Apparatus and method for the measurement of blood viscosity

Abstract

An apparatus 200 for measurement of blood viscosity comprises a sample holder comprising a tube 10 and a bob 30. The bob moves linearly along the length of the tube without rotation. The bob and the tube are attached to the apparatus and the bob may be attached to a spherical magnet 50 with an elongated shaft 38, where an actuator 140, 104 provides linear relative motion between the bob and the tube. A force measurement means is provided that may be a torsion bar 100. A means to control the actuator is provided. The actuator 140 may be connected to the tube independent of the force measurement part. The actuator 104 may be attached to the bob and may form part of the measurement means. Repeated actuation of the bob and measurement of detected force over a period of time may be used to detect blood clotting. The apparatus may include a blood sampling tube comprising a chamber for holding blood sample, an inlet to the blood, a bob located within the tube above the sample in chamber and the chamber maybe sealed.

Description

The present invention relates to an apparatus and method for the measurement of blood viscosity, for the determination of macro physical properties of blood and in particular viscosity and clotting behaviour. Background Hematology is the branch of medicine that deals with the study, diagnosis, treatment, and prevention of blood-related disorders. This includes diseases and conditions that affect the blood cells (red and white blood cells, and platelets), blood proteins, blood vessels, bone marrow, lymph nodes, and spleen. One aspect of haematology is determination of the viscosity of blood and obvious clotting characteristics. Blood viscosity is a measurement creating much interest within the medical profession, but with little by way of practical measurement techniques suitable for a clinical environment. Blood is a complex rheological fluid with properties that change rapidly with both time, shear rate and physiology. The rheological properties of blood have been reviewed recently by Nader et al (Nader. (2019). Blood Rheology: Key Parameters, Impact on Blood Flow, Role in Sickle Cell Disease and Effects of Exercise. Front. Physiol., 17 October 2019). Whilst the underlying mechanisms are complex biochemical pathways the present invention is concerned with the macro physical properties. Specifically, blood is a complex fluid being a suspension of solid components in a liquid base of plasma. The solid components principally comprise red blood cells white blood cells and platelets. Plasma is the liquid component of blood that makes up about 55% of the total blood volume. Red blood cells (RBCs): Red blood cells, also called erythrocytes, are the most abundant cells in the blood, making up about 45% of the total blood volume. White blood cells (WBCs): White blood cells, also called leukocytes, make up less than 1% of the total Platelets: Platelets, also called thrombocytes, are small cell fragments that help to form blood clots. They make up less than 1% of the total blood volume and are essential for stopping bleeding after an injury. Consequently, blood is a non-Newtonian fluid, meaning that its viscosity (resistance to flow) is not constant and varies depending on the shearing force applied to it. The viscosity of blood changes in response to shear stress, which is the force applied to the fluid as it flows through blood vessels. At low shear rates (i.e., when blood is flowing slowly), blood behaves like a Newtonian fluid, with a relatively constant viscosity. However, at higher shear rates (i.e., when blood is flowing more quickly), the viscosity of blood decreases, allowing it to flow more easily. This non-Newtonian behaviour is due to the presence of red blood cells, which can align and form aggregates in response to shear stress, changing the fluid's overall behaviour. Additionally, the plasma proteins and other components of blood can interact with each other in complex ways, further contributing to its non-Newtonian properties. The non-Newtonian behaviour of blood is an important factor in understanding its flow characteristics in the body and can have implications for the diagnosis and treatment of certain blood disorders. The determination of the viscosity of non-Newtonian fluids is complex and the geometry of the shear field and the shear rate are important factors in accurately determining viscosity. The viscosity of blood can be measured in medicine using various techniques, including viscometry and rheometry. Viscometry involves measuring the resistance to flow of blood under standardized conditions in one of a number of measurement systems designed so that the shear rate can be estimated and kept constant. This technique provides a measure of the resistance of the blood to flow, which is related to its viscosity. Rheometry involves subjecting blood to controlled shear stress or strain rate using a rotating or oscillating device. By measuring the torque required to rotate the device and the resulting deformation of the blood, the viscosity and other rheological properties of the blood can be determined. Another technique used to assess blood viscosity is haematocrit, which measures the percentage of red blood cells in the blood. Since red blood cells are the primary determinant of blood viscosity, an increase in haematocrit can lead to an increase in blood viscosity. Blood viscosity can also be estimated indirectly through the use of surrogate markers, such as erythrocyte sedimentation rate (ESR) or plasma viscosity. These markers reflect changes in the concentration of blood cells or proteins that can affect blood viscosity. Overall, the measurement of blood viscosity can provide valuable information about the hemodynamic properties of blood flow and can be used help to diagnose and manage various cardiovascular and haematological conditions. For practical measurement of blood viscosity most measurements are made by either a falling body viscometer, a capillary viscometer or via a cone and plate viscometer. In a falling body viscometer the viscosity is evaluated in terms of the time taken for a body, typically a ball or a rod, and having a density considerably greater than the blood, to fall a fixed distance through the sample under the effect of gravity. Whilst this method is technically simple, the method has no control over shear rate and is effectively a single point measurement. In a capillary viscometer the blood is forced under pressure through a narrow tube and the flow rate measured. The flow rate is a measure of viscosity in