fenofibrate-induced liver injury. The patient reported neurological complaints attributed to hyperviscosity syndrome (induced by lipoprotein-X and lipoprotein-Z). Hepatic recovery was associated with reduction of whole blood viscosity and amelioration of neurological symptoms. (Level of Difficulty: Advanced.).

Blood hyperviscosity in acute and recent COVID-19 infection.

BACKGROUND: Elevated estimated blood viscosity (EBV), derived from hematocrit and globulins, is associated with thrombotic complications, organ failure, and higher mortality in COVID-19 patients. Although informative, EBV does not account for cellular interactions or fibrinogen. OBJECTIVE: Investigate whether patients with acute and recent COVID-19 have altered whole blood viscosity (WBV) when measured at both high and low shear rates using in vitro blood samples from patients. METHODS: Cross-sectional study of 58 patients: 15 in the intensive care unit with acute COVID-19, 32 convalescent (9 < 8weeks [W] from acute infection, 23 > 8 W), and 11 controls without COVID-19. WBV was measured at high (300 s-1) and low (5 s-1) shear rates (HSR, LSR) using a scanning capillary viscometer.RESULTSAcute and convalescent patients < 8 W had mean WBV at LSR (16.0 centipoise [cP] and 15.1 cP) and HSR (5.1 cP and 4.7 cP). Mean WBV of convalescent > 8 W and control patients were 12.3 cP and 13.0 cP at LSR, and 4.1 cP and 4.2 cP at HSR. Acute and < 8 W patients had significantly higher WBV at both HSR and LSR compared to patients > 8 W (all p≤0.01). No significant differences in WBV were observed between acute and < 8 W patients, or between patients > 8 W and controls. CONCLUSIONS: Hyperviscosity provides a possible explanation for thrombotic risk in acute and convalescent (< 8 W) patients. These findings have important implications for thromboprophylaxis.

Association of Blood Viscosity With Mortality Among Patients Hospitalized With COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is characterized by a dysfunctional immune response and abnormal blood rheology that contribute to endothelial dysfunction and thrombotic complications. Whole blood viscosity (WBV) is a clinically validated measure of blood rheology and an established predictor of cardiovascular risk. We hypothesize that increased WBV is associated with mortality among patients hospitalized with COVID-19. OBJECTIVES: This study sought to determine the association between estimated BV (eBV) and mortality among hospitalized COVID-19 patients. METHODS: The study population included 5,621 hospitalized COVID-19 patients at the Mount Sinai Health System from February 27, 2020, to November 27, 2021. eBV was calculated using the Walburn-Schneck model. Multivariate Cox proportional hazards models were used to evaluate the association between eBV and mortality. Considered covariates included age, sex, race, cardiovascular and metabolic comorbidities, in-house pharmacotherapy, and baseline inflammatory biomarkers. RESULTS: Estimated high-shear BV (eHSBV) and estimated low-shear BV were associated with increased in-hospital mortality. One-centipoise increases in eHSBV and estimated low-shear BV were associated with a 36.0% and 7.0% increase in death, respectively (P < 0.001). Compared with participants in the lowest quartile of eHSBV, those in the highest quartile of eHSBV had higher mortality (adjusted HR: 1.53; 95% CI: 1.27-1.84). The association was consistent among multiple subgroups, notably among patients without any comorbidities (adjusted HR: 1.69; 95% CI: 1.28-2.22). CONCLUSIONS: Among hospitalized COVID-19 patients, increased eBV is significantly associated with higher mortality. This suggests that eBV can prognosticate patient outcomes in earlier stages of COVID-19, and that future therapeutics aimed at reducing WBV should be evaluated.

Reduced amputation rate with isovolemic hemodilution in critical limb ischemia patients.

