Posts Tagged ‘Drotrecogin alfa’

What is the Role of Plasma Viscosity in Hemostasis and Vascular Disease Risk?

Author: Larry H Bernstein, MD


Curator: Aviva Lev-Ari, PhD, RN

This is the first of a two part discussion of viscosity, hemostasis, and vascular risk

Part II:  Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Thesis Statement: The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans.  (Seminal study)

G. D. Sloop, MD.
Department of Pathology, Louisiana State University School of Medicine,
New Orleans, LA 70112, U.S.A.

  •  Increased blood or plasma viscosity has been associated with increased atherogenesis, and that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with atherosclerosis risk.
  • Low-density lipoprotein-cholesterol was more strongly correlated with blood viscosity than was total cholesterol (r = 0.4149, P = 0.0281, compared with r = 0.2790, P = 0.1505). High-density lipoprotein-cholesterol levels were inversely associated with blood viscosity (r = – 0.4018, P = 0.0341).
  • To confirm these effects, viscometry was performed on erythrocytes, suspended in saline, which had been incubated in plasma of various low-density lipoprotein/high-density lipoprotein ratios. Viscosity correlated directly with low-density lipoprotein/high-density lipoprotein ratio (n = 23, r = 0.8561, P < 0.01).
  • Low-density lipoprotein receptor occupancy data suggests that these effects on viscosity are mediated by erythrocyte aggregation.
  • These results demonstrate that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity in healthy subjects may play a role in atherogenesis by modulating the dwell or residence time of atherogenic particles in the vicinity of the endothelium.

This discussion is an additional perspective on the series on coagulation, and earlier posts that were on flow dynamics.

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

Atrial Fibrillation: The Latest Management Strategies

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Nitric Oxide Signalling Pathways            AviralvatsaEndothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells

Septic Shock: Drotrecogin Alfa (Activated) in Septic Shock

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation   LHB

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?  SJWilliamspa

Vascular Wall Shear Stress

Shear Stress

  1. The basic principles concerning mechanical stress applies to pathophysiological mechanisms in the vascular bed. In physics, stress is the internal distribution of forces within a body that balance and react to the external loads applied to it. Blood flow in the circulation leads to the development of superficial stresses near the vessel walls in either of two categories:

a) circumferential stress due to pulse pressure variation inside the vessel;
b) shear stress due to blood flow.

  1. The direction of the shear stress vector is determined the blood flow velocity vector adjacent to applied against the vessel wall.
  2. Friction is the opposing force applied by the wall.
  3. Shear stresses are disturbed by turbulent flow, regions of flow recirculation or flow separation.
  4. The notions of shear rate and fluid viscosity are crucial for the assessment of shear stress.

Fluid Flow and Shear Stress

  1. Shear rate is defined as the rate at which adjacent layers of fluid move with respect to each other, usually expressed as reciprocal seconds.
  2. The size of the shear rate gives an indication of the shape of the velocity profile for a given situation.
  3. The determination of shear stresses on a surface is based on the fundamental assumption of fluid mechanics, according to which the velocity of fluid upon the surface is zero (no-slip condition).
  4. Assuming that the blood is an ideal Newtonian fluid with constant viscosity, the flow is steady and laminar and the vessel is straight, cylindrical and inelastic, which is not the case. Under ideal conditions a parabolic velocity profile could be assumed.

The following assumptions have been made:

  1. The blood is considered as a Newtonian fluid.
  2. The vessel cross sectional area is cylindrical.
  3. The vessel is straight with inelastic walls.
  4. The blood flow is steady and laminar.

The Haagen-Poisseuille equation indicates that shear stress is directly proportional to blood flow rate and inversely proportional to vessel diameter.

