Honors & Awards
NIH Clinical Scientist Career Development Award (K08), National Human Genome Research Institute (2018)
NIH Diversity/Research Reentry Award, National Center for Advancing Translational Sciences (2016)
ASA-Bugher Foundation Postdoctoral Fellowship, American Heart Association (2008)
Council of Graduate Schools Dissertation Award, The Pennsylvania State University (2005)
Outstanding Scholarship in Doctoral Research, American Vacuum Society (2005)
Focused Giving Grant for Graduate Research, Johnson & Johnson Ethicon (2003)
Stroke Research Fellow, RNA aptamers and Regulatable Anticoagulation, Duke University (2012)
Fellow, Duke Clinical Research Training Program, Duke University (2011)
Postdoctoral Fellow, Heart & Vascular Institute, Penn State College of Medicine, Penn State University (2008)
PhD, Bioengineering (an interdisciplinary program in the biosciences), Penn State University (2005)
Current Research and Scholarly Interests
Dr. Krishnan's current interests are in the transcriptional and epigenetic mechanisms of blood cell function and dysfunction in human disease. Her primary focus is on blood platelets with multifaceted function in cancer, inflammation or immunity; beyond their classical role in hemostasis and thrombosis.
In the long term, her work aims to develop clinically-meaningful relationships between patient genomic variation, disease-specific transcriptomic variation, and clinical phenotype in hematological diseases.
- Platelet Transcriptomic Signatures in Myeloproliferative Neoplasms; Blood 130: 5288, 2017 Blood 2017; 130 (5288)
The effect of surface contact activation and temperature on plasma coagulation with an RNA aptamer directed against factor IXa
JOURNAL OF THROMBOSIS AND THROMBOLYSIS
2013; 35 (1): 48-56
The anticoagulant properties of a novel RNA aptamer that binds FIXa depend collectively on the intensity of surface contact activation of human blood plasma, aptamer concentration, and its binding affinity for FIXa. Accordingly, anticoagulation efficiency of plasma containing any particular aptamer concentration is low when coagulation is strongly activated by hydrophilic surfaces compared to the anticoagulation efficiency in plasma that is weakly activated by hydrophobic surfaces. Anticoagulation efficiency is lower at hypothermic temperatures possibly because aptamer-FIXa binding decreases with decreasing temperatures. Experimental results demonstrating these trends are qualitatively interpreted in the context of a previously established model of anticoagulation efficiency of thrombin-binding DNA aptamers that exhibit anticoagulation properties similar to the FIXa aptamer. In principle, FIXa aptamer anticoagulants should be more efficient and therefore more clinically useful than thrombin-binding aptamers because aptamer binding to FIXa competes only with FX that is at much lower blood concentration than fibrinogen (FI) that competes with thrombin-binding aptamers. Our findings may have translatable relevance in the application of aptamer anticoagulants for clinical conditions in which blood is in direct contact with non-biological surfaces such as those encountered in cardiopulmonary bypass circuits.
View details for DOI 10.1007/s11239-012-0778-7
View details for Web of Science ID 000312784500007
View details for PubMedID 23054460
Effects of limb posture on reactive hyperemia
EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY
2011; 111 (7): 1415-1420
To examine the role of limb posture on vascular conductance during rapid changes in vascular transmural pressure, we determined brachial (n = 10) and femoral (n = 10) artery post-occlusive reactive hyperemic blood flow (RHBF, ultrasound/Doppler) and vascular conductance in healthy humans with each limb at three different positions-horizontal, up and down. Limb posture was varied by raising or lowering the arm or leg from the horizontal position by 45°. In both limbs, peak RHBF and vascular conductance were highest in the down or horizontal position and lowest in the up position (arm up 338 ± 38, supine 430 ± 52, down 415 ± 52 ml/min, P < 0.05; leg up 1,208 ± 88, supine 1,579 ± 130, down 1,767 ± 149 ml/min, P < 0.05). In contrast, the maximal dynamic fall in blood flow following peak RHBF (in ml/s/s) in both limbs was highest in the limb-down position and lowest with the limb elevated (P < 0.05). These data suggest that the magnitude and temporal pattern of limb reactive hyperemia is in part related to changes in vascular transmural pressure and independent of systemic blood pressure and sympathetic control.