this situation but is again a single point measurement. In a cone and plate viscometer a small quantity of blood is sheared between a rotating conical element and a flat plate, the torque generated is measured and is proportional to the viscosity. This instrument offers a well-defined shear rate but is difficult to apply to blood as the torque generated is very small due to the low viscosity of the blood. The viscosity of blood can change over time in vitro (outside the body) due to a number of factors, such as temperature, shear stress, and exposure to anticoagulants. Further, when blood is removed from the body and placed in a test tube or other container, it begins to coagulate, or clot, due to the activation of the clotting cascade. This process can cause the viscosity of the blood to increase over time as the clotting factors interact with each other and form a fibrin network. In addition, the temperature of the blood can affect its viscosity, as warmer temperatures can decrease the viscosity by reducing the viscosity of the plasma. Conversely, lower temperatures can increase the viscosity of blood by increasing the viscosity of the plasma. The shear stress applied to the blood during testing can also affect its viscosity, as higher shear rates can cause the red blood cells to deform and change shape, leading to changes in the overall viscosity of the blood. As can be seen the measurement of blood viscosity is both complex and important. By further example treatment with anticoagulants, such as heparin or EDTA, can also affect the viscosity of blood in vitro. These agents can interfere with the clotting cascade and prevent blood from coagulating, leading to changes in the rheological properties of the blood. The ability to measure blood viscosity if therefore an important tool in evaluating treatments. The changes between in vitro and in vivo blood viscosity mean that it is important to carefully control the testing conditions and minimize the time between blood collection and testing to obtain accurate measurements of blood viscosity in vitro. A standard method for determining blood viscosity in vitro is the, a falling body viscometer method. Attempts have been made to automate and increase the utility of a falling body viscometer method, such as that disclosed in European Patents EP4083600A1 whereby numerous balls can be released in a timed fashion to measure the viscosity change over a short time period. In the cone and plate method, a measurement system commonly used for the measurement of industrial products, is adapted for the measurement of blood by enclosing the cone and plate geometry in a well. Such a method is disclosed in US Patent US2003 / 036711A1. Other methods that have been used for blood viscosity include capillary viscosity measurement, such as the Benson Viscometer which is largely used for plasma viscosity measurements and cannot study coagulation processed due to the capillary becoming blocked. Current methods of determining the viscosity of blood are complex, expensive, time consuming, in some circumstances be inaccurate. There is therefore a need for an alternative or improved method of determining blood viscosity. As mentioned, the viscosity of blood in vitro changes over time and the determination of this phenomena is also of great importance. Specifically, blood taken from the body, such as for extracorporeal membrane oxygenation (ECMO). ECMO is a life-support technique that uses a pump to circulate blood outside the body through an oxygenator, which adds oxygen and removes carbon dioxide, before returning the blood to the body. During ECMO, a catheter is inserted into a large vein, such as the jugular or femoral vein, to access the patient's blood. The blood is then pumped through a circuit that includes the oxygenator and a heat exchanger to maintain the blood at a normal temperature. The oxygenator removes carbon dioxide and adds oxygen, mimicking the function of the lungs. ECMO is used in patients with severe respiratory or cardiac failure who are not responding to conventional treatments. It can provide temporary support while the underlying condition is treated or can be used as a bridge to transplant or other therapies. ECMO is a complex and invasive procedure that requires specialized equipment and a highly trained medical team. It is typically used in critical care settings, such as intensive care units, and is reserved for patients with life-threatening conditions. The ECMO procedure is beset by problems associated with blood clotting, either inside the ECMO apparatus or when the blood is returned to the patient. Typically, patients undergoing ECMO are given very high doses of anticoagulants to prevent clotting, but this in turn makes surgery difficult and creates a significant risk of haemorrhage. The ability to accurately measure clotting time is very significant in the use of such equipment and a rapid and effective means for doing so is required. In addition, the transfer of blood from a subject to a measurement apparatus can provide a significant source of error. Specifically, blood in vitro not only clots over time but also in response to shear conditions. Hence each successive operation between extracting and measuring viscosity is a source of disturbing the clotting system and this makes measurement, such as measurements suitable for a comparison between patients, specific medical environments and sampling procedures problematic. There is therefore a need to simplify and improve sampling techniques and specifically to provide apparatus to enable this to be achieved. A significant source of error can arise from the conventional means of obtaining a blood sample. One such method uses an evacuated tube system, a representative apparatus being the Vacutainer® the system is a convenient and efficient method for collecting blood samples and is widely used in healthcare settings for diagnostic and therapeutic purposes. The Vacutainer system was developed in 1947 by Joseph Kleiner and subsequently developed and marketed by Becton, Dickinson and Company. The evacuated tube system consists of a sterile, evacuated plastic tube that is pre-coated with an anticoagulant or clot activator, depending on the type of sample being collected. The tube also contains a coloured rubber stopper that indicates the type of additive present in the tube. Whilst this coating provides longevity of a sample greatly disturbs the clotting characteristics and the viscosity characteristics over time. To collect a blood sample using evacuated tube system collection, a healthcare provider first selects an appropriate vein and prepares the site using an antiseptic solution. A hollow needle is then inserted into the vein, the end of the needle remote from that inserted in the vein is then connected to an evacuated tube by inserting the needle through a seal on the tube and blood is drawn into the evacuated container such that the tube is automatically filled with a predetermined volume of blood as the vacuum in the tube draws blood into the tube. Once the tube is filled, the tube is removed from the needle and further evacuated tubes may be used to take further samples. When sampling is finished the needle is removed, and pressure is applied to the puncture site to promote clotting and reduce the risk of bleeding. 