  1. Viscosity is a property of a fluid that offers resistance to flow, and it is a measure of the combined effects of adhesion and cohesion.
  2. Viscosity increases as temperature decreases.
  3. Blood viscosity (non-Newtonian fluid) depends on shear rate, which is determined by blood platelets, red cells, etc.
  4. Blood viscosity is slightly affected by shear rate changes at low levels of hematocrit, but as hematocrit increases, the effect of shear rate changes becomes greater.
  5. the dependence of blood viscosity on hematocrit is more pronounced in the microcirculation than in larger vessels, due to hematocrit variations observed in small vessels (lumen diameter <100 Ìm).

The significant change of hematocrit in relation to vessel diameter is associated with the tendency of red blood cells to travel closer to the centre of the vessels. Thus, the greater the decrease in vessel lumen, the smaller the number of red blood cells that pass through, resulting in a decrease in blood viscosity.

Shear stress and vascular endothelium

  1. Endothelium responds to shear stress depending on the kind and the magnitude of shear stresses.
  2. the exposure of vascular endothelium to shear forces in the normal value range stimulates endothelial cells to release agents with direct or indirect antithrombotic properties, such as
  • prostacyclin,
  • nitric oxide (NO),
  • calcium,
  • thrombomodulin, etc.

Changes in shear stress magnitude activate cellular proliferation mechanisms as well as vascular remodeling processes.

  1. a high grade of shear stress increases wall thickness and expands the vessel’s diameter
  2. low shear stress induces a reduction in vessel diameter.
  3. Shear stresses are maintained at a mean of about 15 dynes/cm2.
  4. The presence of low shear stresses is frequently accompanied by unstable flow conditions
  • turbulence flow,
  • regions of blood recirculation,
  • “stagnant” blood areas.

(Papaioannou TG, Stefanadis C. Vascular Wall Shear Stress: Basic Principles and Methods. Hellenic J Cardiol 2005; 46: 9-15.)

Hemorheology and Microvascular Disorders

Blood flow in large arteries is dominated by inertial forces exhibited at high flow velocities, while viscosity is negligible. When the flow velocity is compromised by deceleration at a bifurcation, endothelial cell dysfunction can occur along the outer wall at the bifurcation.

In sharp contrast, the flow of blood in micro-vessels is dominated by viscous shear forces since the inertial forces are negligible due to low flow velocities. Shear stress is a critical parameter in micro-vascular flow, and a force-balance approach is proposed for determining micro-vascular shear stress. When the attractive forces between erythrocytes are greater than the shear force produced by micro-vascular flow, tissue perfusion itself cannot be sustained.

The yield stress parameter is presented as a diagnostic candidate for future clinical research, specifically, as a fluid dynamic biomarker for micro-vascular 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.

Cho Y-Il, and Cho DJ. Hemorheology and Microvascular Disorders. Korean Circ J 2011; 41:287-295.
Print ISSN 1738-5520 / On-line ISSN 1738-5555

Blood Rheology in Genesis 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 both healthy individuals and 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.

Cowan AQ, Cho DJ, & Rosenson RS. Importance of Blood Rheology in the Pathophysiology of Athero-thrombosis. Cardiovasc Drugs Ther 2012; 26:339–348. DOI 10.1007/s10557-012-6402-4


English: shear stress

English: shear stress (Photo credit: Wikipedia)

English: Shear rate dependency on fluid type a...

English: Shear rate dependency on fluid type and applied shear stress. (Photo credit: Wikipedia)

Inflammatory, haemostatic, and rheological markers

Markers of inflammation, hemostasis, and blood rheology have been ascertained to be risk factors for coronary heart disease and stroke. Their role in peripheral arterial disease (PAD) is not well established and some of them, including the pro-inflammatory cytokine interleukin-6 (IL-6), have not been examined before in prospective epidemiological studies.