View details for DOI 10.1007/s00421-010-1769-z
View details for Web of Science ID 000291602200018
View details for PubMedID 21161263
View details for PubMedCentralID PMC3285391
Volumetric interpretation of protein adsorption: Interfacial packing of protein adsorbed to hydrophobic surfaces from surface-saturating solution concentrations
2011; 32 (4): 969-978
The maximum capacity of a hydrophobic adsorbent is interpreted in terms of square or hexagonal (cubic and face-centered-cubic, FCC) interfacial packing models of adsorbed blood proteins in a way that accommodates experimental measurements by the solution-depletion method and quartz-crystal-microbalance (QCM) for the human proteins serum albumin (HSA, 66 kDa), immunoglobulin G (IgG, 160 kDa), fibrinogen (Fib, 341 kDa), and immunoglobulin M (IgM, 1000 kDa). A simple analysis shows that adsorbent capacity is capped by a fixed mass/volume (e.g. mg/mL) surface-region (interphase) concentration and not molar concentration. Nearly analytical agreement between the packing models and experiment suggests that, at surface saturation, above-mentioned proteins assemble within the interphase in a manner that approximates a well-ordered array. HSA saturates a hydrophobic adsorbent with the equivalent of a single square or hexagonally-packed layer of hydrated molecules whereas the larger proteins occupy two-or-more layers, depending on the specific protein under consideration and analytical method used to measure adsorbate mass (solution depletion or QCM). Square or hexagonal (cubic and FCC) packing models cannot be clearly distinguished by comparison to experimental data. QCM measurement of adsorbent capacity is shown to be significantly different than that measured by solution depletion for similar hydrophobic adsorbents. The underlying reason is traced to the fact that QCM measures contribution of both core protein, water of hydration, and interphase water whereas solution depletion measures only the contribution of core protein. It is further shown that thickness of the interphase directly measured by QCM systematically exceeds that inferred from solution-depletion measurements, presumably because the static model used to interpret solution depletion does not accurately capture the complexities of the viscoelastic interfacial environment probed by QCM.
View details for DOI 10.1016/j.biomaterials.2010.09.075
View details for Web of Science ID 000285675200003
View details for PubMedID 21035180
View details for PubMedCentralID PMC3040988
A real-time device for converting Doppler ultrasound audio signals into fluid flow velocity
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2010; 298 (5): H1626-H1632
A Doppler signal converter has been developed to facilitate cardiovascular and exercise physiology research. This device directly converts audio signals from a clinical Doppler ultrasound imaging system into a real-time analog signal that accurately represents blood flow velocity and is easily recorded by any standard data acquisition system. This real-time flow velocity signal, when simultaneously recorded with other physiological signals of interest, permits the observation of transient flow response to experimental interventions in a manner not possible when using standard Doppler imaging devices. This converted flow velocity signal also permits a more robust and less subjective analysis of data in a fraction of the time required by previous analytic methods. This signal converter provides this capability inexpensively and requires no modification of either the imaging or data acquisition system.
View details for DOI 10.1152/ajpheart.00713.2009
View details for Web of Science ID 000277301400037
View details for PubMedID 20173048
View details for PubMedCentralID PMC2867441
Antithrombotic therapy for ischemic stroke: guidelines translated for the clinician
JOURNAL OF THROMBOSIS AND THROMBOLYSIS
2010; 29 (3): 368-377
Acute ischemic stroke is the result of abrupt interruption of focal cerebral blood flow. The majority of ischemic strokes are caused by embolic or thrombotic arterial occlusions. Acute stroke management is complex, in part because of the varying etiologies of stroke and the very brief window of time for reperfusion therapy. Efforts to optimize stroke care have also encountered barriers including low public awareness of stroke symptoms. As initiatives move forward to improve stroke care worldwide, health care providers and institutions are being called onto deliver the most current evidence-based care. Updated versions of three major guidelines were published in 2008 by the American College of Chest Physicians, the American Heart Association, and the European Stroke Organization. This article presents a concise overview of current recommendations for the use of fibrinolytic therapy for acute ischemic stroke and antithrombotic therapy for secondary prevention. Future directions are also reviewed, with particular emphasis on improving therapeutic options early after stroke onset.
