Nanomedicine, Volume IIA: Biocompatibility

© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003 Nanorobotic Hemolysis

Intravascular hemolysis [4023] occurs when red cells encounter excessive mechanical forces [4024, 4025] in the bloodstream, causing the cells to become damaged or destroyed. The hallmark of this type of hemolysis is the fragmented red cell, an irregularly contracted cell called a schistocyte. Schistocytes are seen in all fragmentation syndromes (except those in athletes) and can take the shape of helmets, triangles, burrs, crescents, or microspherocytes. These objects are formed after the shearing of red cells by mechanical trauma, whereupon the torn membranes reseal around whatever hemoglobin remains. Schistocytes are relatively rigid. They cannot tolerate the rigors of the circulation and are soon destroyed. If the amount of hemoglobin released from disintegrating red cells into the plasma exceeds the ability of blood mucoprotein (e.g., haptoglobin) to combine with it (thus allowing removal by the liver), then the excess hemoglobin is lost through the kidneys and appears in the urine, a condition known as hemoglobinuria.

Red cell fragmentation disorders normally arise in three clinical settings: (1) conditions of rapid, turbulent blood flow in the heart or major arteries (e.g., artificial heart valves [4026, 4027, 5020], stenotic vessels [4028, 4029], aortic coarctation, arteriovenous fistula); (2) athletic activities involving impact or long-lasting exertion (e.g., march hemoglobinuria, swimmer’s hemolysis); and (3) many acquired small blood vessel disorders (e.g., diverse microangiopathies such as hemolytic-uremic syndrome, eclampsia, or vasculitis), which tend to involve variable degrees of thrombosis or disseminated intravascular coagulation [4023], or various erythropathies. The fragmentation syndrome of thrombotic thrombocytopenic purpura apparently results from the shearing of red cells as they traverse platelet-fibrin plugs in arterioles and capillaries, especially near renal glomeruli – red cells can be torn in half by fibrin strands [4023, 4064]. Hemolysis can also occur following the intravenous injection of hypotonic solutions or distilled water. In this case, the red cells swell, become globular, and ultimately burst; all injected solutions must be isotonic with the blood. Finally, at least one case of schistocytic hemolytic anemia has been reported [5393] in a fetus due to a varix (twist) in the intra-abdominal umbilical vein.

Impact hemolysis or “march hemoglobinuria” [4030-4055] is classically seen in marathon runners but has also been described in persons involved in the martial arts [4051-4055], basketball [4049], aerobic dancing [4023], or playing the drums [4048-4050]. Mild intravascular hemolysis also occurs during long swim races [4056, 4057]. Although nonmechanical factors may contribute, it is generally believed that most of the damage is caused by mechanical tearing. A human runner of weight ~103 N whose footfall force is spread over a ~100 cm2 area exerts a momentary tissue overpressure of ~105 N/m2. This is well in excess of the red cell fragmentation shear stress limit of 150-250 N/m2 [4058, 4059]. Shear forces from free-floating nanorobots are of order <0.1 N/m2 (Section and vasculomobile or stentlike nanoaggregates could exert forces of order ~102-103 N/m2 (Section and Chapter 14), presenting only a minor comparative risk of direct mechanical hemolysis. Conventional stent balloon-installation forces (Section or episodic nanorobotic concussive vasculopathies (Section might momentarily apply forces exceeding ~106 N/m2, presenting at least a brief potential risk of hemolysis in these rare circumstances. Exposure of human hands to 120 Hz 250-micron vibrations produces ischemic “vibration white finger,” with increased plasma hemoglobin concentration and viscosity [5409].