In the Edinburgh Artery Study, we studied the development of PAD in the general population and evaluated 17 potential blood markers as predictors of incident PAD. At baseline (1987), 1519 men and women free of PAD aged 55–74 were recruited. After 17 years, 208 subjects had developed symptomatic PAD. In analysis adjusted for cardiovascular risk factors and baseline cardiovascular disease (CVD), only

  1. C-reactive protein 1.30 (1.08, 1.56)
  2. fibrinogen               1.16 (1.05, 1.17)
  3. lipoprotein (a)        1.22 (1.04, 1.44),
  4. hematocrit 1.22 (1.08, 1.38) [hazard ratio (95% CI) ]

-corresponding to an increase equal to the inter-tertile range-

were significantly (P , 0.01) associated with PAD.

These markers provided very little prognostic information for incident PAD to that obtained by cardiovascular risk factors and the ankle brachial index. Other markers included:

  • IL-6
  • intracellular adhesion molecule 1 (ICAM-1)
  • D-dimer
  • tissue plasminogen activator antigen
  • plasma and blood viscosities

having weak associations, were considerably attenuated when accounting for CVD risk factors.

Tzoulaki I, Murray GD, Lee AJ, Rumley A, et al. Inflammatory, haemostatic, and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study. European Heart Journal (2007) 28, 354–362. doi:10.1093/eurheartj/ehl441


Leukocyte and platelet adhesion under flow

Leukocyte adhesion under flow in the microvasculature is mediated by

  • binding between cell surface receptors and
  • complementary ligands expressed on the surface of the endothelium.

Leukocytes adhere to endothelium in a two-step mechanism:

  1. rolling (primarily mediated by selectins) followed by
  2. firm adhesion (primarily mediated by integrins).

These investigators simulated the adhesion of a cell to a surface in flow, and elucidated the relationship between receptor–ligand functional properties and the dynamics of adhesion using a computational method called ‘‘Adhesive Dynamics.’’

Behaviors that are observed in simulations include

  • firm adhesion,
  • transient adhesion (rolling), and
  • no adhesion.

They varied the

  • dissociative properties,
  • association rate,
  • bond elasticity, and
  • shear rate

and found that the

  1. unstressed dissociation rate, kro,
  2. and the bond interaction length, γ,

are the most important molecular properties controlling the dynamics of adhesion.

(Chang KC, Tees DFJ andHammer DA. The state diagram for cell adhesion under flow: Leukocyte rolling and firm adhesion. PNAS 2000; 97(21):11262-11267.)

  • The effect of leukocyte adhesion on blood flow in small vessels is treated as a homogeneous Newtonian fluid is sufficient to explain resistance changes in venular microcirculation.
  • The Casson model represents the effect of red blood cell aggregation and requires the non-Newtonian fluid flow model of resistance changes in small venules.

In this model the blood vessel is considered as a circular cylinder and the leukocyte is considered as a truncated spherical protrusion in the inner side of the blood vessel.

Numerical simulations demonstrated that for a Casson fluid with hematocrit of 0.4 and flow rate Q = 0:072 nl/s, a single leukocyte increases flow resistance by 5% in a 32 m diameter and 100 m long vessel. For a smaller vessel of 18 m, the flow resistance increases by 15%.

(Das B, Johnson PC, and Popel AS. Computational fluid dynamic studies of leukocyte adhesion effects on non-Newtonian blood flow through microvessels. Biorheology  2000; 37:239–258.)

Adhesive interactions between leukocytes

The mechanics of how blood cells interact with one another and with biological or synthetic surfaces is quite complex: owing to

  • the deformability of cells,
  • the variation in vessel geometry, and
  • the large number of competing chemistries present

(Lipowski et al., 1991, 1996).

Adhesive interactions between white blood cells and the interior surface of the blood vessels they contact are important in

  • inflammation and in
  • the progression of heart disease.

Parallel-plate micro-channels have been used to characterize the strength of these interactions. Recent computational and experimental work by several laboratories are directed at bridging the gap between

  • behavior observed in flow chamber experiments, and
  • cell surface interactions observed in the micro-vessels

What follows is a computational simulation of specific adhesive interactions between cells and surfaces under flow. In the adhesive dynamics formulation, adhesion molecules are modeled as compliant springs. The Bell model is used to describe the kinetics of single biomolecular bond failure, which relates

  1. the rate of dissociation kr to
  2. the magnitude of the force on the bond F.