5 Vacuum tube collection, such as Vacutainer tubes are available in a variety of sizes and configurations, with different additives and clot activators designed for specific types of samples. For example, a Vacutainer with a green stopper contains sodium heparin and is commonly used for collecting plasma for chemistry and immunochemistry testing. A Vacutainer with a lavender stopper contains EDTA and is used for collecting whole blood for haematology testing. 10 Whilst such collection is well established and well-regarded it is not entirely suitable for collecting samples for the purposes of blood viscosity and clotting measurement. There is need for a simple, clinically acceptable, method to measure the viscosity of whole blood and to allow the monitoring of that viscosity during the coagulation process. The particular an object of the invention is to allow the measurement of anti-coagulation therapies in patients with a high risk of 15 blood clots. The present invention provides a blood sampling container comprising a body, having chamber for holding a blood sample, an inlet to the chamber for sampling blood, at least a portion of the chamber comprising parallel walled tube, a bob located within the tube and extending outside the chamber, wherein in a first configuration the chamber is sealed and the bob is located so as to create a first chamber volume and in a second configuration the chamber is not sealed and the bob is located so as to create a second chamber volume, were in the first chamber volume is larger than the second change chamber volume, the bob being movable within the tube between the first and second configurations, the bob providing a flow path for blood between the bob and the parallel walled tube so as to, in use, blood to flow out of the chamber past the bob. In the present invention, in the first configuration the chamber may be at below atmospheric pressure. The presence of a partial vacuum in the chamber enables blood to readily enter the chamber from a needle in communication with the chamber, such as the needle in the vein of the patient. Specifically, the pressure in the chamber will be in the region of between 1 and 100 kPa pressure. More particularly the degree of vacuum, i.e., the pressure, in the chamber in the first configuration is preferably such that upon blood entering the chamber fills to between 80 and 98% by volume, i.e., leaving an ullage of between 20 and 2% by volume before residual gas pressure reaches equilibrium and further blood does not enter. This is advantageous since the bob may be advanced along the parallel walled tube without undue force as the ullage allow some degree of compression so is to break the seal between Bob and body when the chamber is no longer sealed and the bob may translate along the tube impeded primarily by the viscosity of the blood, hence the force of movement measured is dominated by the viscous resistance giving improved signal to noise. In the present invention the inlet to the chamber is preferably a septum pierceable by a hollow needle for the admission of blood into the chamber. This provides a simple and convenient means to bring the chamber in communication with the circulatory system of the patient such as by means of a needle inserted into a vein of the patient. The septum may be held in place by means of a septum cap, such as a cylindrical tube 42 inserted over the outer wall of the chamber and having an end with a pre formed aperture accessing a cavity for guiding in a hollow needle for receiving a blood sample. The cap also secures the septum in place, such as without requiring adhesive, which may contaminate a sample. in the present invention, in the first configuration the bob is sealed proximate to where it extends outside the chamber. This seal may be affected by means of an O-ring seal between the bob and the body. The O-ring seal may be located in the body for moveably sealing with the bob. This has the advantage that in the third position, see below, a further portion of the shaft of the bob may engage with the same O-ring seal to again seal the chamber. The O-ring seal may be located in an internal groove on the inside wall of the body. However, placing an O-ring seal on an inside wall is not readily achieved in manufacture therefore it may be preferable to locate the O-ring seal in a groove in the bob, and for a further O-ring seal to be placed in extension of the bob suitable for a same sealing the chamber when the bob is fully advanced into the chamber In the present invention the bob preferably extends out of the body by means of an elongate shaft. Specifically, the shaft of smaller lateral dimensions, such as a smaller radius, than that of a first end of the bob proximate to the inlet. The seal may be by means of an O-ring seal between the shaft and the body. The O-ring seal may be in is located in the shaft for movably sealing with the body. In the present invention the bob may be located within the tube by means of one or more protrusions for enabling the bob to remain centrally located within the tube in moving between the first and second configurations, as the bob is of smaller diameter than the tube. This enables the bob to translate centrally along the tube so is to provide a more even flow of blood over the surface of the bob and therefore a more accurate measure of viscosity. Preferably the protrusions of the bob comprise three equidistant lugs on the circumference of the bob. This provides minimal resistance to blood flow whilst enabling the bob to be maintained centrally. However, protrusions are not essential as a symmetrical end cap such as conical, frusto conical or hemispherical self-centres due to the blood flow and provides a more accurate reading thereby. In the present invention the bob preferably has a cross-section of radial dimensions perpendicular to elongate axis of the parallel walled tube so as to provide an equidistant gap