Nanoscale or submicroscale cables, wires, or other fiberlike protrusions into the bloodstream (Sections and 7.3.3) could directly cause red cell hemolysis. Forcing living cells through a finely-holed rigid strainer destroys them. Red cells can be torn in half by fibrin strands as the cells traverse platelet-fibrin plugs in arterioles and capillaries [4023, 4064]. Hemolytic anemia may be a consequence of mechanical shearing damage to erythrocytes by microangiopathic fibrin strands in peripheral microvessels [4060-4064]. The number of schistocytes (re-formed red cell fragments) naturally present in the blood appears to be correlated with the extent of vascular fibrin deposition [4061]. Moderate schistocytosis is common after organ transplantation, with no clinical significance [4067]. Quantified as the number of fragmented red cells per 1000 red cells, expressed as a percentage, normal human blood may contain 0.1-1% schistocytes in mild schistocytosis [4065-4067]. A schistocyte count up to 2% is considered moderate but abnormal [4065-4067]; >2% is considered clinically serious [4067]; up to 6% may be found within 2 hours of a major surgical procedure [4065]; and up to 10% may be seen after intraoperative blood transfusion [4065], or up to 35% in patients undergoing splenectomy [4065]. Nanorobotic hemolysis of up to ~1%/day of all red cells – the natural rate – or about 0.25 destroyed red cells per nanorobot-day for a 1 terabot dosage (Section can probably be tolerated by the human body. Anemia due to mechanical hemolysis can be ameliorated in some cases by administering erythropoietin [5395].* Materials-induced hemolysis is near-zero for diamond [643, 660, 4726], graphite [643], and alumina [643] powders, although free aluminum ion may be hemolytic [1079]. Bulk Teflon can be very mechanically hemolytic [1347, 1348] and colloidal silica may also be hemolytic [4068]. Intravascular stents do not appear to cause microangiopathic hemolysis or thrombotic microangiopathy [5389], and replacement of heart valves with contemporary mechanical prostheses has been associated only with subclinical (mild) intravascular hemolysis [5390, 5391].

* In contemporary medical practice, such erythropoietin treatment would be too expensive unless the patient is on dialysis or has a bone marrow disorder. Instead, the treatments of choice are transfusion in life-threatening situations, oral iron supplements otherwise. In an era of advanced molecular manufacturing, human hormones such as erythropoietin should be easily synthesized at a cost of pennies per dose or less (Section 2.4.2, Chapter 19).

Careless perforation of red cell plasma membrane by cytopenetrating nanorobots (Section 9.4.5) could result in nanomechanical hemolysis crudely analogous to the hemolysis accompanying certain membrane-perforating parasitic infections such as babesiosis [4069]. Utilization of proper cytopenetration techniques (Section 9.4.5) and the avoidance of extremely rapid manipulator movements (sufficient to rupture RBC plasma membrane) should reduce or eliminate this risk. In some cases, applied forces as small as 10-60 pN may be sufficient [4070] (Section to cause red cell membrane fragmentation. The passage of red cells through catheters at various clinically relevant flow rates can cause significant hemolysis [4071, 4072]. Each trip through a 14-gauge blood dialysis needle at 91 ml/min and a 2.2 m/sec peak velocity damages 0.001% (near the center) to 0.1% (near the needle wall) of the red cells [3690]. Erythrocyte trauma is increased at elevated static pressures, especially in high-shear conditions [5394]. Larger red cells are more susceptible to mechanical hemolysis than smaller red cells [5396]. The additional hemolytic effects of surface hardness and surface texture (e.g., collision against a sanded wall) are being investigated but may be relevant only for flow velocities exceeding 3 m/sec and surface rugosity exceeding ~1 micron [4073]. Patients with spherocytic hereditary elliptocytosis [5398-5403] – a normally benign condition in which the red cells are oval or elliptically shaped, occurring in 1 of 2000 births [2004] – or pyropoikilocytosis may be at slightly higher risk of mechanical red cell fragmentation because of the greater fragility of these abnormal red cell membranes [4074, 5403, 5404].

Drugs can reduce the severity of intravascular hemolysis, e.g., by increasing red cell membrane elasticity and compliance [5397].


Last updated on 30 April 2004