The rate of formation directly follows from the Boltzmann distribution for affinity. The expression for the binding rate must also incorporate the effect of the relative motion of the two surfaces. Unless firmly adhered to a surface, white blood cells can be effectively modeled as rigid spherical particles. This is consistent with good agreement between bead versus cell in vitro experiments (Chang and Hammer, 2000).

Various methods have been used to bring clarity to the complex range of transient interactions between

  • cells,
  • neighboring cells, and
  • bounding surfaces under flow.

Knowledge gained from these investigations of flow systems may prove useful in microfluidic applications where the transport of

  • blood cells and
  • solubilized, bioactive molecules is needed, or
  • in miniaturized diagnostic devices

where cell mechanics or binding affinities can be correlated with clinical pathologies.

(King MR. Cell-Surface Adhesive Interactions in Microchannels and Microvessels.   First International Conference on Microchannels and Minichannels. 2003, Rochester, NY. Pp 1-6. ICMM2003-1012.

Monitoring Blood Viscosity to Improve Cognitive Function

Blood viscosity, the metric for the thickness and stickiness of blood, is associated with all major risk factors for cardiovascular disease, complications of diabetes, and it is highly predictive of stroke and MI, as well as cognitive decline. While elevated blood viscosity has a role in the etiology of atherosclerosis,  there is strong evidence for a causal role in the development of dementia.  It follows that improving blood viscosity should lead to improvements in cognitive as well as cardiovascular function.

Factors Affecting Blood Viscosity

Five cardinal factors are:

  1. Hematocrit,
  2. erythrocyte deformability,
  3. plasma viscosity,
  4. erythrocyte aggregation, and
  5. temperature

First to consider is hematocrit. Erythrocyte deformability is the ability of red blood cells to elongate and fold themselves for better hemodynamic flow in large vessels as well as for more efficient passage through capillaries.  The more deformable the red blood cells, the less viscous the blood.  Young red blood cells are flexible and tend to stiffen over their 120 day life-span.  Erythrocyte deformability is, after hematocrit, the second most important determinant of blood viscosity.

The third factor is plasma viscosity.  An important determinant of plasma viscosity is hydration status, but it is also determined by the presence of high molecular-weight proteins, especially immune globulins and fibrinogen.

Erythrocyte aggregation, the tendency of red blood cells to be attracted to each other and stick together is not well understood, but erythrocyte deformability and plasma proteins play important roles.

Blood, like most other fluids, is less viscous at higher temperatures. It is estimated that a 1°C increase in temperature results in a 2% decrease in blood viscosity.

Viscous Blood is Abrasive Blood

Maintaining efficient blood flow through the vessels forms layers, or lamina, that slide easily over each other.

  • Faster flowing blood can be found in the central layers and
  • Slower moving blood in the outer layers near the vessel walls.
  • Hyper-viscous blood doesn’t slide as smoothly as less viscous blood.
  • The turbulence damages the delicate intima of the blood vessel.

One of the most common locations for the development of atherosclerotic plaques is at the bifurcation of the carotid arteries, and the positioning of these plaques can be mapped to the turbulent blood flow patterns of this region.

Blood viscosity is highly correlated with thickening of the carotid intima-media, a prelude to plaque formation.  As the carotid arteries become progressively more occluded, there is decreased blood supply to the brain.

Hyper-viscosity also impacts the brain at the level of micro-perfusion.  Stiffened red blood cells have a decreased ability to bend and fold as they pass through capillaries. This leads to endothelial abrasion.  The capillary walls thicken and diffusion of oxygen and nutrients into the tissues decreases. The effect is most pronounced in those tissues where perfusion is essential for unimpaired function, such as the brain.