between the bob and the tube, excluding any lugs. This provides more convenient calculation of viscosity based upon blood flow through a defined gap between the bob and the tube. In the present invention the ends of the bob may be conical or hemispherical. This provides channelling of the blood to the gap between the tube wall on the bob to provide lower turbulence and hence more accurate measurement. The preferred geometry is conical, proving more consistent. The ends of the bob are preferably of equivalent shape, e.g., conical or hemispherical, this reduced the dissimilarity in viscosity measurement in movement in either movement direction of the bob in the tube. In the present invention, the end of the bob remote from the inlet may be frustoconical or substantially hemispherical, the frustum being the base of the elongate shaft. But in other terms there is preferably a shoulder between the narrowing cross-section shaft than the end of the bob and that shoulder is preferably conical or hemispherical. This enables more even blood flow when the bob is withdrawn from the chamber. In the present invention, the parallel walled tube is preferably cylindrical. This has been found to provide consistent flow and hence more reproducible measurement. As described earlier the chamber is preferably evacuated to below atmospheric pressure such that, in use, a blood sample is drawn under vacuum into the chamber so as to provide ullage at equilibrium in the second configuration. Similarly, the ullage is preferably of sufficient pressure so start on moving the bob from the first configuration to an unsealed configuration the ullage is not compressed , such as not significantly, above atmospheric pressure. In the present invention the end of the bob remote from the inlet preferably terminates in a ferromagnetic material. This enables a magnetic connection with a viscometer configured to advance and retract the bob of the container, so as to provide a measure of force and thereby measure viscosity. Preferably the ferromagnetic material is a ball bearing. This is advantageous in that force conveyed, protected by compression to the bob is conveyed centrally, as is retraction when the joint is mediated by magnetism. The bob, as previously mentioned preferably comprises a shaft portion and a head portion and the termination is preferably in the shaft portion with said ball bearing. In the present invention, the container may have a third configuration wherein the bob is located so as to provide a third chamber volume larger than the second chamber volume and wherein the chamber is sealed. This enables a disposing configuration in which the device can be disposed of without the risk of liquid spillage and resultant contamination for a safer and more effective determination. The bob may be sealed to the body, such as a described above or by means of a further O-ring seal located on the shaft proximate to all the end of the shaft remote from the inlet. This provides an improved seal for end of use and disposal. In particular, in combination with an enlarged elongate shaft portion this provides both a scope of movement of the bob without any frictional component, for more accurate measurement, from the seal but upon withdrawal to the third position enables the seal to seal to the enlarged elongate shaft portion proximate to the head of the bob. In the present invention the container may be made of a plastics material. This enables precision moulding to provide a disposable part. Preferably the plastics material is transparent, this enables the progress of the test and adequate filling of the container to be determined visually. The plastics material may be selected from one or more of Polypropylene, Polystyrene, Polyethylene, PETG (glycol-modified PET) and Polycarbonate (PC). These plastics provide a combination of credulity for precision moulding and potential clarity for observation, polycarbonate is the preferred plastic giving also low friction and hence more accurate readings. The body and bob of the present invention is preferably made from one or more of: Polypropylene (PP): This thermoplastic polymer is a popular choice for producing evacuated blood collection tubes due to its high resistance to impact, chemicals, and heat. PP is also autoclavable, which makes it easy to sterilize and reuse should this be necessary. Polystyrene (PS): This thermoplastic polymer is another common material used for producing evacuated blood collection tubes due to its transparency, strength, and ease of moulding. PS is also lightweight and cost-effective. Polyethylene (PE): This thermoplastic polymer is used for producing evacuated blood collection tubes that require a soft and flexible material. PE is also resistant to chemicals and can withstand low temperatures. PETG (glycol-modified PET): This thermoplastic polymer is a type of polyester that is used for producing evacuated blood collection tubes that require high clarity and low gas permeability. PETG is also strong, lightweight, and recyclable. Polycarbonate (PC): This thermoplastic polymer is used for producing evacuated blood collection tubes that require high impact resistance and transparency. PC is also heat-resistant and can withstand sterilization. In the present invention the container may be substantially transparent. As mentioned, this enables ready visual inspection to corroborate instrumental data. In the present invention the body may be substantially opaque to ultraviolet radiation, such as UV A and / or UV B. Ultraviolet radiation can stimulate blood clotting and when using an otherwise optically transparent container enables visual inspection without electromagnetic radiation substantially disturbing the measurement. In the present invention the bob may be held in place in the first configuration by a releasable fastening such as clip or moulded breakable link. This enables the bob to maintain vacuum whilst in the third position so that vacuum sampling may take place. The bob may also be held in place in the third configuration by means of a fastening, such as the or a clip or moulded breakable link. The present invention includes a kit of parts comprising a container of any preceding claim and a sampling needle for, at a first end piercing the vein of a patient and at a second end suitable for opening the inlet of the chamber. This this greatly improves the efficacy of use as the components are matched up together The present invention also provides a method of using measuring the viscosity of blood sampled using a container of the present invention wherein the bob is advanced from the position in