AIMS: Critical limb ischemia (CLI) patients are characterized by intractable pain in spite of medication, non-healing ulcers, and gangrene. The objective of this study was to investigate whether or not isovolemic hemodilution treatment can reduce the rate of major amputations in CLI. METHODS: 28 patients were studied who had tissue loss on Rutherford Grade III, Category 5 or 6. The subjects were divided into two arms: standard-of-care, conventional therapy (CT) (n = 15) as a control group and hemodilution therapy (HT) (n = 13) as a study group. For the HT group, weekly isovolemic hemodilution was performed over 4 consecutive weeks, removing 250 ml of whole blood with the infusion of hydroxyl-ethyl starch solution. Blood viscosity, hematocrit, hemoglobin, ankle-brachial index, VA pain scale, time-to-amputation from admission, and survival time were measured. RESULTS: The mean Hct gradually decreased from 36.6 to 35.1, whereas the WBV at a shear rate of 1 s-1 significantly decreased from 18.2 to 10.5 during the same period. Subsequently, tissue oxygen delivery index, defined as the ratio of Hct to WBV at a shear rate of 1 s-1, increased from 24.4 to 37.0 by 51.7%, suggesting improvements in oxygen delivery in the patients. The average rate of lower limb major amputation in the control group was 93% (14/15), whereas that in the study group was 31% (4/13) (p = 0.001). Amputation-free median survival time and amputation-free 5-year survival rate in the control group were 1.2 months and 7%, while those in the study group were 30.2 months and 44% (p = 0.001). There were no adverse effects from repetitive hemodilution in the study group. CONCLUSIONS: Isovolemic hemodilution treatment of CLI patients was found to be well-tolerated and reduced the rate of major amputation resulting from the deterioration of CLI.

Effect of electrolyzed high-pH alkaline water on blood viscosity in healthy adults.

BACKGROUND: Previous research has shown fluid replacement beverages ingested after exercise can affect hydration biomarkers. No specific hydration marker is universally accepted as an ideal rehydration parameter following strenuous exercise. Currently, changes in body mass are used as a parameter during post-exercise hydration. Additional parameters are needed to fully appreciate and better understand rehydration following strenuous exercise. This randomized, double-blind, parallel-arm trial assessed the effect of high-pH water on four biomarkers after exercise-induced dehydration. METHODS: One hundred healthy adults (50 M/50 F, 31 ± 6 years of age) were enrolled at a single clinical research center in Camden, NJ and completed this study with no adverse events. All individuals exercised in a warm environment (30 °C, 70% relative humidity) until their weight was reduced by a normally accepted level of 2.0 ± 0.2% due to perspiration, reflecting the effects of exercise in producing mild dehydration. Participants were randomized to rehydrate with an electrolyzed, high-pH (alkaline) water or standard water of equal volume (2% body weight) and assessed for an additional 2-h recovery period following exercise in order to assess any potential variations in measured parameters. The following biomarkers were assessed at baseline and during their recovery period: blood viscosity at high and low shear rates, plasma osmolality, bioimpedance, and body mass, as well as monitoring vital signs. Furthermore, a mixed model analysis was performed for additional validation. RESULTS: After exercise-induced dehydration, consumption of the electrolyzed, high-pH water reduced high-shear viscosity by an average of 6.30% compared to 3.36% with standard purified water (p = 0.03). Other measured biomarkers (plasma osmolality, bioimpedance, and body mass change) revealed no significant difference between the two types of water for rehydration. However, a mixed model analysis validated the effect of high-pH water on high-shear viscosity when compared to standard purified water (p = 0.0213) after controlling for covariates such as age and baseline values. CONCLUSIONS: A significant difference in whole blood viscosity was detected in this study when assessing a high-pH, electrolyte water versus an acceptable standard purified water during the recovery phase following strenuous exercise-induced dehydration.

Influence of non-Newtonian viscosity of blood on microvascular impairment.

The present research investigated the role of blood viscosity on flow within a microvascular network to identify the conditions of blood flow stagnation. When the yield stress of blood was less than 0.005 Pa, there were no stagnant regions in the microvasculature. However, when the yield stress increased to 0.05 Pa, stagnant or reduced flow areas began to appear, which grew and expanded rapidly with further increase in the yield stress. Thus, the yield stress determined from blood viscosity profile of a patient can be utilized to evaluate the risk of circulatory impairment.

Reduction of low-density lipoprotein cholesterol, plasma viscosity, and whole blood viscosity by the application of pulsed corona discharges and filtration.