Diabetes, Blood Viscosity, and Dementia

While diabetics have elevated blood viscosity, blood viscosity is a risk factor that predicts progression from metabolic syndrome to diabetes. Red blood cell flexibility is greatly reduced by fluctuations in the osmolality of the blood which is affected by blood glucose concentration.  Uncontrolled, this leads to  small vessel disease.

  • Blindness,
  • kidney insufficiency, and
  • leg ischemia

develop as these organs are the dependent on micro-perfusion.

The Rotterdam Study and other research point to decreased cognitive function and increased dementia among diabetics as being further manifestations of the decreased perfusion that accompanies elevated blood viscosity.


Blood Viscosity, Cognitive Decline, and Alzheimer’s

Multiple forms of cognitive decline, including dementia and Alzheimers’ are impacted by increased blood viscosity. The Edinburgh Artery Study (2010) showed that blood viscosity predicted cognitive decline over a four year period in 452 elderly subjects (p<0.05).  Blood viscosity, an important determinant of the circulatory flow, was significantly linked with cognitive function.  The associations between cardiovascular risk factors, vascular dementia, and Alzheimer’s disease were presented by de la Torre (2002) (nine points of evidence) in a compelling argument that Alzheimer’s is a vascular disorder characterized by impaired micro-perfusion to the brain.

Testing for Blood Viscosity

The most recent technology uses an automated scanning capillary tube viscometer capable of measuring viscosity over the complete range of physiologic values experienced in a cardiac cycle (10,000 shear rates) with a single continuous measurement. This test provides clinicians with measurements of blood viscosity at both systolic and diastolic pressures.

Blood viscosity testing is indicated for a wide range of patients, as good tissue perfusion is central to good health regardless of what system is being addressed.  Patients with signs of cognitive decline should be high on the list of those appropriate to test, and those patients with a history or family history of heart disease, stroke, hypertension, diabetes, metabolic syndrome, migraines, smoking, alcoholism or other risk factors associated with the development of Alzheimer’s disease.

Source: Larsen P, Monitoring Blood Viscosity to Improve Cognitive Function

  1. World Health Organization. Dementia: A Public Health Priority. April, 2012.
  2. Sloop GD. A unifying theory of atherogenesis. Med Hypotheses. 1996; 47:321-5.
  3. Kensey KR and Cho, Y. Physical Principles and Circulation: Hemodynamics. In: The Origin of Atherosclerosis: What Really Initiates the Inflammatory Process. 2nd Ed. Summersville, WV: SegMedica; 2007:33-50.
  4. Hofman A., Ott A, et. al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet, 1997, 349 (9046): 151-154


 Sleep Apnea and Blood Viscosity.

Obstructive sleep apnea (OSA) is an important public health concern, which affects around 2–4% of the population. Left untreated, it causes a decrease not only in quality of life, but also of life expectancy. Despite the fact that knowledge about the mechanisms of development of cardiovascular disease in patients with OSA is still incomplete, observations confirm a relationship between sleep disordered breathing and the rheological properties of blood.

Tażbirek M, Słowińska L, Kawalski M, Pierzchała W.   The rheological properties of blood and the risk of cardiovascular disease in patients with obstructive sleep apnea syndrome (OSAS) Folia Histochemica et Cytobiologica 2011; 49(2):206–210.

Hemostatic and Rheological Risk Factors and the Risk Stratification

Backgound: Thrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease (CAD). We hypothesize, that hemostatic
and rheological risk factors may be of major relevance for the incidence and the risk stratification of these patients.

  • Methods: In 243 patients with coronary artery disease and stable angina pectoris parameters of metabolism, hemostasis, blood rheology and endogenous fibrinolysis were assessed.

Patients were prospectively followed for 2 years in respect to elective revascularizations and acute coronary syndromes.

Results: During follow-up 88 patients presented with cardiac events, 22 of those were admitted to the hospital because of acute events, 5 Patients were excluded due to non- cardiac death.