the first configuration to a position in the second or third configuration and the force required to advance the bob is measured for correlation to a blood viscosity. Detailed description The present invention is illustrated by the following figures. Like features are provided with like numerals, the figures which provide: Figure 1 shows a schematic of an apparatus for use with the present invention so is to measure viscosity; figure 12 shows a close-up of the coupling between an apparatus of the present invention and the measuring apparatus; figure 3 shows an example of raw data from two measurements using the present invention with different blood samples; figure 4 shows schematic of the device of the present invention; figure 5 shows a vertical cross-section of the device of the present invention in conjunction with a fluid to be measured, namely blood; (Figures 4 and 5 show a gap around the bob but other figures do not, the other figures are also schematic and for the convenience of representation any gap is not shown) figure 6 shows a vertical cross-section of a further device of the present invention with an alternate geometry in conjunction with the fluid to be measured; figure 7 shows a specific device of the present invention in side view and to a scale (on A4 paper) representative of the device itself; figure 8 shows a cross-section along A-A figure 7 of a specific device of the present invention; figure 9 shows a close-up of the bob and tube of the present invention including the end of the body remote from the inlet; figures 10, 11 and 12 show the cross-section of figure 2 in the first, second and third configurations respectively. The features of the figures illustrating the present invention are now listed, like a numbered features have the same designation across all drawings: in the present invention, as illustrated by the figures the following features are present: 10 blood sampling container 10A container in 1st configuration 10B container in the 2nd configuration 10C container in 3rd configuration 12 chamber 14 chamber filled with fluid 20 parallel walled tube 22 tube piece, being the parallel walled tube portion of 20 24 outer wall of chamber formed by parallel walled tube 26 in a wall of chamber formed by parallel walled tube 30 bob (when whole piece), head when a portion. 32 elongate shaft of the bob 34 hemispherical head of bob, aka bob end 35 conical head of bob 36 lugs for distancing Bob from the inner wall of the parallel walled tube 38 end of bob remote from inlet 40 end closure of container 42 septum cap 44 septum 46 cavity 48 sides of septum cap 50 ferromagnetic ball, such as ball bearing 52 release catch for retaining seal 58 54 guiding shaft for elongate member of bob 56 O-ring seal for sealing elongate shaft or lug with the guiding shaft in the first configuration 58 retaining seal assembly 60 enlarged portion of elongate shaft between main body of lug 30 and elongate shaft 32 62 Ridge for engaging sealing member for securing Bob in position when sealing member present 64 O-ring seal for sealing the bob in the third configuration 100 detector assembly 104 optional actuator for management head 110 torsion bar 120 platform mounting torsion bar 138 elongate shaft of torsion bar 140 sampling container holding and optional actuator 150 ferromagnetic ball 160 sample fluid 200 measurement apparatus 250 management process flow diagram 210 Gather force data 220 Calculate viscosity 230 Report instantaneous viscosity 240 Monitor viscosity over time 260 Report and export viscosity vs time and clotting characteristics 300 example output of measurement test 320 example trace of viscosity versus time for a blood sample from a patient treated with anticoagulant therapy 340 example trace of viscosity versus time for a normal blood sample Detailed description The blood sampling container on the present invention is shown in Figures 4 to 9, in schematic form, both as an assembly and in section. The blood sampling container 10 comprises a body 20 in the form of a parallel walled tube laterally defining chamber 12 for holding a blood sample. The chamber is further defined by an end closure 40 at a first end and at a second end a guiding shaft in conjunction with a shaft. The septum 44 provides, an inlet to the chamber for sampling blood, such as created by the insertion of a hollow needle remote end of which is inserted into the vein of a patient for obtaining blood. At least a portion of the chamber 20 comprises a parallel walled tube, a bob located within the tube and extending outside the chamber by means of a shaft 32, wherein in a first configuration 10A the chamber is sealed and the bob is located so as to create a first chamber volume and in a second 10B configuration the chamber is not sealed and the bob is located so as to create a second chamber volume, were in the first chamber volume is larger than the second change chamber volume, the bob being movable within the tube between the first and second configurations, the bob providing a flow path for blood between the bob and the parallel walled tube so as to, in use, blood to flow out of the chamber past the bob. In a third configuration 10C the chamber is again sealed. Referring now to the parts of the blood sampling container 10, this comprises a parallel walled tube, i.e., a tube of uniform bore 20, such as formed by a moulding process. The tube is sealed at one end by 40, such as by a septum seal 44 retained in place by means of a cap 42. The Having sides 48 encompassing the outer wall of the chamber 12, being the outer wall of the parallel walled tube 20. This may be a push, friction fit or it may be adhered in place. The septum cover, 42, having an end face comprising an aperture to access the septum, preferably in the form of an aperture which can guide, in use, a hollow needle into a cavity 46 in the septum for ease of operation. The other end of the cavity 12 is provided were the parallel walled tube 20, having outer 24 and inner 26 walls culminate in a guiding shaft or channel this comprises seal 56 for engaging between the guiding shaft 54 and the enlarged 60 portion of the shaft 32 of the bob 30. In the first position 10A the tube, and hence the cavity 12, is sealed at the other end by the shaft (32) of the bob 30, located within the tube, and sealed via a rubber O-ring 56, that seal providing a seal between the guiding shaft 54 and the enlarged portion 60 of shaft 32. The O-ring is installed on an enlarged section 60 of the shaft 32, such that when the bob is pushed into the tube the remaining shaft can pass freely within the opening. The bob is held in