The present study investigated the feasibility of applying pulsed corona discharges to blood plasma to reduce the viscosity of blood plasma and whole blood. Blood plasma was separated from blood cells, treated with corona discharges, and filtered before it was re-mixed with blood cells. Plasma viscosity (PV), whole blood viscosity (WBV), and low-density lipoprotein (LDL)-c concentration were measured before and after the corona treatment and filtration. Both PV and WBV increased in the case of the corona treatment only, whereas both of them decreased in the case of the corona treatment plus filtration. In particular, the LDL-c decreased in the case of the corona treatment plus filtration by 31.5% from the baseline value. The effect of the corona treatment on the reduction of the WBV was significant at low shear rates, but not at high shear rates, suggesting that the precipitation of the molecules in blood plasma by the corona treatment and subsequent removal may suppress the aggregation of erythrocytes and improve rheological properties of blood.

The effect of hemodialysis ultrafiltration on changes in whole blood viscosity.

Increased whole blood viscosity (WBV) can be injurious to the vascular endothelium and increase the risk of atherothrombotic events. This study examined the effect of hemodialysis ultrafiltration (UF) on WBV, with a focus on high vs. low-volume UF patients. In stable hemodialysis patients, blood was drawn for hematocrit (Hct) and WBV at the start, midpoint, and at the end of dialysis. For analysis, patients were divided into high UF (≥2700 mL) or low UF (<2700 mL) groups. A total of 59 patients completed the study. Mean Hct increased during dialysis in both groups. The intradialytic increase in Hct was significantly greater in the high vs. the low UF group (3.2% vs. 1.28%, P = 0.01), with a significantly higher end-dialysis Hct in the high UF group (40.5% vs. 38%, P = 0.02). At the end of dialysis, both high shear rate WBV (P < 0.01) and low shear rate WBV (P < 0.01) were significantly higher in the high UF compared with the low UF group. There was an approximately two-fold greater increase in high shear rate (P < 0.01) and low shear rate (P = 0.01) WBV during dialysis in high vs. low UF groups. The increase in high shear rate WBV during dialysis was significantly correlated with an increase in Hct (R(2) = 0.63, P < 0.01). We found that hemodialysis UF causes a surge in WBV. The surge was of greater magnitude in high than in low UF patients.

Hemorheology and microvascular disorders.

The present review presents basic concepts of blood rheology related to vascular diseases. Blood flow in large arteries is dominated by inertial forces exhibited at high flow velocities, while viscous forces (i.e., blood rheology) play an almost negligible role. When high flow velocity is compromised by sudden deceleration as at a bifurcation, endothelial cell dysfunction can occur along the outer wall of the bifurcation, initiating inflammatory gene expression and, through mechanotransduction, the cascade of events associated with atherosclerosis. In sharp contrast, the flow of blood in microvessels is dominated by viscous shear forces since the inertial forces are negligible due to low flow velocities. Shear stress is a critical parameter in microvascular flow, and a force-balance approach is proposed for determining microvascular shear stress, accounting for the low Reynolds numbers and the dominance of viscous forces over inertial forces. Accordingly, when the attractive forces between erythrocytes (represented by the yield stress of blood) are greater than the shear force produced by microvascular flow, tissue perfusion itself cannot be sustained, leading to capillary loss. The yield stress parameter is presented as a diagnostic candidate for future clinical research, specifically, as a fluid dynamic biomarker for microvascular disorders. The relation between the yield stress and diastolic blood viscosity (DBV) is described using the Casson model for viscosity, from which one may be able determine thresholds of DBV where the risk of microvascular disorders is high.

Hemorheological disorders in diabetes mellitus.

The objective of the present study is to review hemorheological disorders in diabetes mellitus. Several key hemorheological parameters, such as whole blood viscosity, erythrocyte deformability, and aggregation, are examined in the context of elevated blood glucose level in diabetes. The erythrocyte deformability is reduced, whereas its aggregation increases, both of which make whole blood more viscous compared to healthy individuals. The present paper explains how the increased blood viscosity adversely affects the microcirculation in diabetes, leading to microangiopathy.