Patients with clinical events were found to be more frequently diabetic and presented with a more progressed coronary atherosclerosis. Even though patients with diabetes mellitus demonstrated a comparable level of multivessel disease (71% vs. 70%) the rate of elective revascularization was higher (41% vs. 28%, p < 0.05). The results were also unfavorable for
the incidence of acute cardiovascular events (18% vs. 8%, p < 0.01).

In comparison to non-diabetic patients diabetics demonstrated significantly elevated levels of

  • fibrinogen (352 ± 76 vs. 312 ± 64 mg/dl, p < 0.01),
  • plasma viscosity (1.38 ± 0.23 vs. 1.31 ± 0.16 mPas, p < 0.01),
  • red blood cell aggregation (13.2 ± 2.5 vs. 12.1 ± 3.1 E, p < 0.05) and

plasmin-activator-inhibitor (6.11 ± 3.4 vs. 4.7 ± 2.7 U/l, p < 0.05).

Conclusion: Pathological alterations of fibrinogen, blood rheology and plasminogen-activatorinhibtor as indicators of a procoagulant state are of major relevance for the
short-term incidence of cardiac events, especially in patients with diabetes mellitus type 2, and may be used to stratify patients to specific therapies.

parameters of metabolism, hemostasis, endogenous fibrinolysis and blood rheology for patients with and without diabetes mellitus.

diabetes mellitus non-diabetic patients p-value
glucose (mg/dl) 157 ± 67 88 ± 12 <0,0001
fibrinogen (mg/dl) 351 ± 76 312 ± 64 <0,01
plasma viscosity (mPa × s-1) 1,38 ± 0,23 1,31 ± 0,16 <0,01

Jax TW, Peters AJ, Plehn G, and  Schoebel FC. Hemostatic risk factors in patients with coronary artery disease and type 2 diabetes – a two year follow-up of 243 patients. Cardiovascular Diabetology 2009; 8:48-57.  doi:10.1186/1475-2840-8-48


Abnormal Viscosity in Pregnancy

Abnormal hemorheology has been shown to be in almost all conditions associated with accelerated atherosclerotic cardiovascular disorders. The aim of this study is to test the hypothesis that high concentration of plasma Triglyceride (TG) predicts altered hemorheological variables in normal pregnancy.

Sixty pregnant women attending antenatal clinic of the University of Ilorin Teaching Hospital at 14-36 weeks of gestation (aged 21-36 years) were recruited after giving informed consent to participate in the study. They consisted of 28 primigravidae and 32 multigravidae. Twenty-four healthy non-pregnant women of similar age and socioeconomical status were also recruited. The study showed that fasting plasma Triglyceride (TG) increased significantly in primigravidae and multigravidae.

There was a positive correlation between plasma TG level and blood viscosity (r = 0.36, p<0.01). TG also correlated positively with hematocrit (r = 0.48, p<0.001), hemoglobin concentration (r = 0.43, p<0.001) and white blood cell count (r = 0.38, p<0.01) in the pregnant group as a whole. In primigravidae, there was a strong correlation between TG and

o          blood viscosity (r = 0.63, p<0.001),

o          hematocrit (r = 0.88, p<0.001),

o          hemoglobin concentration (r = 0.85, p<0.001).

However, there was an insignificant correlation between TG and the hemorheological variables in multigravidae.

Plasma TG concentration in primigravidae is strongly associated with blood viscosity also with hematocrit and hemoglobin concentration, but the association is lost in multigravidae. Therefore, TG could be considered as an important potential indicator of altered blood rheology in primigravidae, but not in multigravidae.

Olatunji LA, Soladoye AO, Fawole AA, Jimoh RO and Olatunji VA. Association between Plasma Triglyceride and Hemorheological Variables in Nigerian Primigravidae and Multigravidae.

Research Journal of Medical Sciences 2008; 2(3):116-120. ISSN: 1815-9346.