place by a clip 54, or moulded breakable joining, which engages with the shaft to prevent the bob moving into the sample tube until the test is ready to start. The tube is evacuated to a pressure of approximately lOkPa (0.1 Bar) absolute, or more. The bob is manufactured, such that it is a precise diameter dimension relative to the tube, so that the annular gap between the bob and the tube is constant along the entire length of the tube. The annular gap is typically 0.2mm, but could be a small as 0.05mm, or as large as 1mm. The bob has an easement 30, 38 at each end to aid the flow of fluid into the annular gap. In use, the container 10, and specifically the chamber 12 is first filled with blood direct from a patient using a blood sampling needle assembly. The vacuum in the tube is configured such that the tube will fill to a 90% fill level. The full level may be in a range such as from 80 to 99% but is optimally in the range 85 to 95% and most preferably about 90% The tube is placed in the measurement unit 200 and the clip 54 removed to release the bob, where a breakable link is used the engagement of the drive system is preferably sufficient to break the link. Interaction between the sampling container and the measurement apparatus After a sample has been introduced into the chamber 12 of the sampling container 10, the container being in the first configuration, the container is introduced into the measurement apparatus 200. The container is held firmly in the apparatus by means of physical attachment to the outer wall 24 of the container. However, septum 44 and septum cap 42 and in particular cavity 46 may be used to help locate the second end of the container 10 in the apparatus for ease of alignment. The measurement apparatus 200 comprises a measurement head 100 for the purposes of measuring forces transmitted by the shaft 32 of the container 10 by means of a connection, here shown in the manner of a ferromagnetic ball, such as a ball bearing 50 in conjunction with a further ferromagnetic ball 150, such as in the form of a neodymium magnet. These forces are measured, as transmitted along an elongate shaft 138 attached to one end of a torsion bar 100, the other end of the torsion bar being attached to a mounting plate 120 in the apparatus. The torsion bar, such as by means of a Wheatstone bridge or similar stress / strain sensor is in communication with data processing means to process the signals, in conjunction with signals from a drive mechanism 140 of the container 10, so as to determine viscosity of the sample 160 in the chamber 12. The drive mechanism may drive the container 10 in a reciprocating motion or may preferably drive the measurement head in a reciprocating motion. This preferably is at low speed, typically about Imm / sec, but this value may be as low as O.Olmm / sec or as high as lOmm / s. The speed at which the bob is driven effectively sets the shear rate in the annular gap. The measurement apparatus 200 drive head 100 (i.e. the measurement head when equipped with a driving mechanism 104), engages magnetically with the steel ball (50) on the end of the shaft and drives down to push the bob into the tube such that the narrow part of the shaft is now within the neck area and the bob can move freely. In an alternative embodiment the drive mechanism now drives the bob in a reciprocating up and down motion at low speed, typically Imm / sec but this value may be as low as O.Olmm / sec or as high as lOmm / s. The speed at which the bob is driven effectively sets the shear rate in the annular gap. Whilst the bob is being driven in this way, the force required to drive the bob or the tube pressure is monitored, to give a measure of the blood viscosity. An important feature of the present invention is that the reciprocating motion whether motivated by the drive head 104 or by the drive mechanism 140 is that the rate and extent of movement is controlled. This differs significantly from the falling weight type measurement apparatus were the rate of movement, being acceleration and gravity, is not constant and given that blood is a non-newtonian fluid this makes it virtually impossible to obtain meaningful viscosity data, certainly in absolute terms and more particularly in the form of a repeat measurements. Of the two means of motivating the movement of the bob the preferred is using the drive mechanism 104, i.e. moving the measurement head as this is technically less demanding and gives more accurate and less noisy measurements. The magnetic coupling of the bob to the drive system via the ball linkage is important, as it allows the bob to self-centre in the measurement tube. If a fixed linkage were used it would be necessary to closely control the alignment of the tube with the drive system. Method of Measurement The measurement system used is shown schematically in Figure ID. The mechanism comprises a drive system capable of driving the bob (5) in a reciprocating fashion within the tube (10). The sample under test (4) is forced, by the bob motion, to flow through the annular gap between the bob and the tube and shearing of the sample occurs. The viscosity is measured either in terms of the force applied to the bob (30), or the pressure exerted by the sample at (4) in container (10). Both pressure and force are proportional to viscosity. Blood is a difficult sample for rheological evaluation. The viscosity is typically low with fresh blood having a viscosity of 3-7mPaS. This is a problematic value for rotational viscometers such as the cone and plate, as the torque generated by shearing the fluid is low and is comparable to losses experienced in the viscometer bearings. In capillary and falling object viscometers the low viscosity is less of a problem, however, these methods suffer from a poorly defined and fixed shear rate. This is not ideal for a complex rheological fluid. A specific type of viscometer used in the paint industry is a falling piston viscometer. A heavy piston falls under its own weight in a close-fitting bore. The sample is sheared by passage through the annular gap between the piston and the bore. The measurement system used is shown schematically in Figure 1. The mechanism comprises a drive system capable of driving the bob (30) in a reciprocating fashion within the tube (10). The sample under test (160) is forced, by the bob motion, to flow through the annular gap between the bob and the tube and shearing of the sample occurs. The viscosity is measured either in terms of the force applied to the bob or the pressure exerted by the sample.Both pressure and force are proportional to viscosity. The correlation