View details for DOI 10.1007/s11239-010-0439-7
View details for Web of Science ID 000275555100018
View details for PubMedID 20127273
Interfacial energetics of protein adsorption from aqueous buffer to surface with varying hydrophilicity
2008; 24 (6): 2553-2563
Adsorption isotherms constructed from time-and-concentration-dependent advancing contact angles thetaa show that the profound biochemical diversity among ten different blood proteins with molecular weight spanning 10-1000 kDa has little discernible effect on the amount adsorbed from aqueous phosphate-buffered saline (PBS) solution after 1 h contact with a particular test surface selected from the full range of observable water wettability (as quantified by PBS adhesion tension tauoa=gammaolv cos thetaoa; where gammaolv is the liquid-vapor interfacial tension and thetaoa is the advancing PBS contact angle). The maximum advancing spreading pressure, Pimaxa, determined from adsorption isotherms decreases systematically with tauoa for methyl-terminated self-assembled monolayers (CH3 SAM, tauo=-15 mN/m), polystyrene spun-coated onto electronic-grade SiOx wafers (PS, tauo=7.2 mN/m), aminopropyltriethoxysilane-treated SiOx surfaces (APTES, tauo = 42 mN/m), and fully water wettable SiOx (tauo=72 mN/m). Likewise, the apparent Gibbs' surface excess [Gammasl-Gammasv], which measures the difference in the amount of protein adsorbed Gamma (mol/cm2) at solid-vapor (SV) and solid-liquid (SL) interfaces, decreases with tauo from maximal values measured on the CH3 SAM surface through zero (no protein adsorption in excess of bulk solution concentration) near tauo=30 mN/m (thetaa=65 degrees). These latter results corroborate the conclusion drawn from independent studies that water is too strongly bound to surfaces with tauo>or=30 mN/m to be displaced by adsorbing protein and that, as a consequence, protein does not accumulate within the interfacial region of such surfaces at concentrations exceeding that of bulk solution ([Gammasl-Gammasv]=0 at tauo=30 mN/m). Results are collectively interpreted to mean that water controls protein adsorption to surfaces and that the mechanism of protein adsorption can be understood from this perspective for a diverse set of proteins with very different amino acid compositions.
View details for DOI 10.1021/la703310k
View details for Web of Science ID 000253941000042
View details for PubMedID 18229964
- Interfacial energetics of protein adsorption from aqueous buffer to surfaces with varying hydrophilicity Langmuir 2008; 24 (6): 2553
The role of the cyclooxygenase products in evoking sympathetic activation in exercise
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2007; 293 (3): H1861-H1868
Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied, in part because of systemic effects of pharmacological agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and postexercise muscle ischemia (PEMI) before and after local infusion of 6 mg of ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n = 10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to approximately 33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: Delta502 +/- 111; post ketorolac: Delta348 +/- 62%, P = 0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P = 0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip and suggest that prostaglandins contribute to the exercise pressor reflex.
View details for DOI 10.1152/ajpheart.00258.2007.
View details for Web of Science ID 000249237800068
View details for PubMedID 17604332
View details for PubMedCentralID PMC2559802
Interfacial energetics of blood plasma and serum adsorption to a hydrophobic self-assembled monolayer surface
2006; 27 (17): 3187-3194
Interfacial energetics of blood plasma and serum adsorption to a hydrophobic, methyl-terminated self-assembled monolayer (SAM) surface (solid-liquid SL interface) are shown to be essentially the same as to the buffer-air interface (liquid-vapor LV interface). Specifically, spreading pressure (Pia) isotherms scaled on a w/v concentration basis constructed from advancing contact angles (thetaa) of serially diluted plasma/serum derived from four different mammalian species (bovine, equine, human, and ovine) on the SAM surface are not resolvable at the 99% confidence level and furthermore are found to be strikingly similar to isotherms of purified human-blood proteins. Maximum advancing spreading pressures Piamax for protein mixtures fall within a relatively narrow 17
View details for DOI 10.1016/j.biomaterials.2005.12.032
View details for Web of Science ID 000236564000004
View details for PubMedID 16494939
Interfacial rheology of blood proteins adsorbed to the aqueous-buffer/air interface
2006; 27 (18): 3404-3412
Concentration-dependent, interfacial-shear rheology and interfacial tension of albumin, IgG, fibrinogen, and IgM adsorbed to the aqueous-buffer/air surface is interpreted in terms of a single viscoelastic layer for albumin but multi-layers for the larger proteins. Two-dimensional (2D) storage and loss moduli G(') and G(''), respectively, rise and fall as a function of bulk-solution concentration, signaling formation of a network of interacting protein molecules at the surface with viscoelastic properties. Over the same concentration range, interfacial spreading pressure Pi(LV) identical with gamma(lv)(o)-gamma(lv) rises to a sustained maximum Pi(LV)(max). Mixing as little as 25 w/v% albumin into IgG at fixed total protein concentration substantially reduces peak G('), strongly suggesting that albumin acts as rheological modifier by intercalating with adsorbed IgG molecules. By contrast to purified-protein solutions, serially diluted human blood serum shows no resolvable concentration-dependent G(')and G('').
View details for DOI 10.1016/j.biomaterials.2006.02.005
View details for Web of Science ID 000236783000009
View details for PubMedID 16504286
- Interfacial energetics of globular?blood protein adsorption to a hydrophobic interface from aqueous-buffer solution J. Royal Soc. Interface 2006; 3 (7): 283
Scaled interfacial activity of proteins at a hydrophobic solid/aqueous-buffer interface.