Retinal Vein Occlusion

Retinal vein occlusion (RVO) is an important cause of permanent visual loss. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of RVO. Aim of this case-control study was to evaluate the possible association between hemorheology and RVO. In 180 RVO patients and in 180 healthy subjects comparable for age and gender we analysed the whole hemorheological profile: [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV), and fibrinogen]. WBV and PLV were measured using a rotational viscosimeter, whereas DI was measured by a microcomputer-assisted filtrometer. WBV at 0.512 sec-1 and 94.5 sec-1 shear rates as well as DI, but not PLV, were significantly different in patients as compared to healthy subjects.

At the logistic univariate analysis, a significant association between the

  • highest tertiles of WBV at 94.5 sec-1 shear rate (OR:4.91,95%CI 2.95–8.17;p<0.0001),
  • WBV at 0.512 sec-1 shear rate (OR: 2.31, 95%CI 1.42–3.77; p<0.0001), and
  • the lowest tertile of DI (OR: 0.18, 95%CI 0.10–0.32; p<0.0001) and RVO was found.

After adjustment for potential confounders,

  • the highest tertiles of WBV at 0.512 sec-1 shear rate (OR: 3.23, 95%CI 1.39–7.48; p=0.006),
  • WBV at 94.5 sec-1 shear rate (OR: 6.74, 95%CI 3.06–14.86; p<0.0001) and
  • the lowest tertile of DI (OR:0.20,95%CI 0.09–0.44,p<0.0001)

remained significantly associated with the disease. In conclusion, the data indicate that an alteration of hemorheological parameters may modulate the susceptibility to the RVO.

Sofi F, Mannini L, Marcucci R, Bolli P, Sodi A, et al.  Role of hemorheological factors in patients with retinal vein occlusion. In Blood Coagulation, Fibrinolysis and Cellular Haemostasis.  Thromb Haemost 2007; 98:1215–1219.

Summary:  This discussion is a two part sequence that first establishes the known strong relationship between blood flow viscosity, shear stress, and plasma triglycerides (VLDL) as risk factors for hemostatic disorders leading to thromboembolic disease, and the association with atherosclerotic disease affecting the heart, the brain (via carotid blood flow), peripheral circulation, the kidneys, and retinopathy as well.

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Reporter: Aviva Lev-Ari, PhD, RN

Correspondence in NEJM

To the Editor:

Ranieri et al. (May 31 issue)1 report the results of yet another negative trial involving patients with septic shock. I cannot help but wonder whether these negative trials reflect a failure of the study design rather than the study drug. The Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) protocol required patients to begin treatment “within 24 hours after the first dose of a vasopressor.” Did the patients simply receive treatment after the opportunity to affect the sepsis cascade was missed? The authors provide data on the median time from the initiation of antibiotics to initial vasopressor therapy (2.5 hours), but they do not provide information regarding the time from diagnosis, from initiation of vasopressors, or from arrival in the emergency department until study-drug administration. It is hard to close the book on any therapy for critically ill patients until it is known whether it was administered during the time frame when the therapy would be most likely to show benefit. Common sense dictates that early interventions would be more helpful than later interventions.

Judd E. Hollander, M.D.
University of Pennsylvania, Philadelphia, PA

No potential conflict of interest relevant to this letter was reported.

1 References


Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012;366:2055-2064
Full Text | Web of Science | Medline

To the Editor:

Although disappointing, the results of the PROWESS-SHOCK study in which drotrecogin alfa (activated) (DrotAA) (recombinant human activated protein C) was used for severe sepsis are not surprising. Biologically active molecules such as DrotAA are likely to be effective in targeting specific pathophysiological disturbances in disease states such as severe meningococcal sepsis with disseminated intravascular coagulation or purpura fulminans as the dominant clinical feature.1That no biologically active substance has shown benefit in sepsis may have more to do with studies that involve heterogeneous groups of patients with diverse causes of sepsis rather than a single disease entity. Anecdotal reports of the use of activated protein C in severe meningococcal disease in children and adults2-4 provide support for the view that DrotAA could be therapeutically useful in this condition. Unfortunately, DrotAA was abruptly withdrawn from the market. This means that clinical trials of human recombinant activated protein C in life-threatening meningococcal infection can no longer be conducted.