between force and viscosity is established by using calibration samples of fluids of known properties so is to calibrate the apparatus. This may be supplemented by a measurement of the same movement of an empty container 10 as a baseline. In order to make reliable measurements, a disposable measurement system suitable for clinical use has been devised and is the subject of this disclosure. In a clinical setting, almost all blood samples are collected via an evacuated tube system or vacutainer marketed extensively by Beck and Dickinson. This disclosure is a specific form of vacutainer designed for viscosity measurement. The blood viscosity begins at 3-7mPa.s but will increase over time as the blood clots. This clotting process can thereby be monitored and measured. After some time has passed the blood viscosity will increase abruptly and a clot will form. The viscosity of the clot will increase by several orders of magnitude and the test will end. The clot strength, a value of some physiological importance, can be estimated from the ultimate viscosity reached. At the end of the test, the measurement machine drives the bob down beyond the range of reciprocation, until the enlarged area 38 at the drive end of the shaft 32 plugs the tube and seals it with the O-ring (9). The sample is now ejected from the machine, ready for the next measurement. Utility of the Disclosed Method Figure 3 shows a comparison of the blood viscosity of two patients. Patient 1 (340) is in good general health and is included as a control sample. Patient 2 (320) suffers from atrial fibrillation and is treated with a daily dose of an anti-coagulant medication. The test was carried out with a bob speed of Imm / s with the bob reciprocating over a distance of 10mm. The internal diameter of the measurement tube was 14mm and the outside diameter of the bob was 13.6mm to give an annular gap of 0.2mm. It is apparent that patient 1 showed clotting after a time of 400 seconds and that the clot formed with high strength exceeding a viscosity of 1000 mPa.s. For patient 2 the clotting time is extended to 900 seconds and the clot strength is significantly lower. It is clear that the disclosed method has utility in the study of the effects of anticoagulant medication and in the optimisation of anticoagulation.

Claims

1) An apparatus for the measurement of blood viscosity, the apparatus for use in conjunction with a sample holder, the sample holder being a bob in a tube, the bob being configured for linear movement along the length of the tube, substantially without rotation; the apparatus comprising:a. first attachment means for attaching the apparatus to a portion of the bob;b. second attachment means for attaching the apparatus to a portion of the tube;c. an actuator for moving the bob relative to the tube;i. the movement being linear along an axis; being when combined with this sample holder the elongate axis of the tube;d. force measurement means for detecting the force transmitted by the bob when moved along the axis of the tubee. control means for actuating the actuator and measuring the resultant force thereby providing a measurement.2) The apparatus of claim 1 wherein the actuator is configured to move reciprocally along the linear axis.3) The apparatus of claim one or claim 2 were in the actuator is configured to move along the linear axis at a rate of between 0.01 and 10 mm per second.4) The apparatus of any preceding claim wherein the actuator is configured to attach to a first part of the sample container, being either the bob or the tube and the force measurement means is configured to attached to the other part of the sample container, being either the tube or the bob, not attached to the actuator.5) The apparatus of any of claims 1 to 3 were in the actuator and the force measurement means are combined and configured to attached to a first part of the sample container, by that beingeither the bob or the tube and clamping means is provided to attach the other part of the sample container being the tube or you bob to the apparatus.6) The apparatus of any preceding claim wherein the measurement provided is a measurement of viscosity.7) The apparatus of any preceding claim wherein the force measurement means comprises an elongate shaft 38 culminating in a spherical, magnetic, attachment means, the shaft being configured to be in line with the linear axis of the sample container.8) The apparatus of any preceding claim wherein the force measurement means is a torsion bar.9) The apparatus of claim 8 were in the torsion bar is attached perpendicular to the elongate shaft 38.10) The apparatus of any preceding claim wherein the elongate axis is configured to be vertical in normal use.11) The apparatus of any preceding claim wherein the apparatus is configured, for a given sample, to repeat an actuation and corresponding measurement repeatedly over a period of time to determine when a viscosity of increase, as determined by change in force detected by the force measurement means increases by of a least 100% and report at or after this change a measurement related to blood clotting.12) The apparatus of any preceding claim in conjunction with a blood sampling container comprising a body having chamber for holding a blood sample, an inlet to the chamber for sampling blood, at least a portion of the chamber comprising parallel walled tube, a bob located within the tube and extending outside the chamber, wherein in a first configuration the chamber is sealed and the bob is located so as to create a first chamber volume and in a second configuration the chamber is not sealed and the bob is located so as to create a second chamber volume, were in the first chamber volume is larger than the second change chamber volume, the bob being movable within the tube between the first and second configurations,the bob providing a flow path for blood between the bob and the parallel walled tube so as to, in use, blood to flow out of the chamber past the bob.13) A method of determining the viscosity of blood in vitro using the apparatus of claim 12, the method comprising the steps:a. Obtaining a sample of blood in the sampling container, the sampling container being in a first configuration 10A,b. attaching the sampling container to the apparatus, by means of a first attachment to the bob and a second attachment to the container body;c. wherein the bob is advanced from the position in the first configuration to a second configuration in which a shaft of the bob is released from direct contact with the sample container;d. moving the bob in the tube for the measurement of viscosity14) A method