Journal of biomedical materials research. Part A
2005; 75 (2): 445-457
Contact-angle goniometry confirms that interfacial energetics of protein adsorption to the hydrophobic solid/aqueous-buffer (solid-liquid, SL) surface is not fundamentally different than adsorption to the aqueous-buffer/air (liquid-vapor, LV) interface measured by pendant-drop tensiometry. Adsorption isotherms of 9 globular blood proteins with molecular weight (MW) spanning from 10 to 1000 kDa on methyl-terminated self-assembled monolayer surfaces demonstrate that (i) proteins are weak surfactants, reducing contact angles by no more than about 15 degrees at maximum solution concentrations ( approximately 10 mg/mL); (ii) the corresponding dynamic range of spreading pressure Pi(a) < 20 mN/m; and (iii) the maximum spreading pressure Pi(max) (a) for these diverse proteins falls within a relatively narrow 5 mN/m band. As with adsorption to the LV interface, we find that concentration scaling substantially alters perception of protein interfacial activity measured by Pi(a). Proteins appear more similar than dissimilar on a weight/volume basis whereas molarity scaling reveals a systematic ordering by MW, suggesting that adsorption is substantially driven by solution concentration rather than diversity in protein amphilicity. Scaling as a ratio-to-physiological-concentration demonstrates that certain proteins exhibit Pi(max)(a) at-and-well-below physiological concentration whereas others require substantially higher solution concentration to attain Pi(max)(a). Important among this latter category of proteins is blood factor XII, assumed by the classical biochemical mechanism of plasma coagulation to be highly surface active, even in the presence of overwhelming concentrations of other blood constituents such as albumin and immunoglobulin that are shown by this work to be among the class of highly surface-active proteins at physiologic concentration. The overarching interpretation of this work is that water plays a dominant, controlling role in the adsorption of globular-blood proteins to hydrophobic surfaces and that energetics of hydration control the amount of protein adsorbed to poorly water-wettable biomaterials.
View details for PubMedID 16104049
An evaluation of methods for contact angle measurement
COLLOIDS AND SURFACES B-BIOINTERFACES
2005; 43 (2): 95-98
A systematic comparison of Wilhelmy-balance tensiometry (WBT), tilting-plate goniometry (TPG) and captive-drop goniometry (CDG), using a variety of silane-treated glass surfaces of variable wetting characteristics is reported. WBT was assumed to be the benchmark of comparison (gold standard). Advancing angles measured by TPG and CDG were in statistical agreement with corresponding WBT measurements. In contrast, receding angles from both goniometric techniques were systematically higher than WBT.
View details for DOI 10.1016/j.colsurfb.2005.04.003
View details for Web of Science ID 000230572600004
View details for PubMedID 15922578
Liquid-vapor interfacial tension of blood plasma, serum and purified protein constituents thereof
2005; 26 (17): 3445-3453
A systematic study of water-air (liquid-vapor, LV) interfacial tension gamma(lv) of blood plasma and serum derived from four different mammalian species (human, bovine, ovine and equine) reveals nearly identical concentration-dependence (dgamma(lv)/dlnC(B); where C(B) is plasma/serum dilution expressed in v/v concentration units). Comparison of results to a previously-published survey of purified human-blood proteins further reveals that dgamma(lv)/dlnC(B) of plasma and serum is surprisingly similar to that of purified protein constituents. It is thus concluded that any combination of blood-protein constituents will be substantially similar because dgamma(lv)/dlnC(B) of individual proteins are very similar. Experimental results are further interpreted in terms of a recently-developed theory emphasizing the controlling role of water in protein adsorption. Accordingly, the LV interphase saturates with protein adsorbed from bulk solution at a fixed weight-volume concentration ( approximately 436 mg/mL) independent of protein identity or mixture. As a direct consequence, dgamma(lv)/dlnC(B) of purified proteins closely resembles that of mixed solutions and does not depend on the relative proportions of individual proteins comprising a mixture. Thus variations in the plasma proteome between species are not reflected in dgamma(lv)/dlnC(B) nor is serum different from plasma in this regard, despite being depleted of coagulation proteins (e.g. fibrinogen). A comparison of pendant-drop and Wilhelmy-balance tensiometry as tools for assessing protein gamma(lv) shows that measurement conditions employed in the typical Wilhelmy plate approach fails to achieve the steady-state adsorption state that is accessible to pendant-drop tensiometry.