Vineet Nayyar, F.R.A.C.P., F.C.I.C.M.
Thomas Solano, F.R.A.C.P., F.C.I.C.M.
Westmead Hospital, Westmead, NSW, Australia

No potential conflict of interest relevant to this letter was reported.

4 References

4 References

    1. 1

      Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001;345:408-416
      Full Text | Web of Science | Medline

    1. 2

      Veldman A, Fischer D, Wong FY, et al. Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome of 94 pediatric patients.Crit Care 2010;14:R156-R156
      CrossRef | Web of Science

    1. 3

      Thomas GL, Wigmore T, Clark P. Activated protein C for the treatment of fulminant meningococcal septicaemia. Anaesth Intensive Care 2004;32:284-287
      Web of Science

  1. 4

    Vincent J-L, Nadel S, Kutsogiannis DJ, et al. Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies. Crit Care 2005;9:R331-R343
    CrossRef | Web of Science

Author/Editor Response

We agree with Hollander’s implication that multiple reasons may explain why a study such as PROWESS-SHOCK did not show a benefit. However, PROWESS-SHOCK showed that DrotAA did not benefit patients who met the specific criteria for septic shock that were defined for enrollment in the trial.

It is difficult to define precisely when sepsis begins. We did record the time from the start of treatment with a vasopressor to the start of study-drug infusion1 and found no heterogeneity in the treatment effect on 28-day mortality (see Fig. S1 in the Supplementary Appendix, available with the full text of our article at NEJM.org) and 90-day mortality (Figure 2B of our article), according to quartiles of time of this interval. The mean (±SD) time from the start of a vasopressor to the start of DrotAA was 17.2±5.7 hours, which is similar to the interval from the first organ failure to the start of DrotAA reported in the PROWESS study (17.5±12.8 hours).2 The shortest interval was 4 hours. Thus, we found no evidence of a beneficial effect of DrotAA early during the course of septic shock.

Meningitis was listed as the cause of septic shock in only 24 of 1696 patients enrolled in PROWESS-SHOCK, and Neisseria meningitidis was cultured in samples obtained from only 7 patients. Thus, our study cannot address the question of the efficacy of DrotAA for that specific population. However, as Nayyar and Solano suggest, we did anticipate that if DrotAA was beneficial, the benefit would be greatest among patients presenting with a more coagulopathic phenotype. Thus, there were also predefined subgroups according to the protein C class and baseline Sequential Organ Failure Assessment score for coagulation. There was no heterogeneity in the treatment effect on 28-day mortality (Fig. S1 in the Supplementary Appendix of our article) and 90-day mortality (Figure 2B of our article) in these subgroups. Furthermore, the relatively small Resolution of Organ Failure in Pediatric Patients with Severe Sepsis trial included subgroups of children with septic coagulopathy and purpura fulminans and showed no treatment effect of DrotAA as compared with placebo.3 That all six remaining subgroups in PROWESS-SHOCK did not show a treatment effect should reassure clinicians who no longer have DrotAA available for the treatment of septic shock.

B. Taylor Thompson, M.D.
Massachusetts General Hospital, Boston, MA

V. Marco Ranieri, M.D.
Università di Torino, Turin, Italy

for the PROWESS-SHOCK Steering Committee

    1. 1

      PROWESS SHOCK Steering Committee, Thompson BT, Ranieri VM, et al. Statistical analysis plan of PROWESS SHOCK study. Intensive Care Med 2010;36:1972-1973
      CrossRef | Web of Science

    1. 2

      Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
      Full Text | Web of Science | Medline

  1. 3

    Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet2007;369:836-843
    CrossRef | Web of Science | Medline



N Engl J Med 2012; 367:968-969  September 6, 2012

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