of using measuring the viscosity of blood sampled using a container of any of claims 12, wherein the bob reciprocated between the position in the first configuration to a position in the second configuration and the force required to advance or withdraw the bob is measured for correlation to a blood viscosity.15) The apparatus of claim 12 wherein the apparatus is configured to require a predetermined force to move the bob of the sample container from a first configuration the sample container 10 A3 second configuration of the sample container 10 be so is to validate that a sample is present of required volume in the sample container before making a measurement.16) The apparatus of claim 12 wherein the apparatus is configured to move the bob to a third configuration 10 a so is to seal the sample container for subsequent disposal.17) A kit of parts comprising the apparatus of any of claims 1 to 10 in conjunction with said sampling container and a sampling needle for, at a first end piercing the vein of a patient andat a second end suitable for opening the inlet of the chamber.Amendments to the Claims have been filed as follows:-20 05 24Claims1) An apparatus for the measurement of blood viscosity, the apparatus for use in conjunction with a sample holder, the sample holder being a bob in a tube, the bob being configured for linear movement along the length of the tube, substantially without rotation; the apparatus comprising:a. first attachment means for attaching the apparatus to a portion of the bob;b. second attachment means for attaching the apparatus to a portion of the tube;c. an actuator for moving the bob relative to the tube;i. the movement being linear along an axis; being when combined with this sample holder the elongate axis of the tube;d. force measurement means for detecting the force transmitted by the bob when moved along the axis of the tubee. control means for actuating the actuator and measuring the resultant force thereby providing a measurementwherein the apparatus is configured, for a given sample, to repeat an actuation and corresponding measurement repeatedly over a period of time to determine when a viscosity increase, as determined by change in force detected by the force measurement means increases by, of a least 100% and report at or after this change, a measurement related to blood clotting.2) The apparatus of claim 1 wherein the actuator is configured to move reciprocally along the linear axis.3) The apparatus of claim one or claim 2 wherein the actuator is configured to move along the linear axis at a rate of between 0.01 and 10 mm per second.4) The apparatus of any preceding claim wherein the actuator is configured to attach to a first part of the sample holder, being either the bob or the tube and the force measurement means20 05 24is configured to attached to the other part of the sample container, being either the tube or the bob, not attached to the actuator.5) The apparatus of any of claims 1 to 3 wherein the actuator and the force measurement means are combined and configured to attached to a first part of the sample holder, by that being either the bob or the tube and clamping means is provided to attach the other part of the sample container being the tube or you bob to the apparatus.6) The apparatus of any preceding claim wherein the measurement provided is a measurement of viscosity.7) The apparatus of any preceding claim wherein the force measurement means comprises an elongate shaft 38 culminating in a spherical, magnetic, attachment means, the shaft being configured to be in line with the linear axis of the sample container.8) The apparatus of any preceding claim wherein the force measurement means is a torsion bar.9) The apparatus of claim 8 wherein the torsion bar is attached perpendicular to the elongate shaft 38.10) The apparatus of any preceding claim wherein the elongate axis is configured to be vertical in normal use.11) The apparatus of any preceding claim in conjunction with the sample holder in the form of a blood sampling container comprising a body having chamber for holding a blood sample, an inlet to the chamber for sampling blood, at least a portion of the chamber comprising the tube being a parallel walled tube, the bob located within the tube and extending outside the chamber, wherein in a first configuration the chamber is sealed and the bob is located so as to create a first chamber volume and in a second configuration the chamber is not sealed and the bob is located so as to create a second chamber volume, wherin the first chamber volume is larger than the second change chamber volume, the bob being movable within the tube between the first and second configurations, the bob providing a flow path for blood between20 05 24the bob and the parallel walled tube so as to, in use, allow blood to flow out of the chamber past the bob.12) A method of determining the viscosity of blood in vitro using the apparatus of claim 11, the method comprising the steps:a. Obtaining a sample of blood in the sampling container, the sampling container being in a first configuration 10A,b. attaching the sampling container to the apparatus, by means of the first attachment to the bob and the second attachment to the container body;c. wherein the bob is advanced from the position in the first configuration to a second configuration in which a shaft of the bob is released from direct contact with the sample container;d. moving the bob in the tube for the measurement of viscosity13) A method of using measuring the viscosity of blood sampled using a container of any of claim 1, wherein the bob is reciprocated between the position in the first configuration to a position in the second configuration and the force required to advance or withdraw the bob is measured for correlation to a blood viscosity.14) The apparatus of claim 11 wherein the apparatus is configured to require a predetermined force to move the bob of the sample holder from a first configuration of the sample holder 10A to a second configuration of the sample container 10B so is to validate that a sample is present of required volume in the sample container before making a measurement.15) The apparatus of claim 11 wherein the apparatus is configured to move the bob to a third configuration IOC so is to seal the sample container for subsequent disposal.16) A kit of parts comprising the apparatus of any of claims Ito 11 comprising said sample holder; and a sampling needle for, at a first end piercing the vein of a patient and at a second end suitable for opening the inlet of the chamber.

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