42 – August 2008
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Impedance Measurement Monitors Blood Coagulation
coagulation is a complex, dynamic physiological process by which clots
are formed to end bleeding at an injured site. During heart-bypass surgery,
blood is diverted out of the body to a heart-lung machine, which maintains
heart- and lung functions. The machine is operated by a perfusionist,
whose role includes monitoring appropriate parameters to ensure that the
patient is effectively treated with an anticoagulant to avoid blood clots.
For this purpose, heparin, an anticoagulant drug, is administered during
surgery—followed by a rapid reversal afterwards to prevent excessive bleeding.1
To maintain the delicate balance between clotting and bleeding, the clotting
time of the patient is monitored every 30 to 60 minutes during surgery
and several times after surgery, until a normal clotting time is restored.2
Currently, blood samples taken from a patient’s intravenous line are tested
at bedside, with measured clotting-time values used to adjust the anticoagulation
Analog Devices is
a partner in the Biomedical
Diagnostics Institute (BDI),3 a Centre for
Science, Engineering, and Technology, funded by Science
Foundation Ireland.4 BDI is a multidisciplinary
research institute focused on the development of next-generation biomedical
diagnostic devices. Under one of the BDI Integration Programs, Analog
Devices is working with Dublin City
University5 and a global specialty pharmaceutical
and medication delivery company to develop a coagulation-monitoring device
for patients undergoing treatment in the critical-care environment. This
system will provide rapid, automated information on patient clotting status—improving
patient safety, workflow, and decision support—leading to improvements
in patient outcomes.
of Blood Coagulation
coagulation in the body is modulated by a number of cellular and other
active components. The coagulation cascade describes the components
of blood and how they are involved in the process of clot formation. As
the cascade becomes activated, the blood progresses from a nonclotting
to a clotting state, causing changes in both molecular charge states and
effective charge mobility. The final steps of the cascade involve two
components, thrombin and fibrinogen. Thrombin acts by cutting
the fibrinogen, forming fibrin filaments—which spontaneously aggregate.
The endpoint of clotting time has been defined as the time at which a
fibrin clot is formed.6,7
By monitoring the
global impedance of a clotting blood sample, the changes in conductivity
associated with clot formation are measured. To evaluate instrument performance,
the clotting time determined from the data was correlated to a “gold-standard”
clinical measurement of clotting time.
Using the AD5933
fully integrated single-chip impedance analyzer (Figure 1) is a high-precision
impedance-converter system that combines an on-board frequency generator
with a 12-bit, 1 MSPS, analog-to-digital converter (ADC). The frequency
generator provides an excitation voltage to an external complex impedance
at a known frequency. The response signal (current) is sampled by the
on-board ADC, and a discrete Fourier transform (DFT) is processed by an
on-board DSP engine. The DFT algorithm returns real (R) and imaginary
(I) data-words at each output frequency. Using these components, the magnitude
and relative phase of the impedance at each frequency point along the
sweep can be easily calculated.
1. Functional block diagram of impedance-measurement system.
The block diagram
of the AD5933 demonstrates the full integration of the impedance-measurement
system. Local digital processing enables the calculation of the complex
impedance of the circuit under test. The system requires initial calibration:
a precision resistor is substituted for the impedance to be measured;
and a scaling factor is calculated for subsequent measurements. The AD5933
can measure impedance values between 100 Ω and 10 MΩ to a system
accuracy of 0.5% for excitation frequencies from 1 kHz to 100 kHz.
of blood clotting with impedance changes has long been established in
the literature.9,10,11,12,13 However, the recent availability
of integrated-circuit complex-impedance measuring devices means that the
blood clotting time measurement instrument can be miniaturized. This offers
significant advantages in terms of power savings, portability, and final
instrument footprint, a key consideration in the critical-care setting.
such as the AD5933, often center signal swings around a fixed value of
dc bias. This is not an important consideration in most impedance measurements,
but dc voltages above a specific threshold cause electrochemical processes
to take place in aqueous conducting media in contact with electrodes,
altering the sample. To prevent this electrolysis from occurring in blood-sample
measurements with the AD5933 in the current project, the voltage excitation
and the current measurement were ac-coupled using the signal conditioning
circuit shown in Figure 2.
2. AD5933 with output signal conditioning.
between the blood-sample delivery and the measurement instrumentation
is critical. In this case, a specific microfluidic channel into which
the blood sample was delivered was designed to connect to the AD5933 instrumentation
circuit (Figure 3). The microfluidic device consists of three layers.
The bottom layer comprises two screen printed electrodes, which were connected
to the input/output port pins of the AD5933 circuit. The top micromolded
polymer channel consists of two reservoirs connected via a microchannel.
The chemical reagents that modulate the clotting reaction can be contained
either within this microchannel or on the central bonding layer. The top-
and bottom channels are bonded using a pressure-sensitive adhesive (PSA).