View details for DOI 10.1016/j.biomaterials.2004.09.016
View details for Web of Science ID 000226968200008
View details for PubMedID 15621233
- An Evaluation of Goniometric Methods J. Coll. Interface 2005; 43: 95
Mixology of protein solutions and the Vroman effect
2004; 20 (12): 5071-5078
Mixing rules stipulating both concentration and distribution of proteins adsorbed to the liquid-vapor (LV) interphase from multicomponent aqueous solutions are derived from a relatively straightforward protein-adsorption model. Accordingly, proteins compete for space within an interphase separating bulk-vapor and bulk-solution phases on a weight, not molar, concentration basis. This results in an equilibrium weight-fraction distribution within the interphase that is identical to bulk solution. However, the absolute interphase concentration of any particular protein adsorbing from an m-component solution is 1/mth that adsorbed from a pure, single-component solution of that protein due to competition with m - 1 constituents. Applied to adsorption from complex biological fluids such as blood plasma and serum, mixing rules suggest that there is no energetic reason to expect selective adsorption of any particular protein from the mixture. Thus, dilute members of the plasma proteome are overwhelmed at the hydrophobic LV surface by the 30 classical plasma proteins occupying the first 5 decades of physiological concentration. Mixing rules rationalize the experimental observations that (i) concentration-dependent liquid-vapor interfacial tension, gammalv, of blood plasma and serum (comprised of about 490 different proteins) cannot be confidently resolved, even though serum is substantially depleted of coagulable proteins (e.g., fibrinogen), and (ii) gammalv of plasma is startlingly similar to that of purified protein constituents. Adsorption-kinetics studies of human albumin (66.3 kDa) and IgM (1000 kDa) binary mixtures revealed that relatively sluggish IgM molecules displace faster-moving albumin molecules adsorbing to the LV surface. This Vroman-effect-like process leads to an equilibrium gammalv reflecting the linear combination of weight/volume concentrations at the surface predicted by theory. Thus, the Vroman effect is interpreted as a natural outcome of protein reorganization to achieve an equilibrium interphase composition dictated by a firm set of mixing rules.
View details for DOI 10.1021/la036218r
View details for Web of Science ID 000221846000042
View details for PubMedID 15984270
Scaled interfacial activity of proteins at the liquid-vapor interface.
Journal of biomedical materials research. Part A
2004; 68 (3): 544-557
A principal conclusion drawn from observations of time- and concentration-dependent liquid-vapor (LV) interfacial tension gamma(lv) of a diverse selection of proteins ranging from albumin to ubiquitin spanning nearly three decades in molecular weight (MW) is that concentration scaling substantially alters perception of protein interfacial activity as measured by reduction in gamma(lv). Proteins appear more similar than dissimilar on a weight/volume basis, whereas molarity scaling reveals a "Traube-rule" ordering by MW, suggesting that adsorption is substantially driven by solution concentration rather than diversity in protein amphilicity. Scaling as a ratio-to-physiological-concentration demonstrates that certain proteins exhibit the full possible range of interfacial activity at and well-below physiological concentration, whereas others are only weakly surface active within this range, requiring substantially higher solution concentration to achieve reduction in gamma(lv). Important among this latter category of proteins are the blood factors XII and XIIa, assumed by the classical biochemical mechanism of plasma coagulation to adsorb to procoagulant surfaces, even in the presence of overwhelming concentrations of other blood constituents such as albumin and immunoglobulin that are shown by this work to be among the class of highly surface-active proteins at physiologic concentration. A comparison of pendant drop and Wilhelmy balance tensiometry as tools for assessing protein interfacial activity shows that measurement conditions employed in the typical Wilhelmy plate approach fails to achieve the steady-state adsorption condition that is accessible to pendant drop tensiometry.
View details for PubMedID 14762935
- Traube-rule interpretation of protein adsorption at the liquid-vapor interface LANGMUIR 2003; 19 (24): 10342-10352
- Increased Mortality and Bleeding in a Large Cohort of Patients on Heparin Anticoagulation Therapy with Discordant Anti-Factor Xa Activity and Activated Partial Thromboplastin Time (PTT); Implications for Clinical Management AMER SOC HEMATOLOGY. 2019
PLATELET TRANSCRIPTOMIC SIGNATURES IN MYELOPROLIFERATIVE NEOPLASMS
WILEY. 2018: E34
View details for Web of Science ID 000446055700086
IMPROVING CLINICAL DECISION MAKING FOR HEPARINIZED PATIENTS WITH DISCORDANT ANTI-FACTOR XA ACTIVITY AND ACTIVATED PARTIAL THROMBOPLASTIN TIME.
WILEY. 2017: 40
View details for Web of Science ID 000402838000064