The blood sample applied to one reservoir filled the microchannel. This
was contacted by the screen-printed electrodes, which were in turn interfaced
to the AD5933 circuit.
3. A schematic illustration of the impedance-measurement system with the
polymer microchannel that contains the blood sample to be measured. It
allows the sample to interact with the specific reagents that modulate
the clotting event, and creates the interface between the sample and the
response curves of a clotting and nonclotting blood sample are compared
in Figure 4. The arrow on the figure indicates the point at which the
clotting time of the sample is established.
4. Comparison of impedance profiles for a nonclotting (black) and clotting
(red) blood sample.
The impedance response
of Figure 5 shows the increase in clotting time with increasing concentrations
of heparin in the blood sample. The arrows indicate the clotting time
of the different samples.
5. Comparison of impedance profiles for increasing clotting times: shortest
(blue) to longest (black).
The clotting times
of a number of clinically relevant blood donor samples were measured using
the system described above, and these were correlated with measurements
performed on the sample donor samples, using the clinical gold-standard
measurement system (Figure 6).
6. Correlation of extracted clotting time measured using the AD5933 measurement
the clinical gold-standard measurement of clotting time, n = 6 for each
single-chip impedance analyzer has been successfully applied to the measurement
of blood-impedance changes during coagulation. It offers flexibility,
power, and size advantages to the end user over the existing commercially
available solutions. Combining integrated-circuit technologies of this
sort with new technologies in other media, such as microfluidics and sample
handling, provides a powerful platform for future medical device research
in this article is based upon work supported by the Science Foundation
Ireland under Grant No. 05/CE3/B754. Thanks to Dermot Kenny, Gerardene
Meade, Sarah O’Neill, and all at the Department of Molecular and Cellular
Therapeutics at Royal College of Surgeons in Ireland for provision of
facilities and expertise. Thanks to Nigel Kent for the microfabrication
work—and to the Coagulation Monitor research team at the Biomedical Diagnostics
Institute, DCU, Dublin, led by Principal Investigator, Dr. Tony Killard.
John and James J. Ferguson. “Use of the Activated Clotting Time in Anticoagulation
Monitoring of Intravascular Procedures.” Texas
Heart Institute Journal. 20 (4). 1993. 258–263.
Gerald, J., ed. Principles and Practice of Point-of-Care Testing.
Lippincott, Williams and Wilkins. 2002.
M.M. “Circulatory Effects of Blood Clotting, Fibrinolysis, and Related
Hemostatic Processes.” Handbook of Physiology, Circulation III,
American Physiological Society. Washington, DC. 1964.
K., T. Orfeo, Jenny N. Swords, S.J. Everse, and K.G. Mann. “Blood Coagulation
and Fibrinolysis.” Chapter 21 in Wintrobe’s Clinical Hematology.
11th edition. Volume 1. M.M. Wintrobe and J.P. Greer, eds.
Lippincott, Williams, and Wilkins. 2004.
8ADI website: www.analog.com (Search)
A. “Changes in the electrical impedance of blood during coagulation.”
Nature 226. 1970a. 269–270.
A. “Determination of blood coagulation using impedance measurements.”
Biomedical Engineering 5 (7). 1970b. 342–345.
A. “Detection of clot retraction through changes of the electrical impedance
of blood during coagulation.” American Journal of Clinical Pathology
56 (6). 1971. 713–717.
A. “Analysis and interpretation of the impedance blood coagulation curve.”
American Journal of Clinical Pathology 67 (5). 1977. 470–476.
W. and A. Ulmer. “Comparative and direct measurement of the electrical
impedance in blood coagulation.” Thrombosis Research 13. 1978.
a research engineer with the Healthcare Products Division, joined
Analog Devices in February 2006. She is a graduate of Dublin City
University with a BSc in Biotechnology, and has a PhD in the area
of silicon-based immunosensing diagnostics from University College,
Cork, Ireland. Previously, she worked on the development of sensors
and integrated systems for biomedical applications at National Microelectronics
Research Centre, Cork. She was awarded a Leverhulme Fellowship to
work at the Centre for Nanoscale Science and Technology at the University
of Newcastle-upon-Tyne, UK, on the development of microelectronics
and nanotechnology for biomedical research innovation.
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after graduating from the University of Limerick in 1984 with a
BEng degree, joined the Test Development department of Analog Devices
Limerick (Ireland). In 1998 he received his Master’s in Computer
Systems—also from the University of Limerick. Specializing in test
technology development, he has developed test programs for the first
products and test capability for
high-resolution DACs, Σ-∆ converters, low-leakage switches,
and other products. More recently, J.J. has been working in healthcare
technology, where he designed and built products such as a blood-coagulation
monitor and a glucose meter. In his spare time, J.J. enjoys all
kinds of sports and is an ICF-certified life and business coach.
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