Annotations
Hematocrit,
viscosity
and cerebral
The relationship between elevated hematocrit (Hct) and brain disease has been of interest for some time. There is an increased incidence of strokes and transient ischemic attacks (T.I.A.‘s) in patients with polycythemia Vera, although platelet function abnormalities may play a critical role in this disorder. The concept that a pure erythrocytosis may be significant in a variety of disease states has recently received much attention. For example, it has been reported that Hct elevations may be related to intermittent claudication and ischemic heart disease.’ In addition, it has been claimed that there is a sixfold elevation in mortality rate in patients with pseudopolycythemia (Geisbtick’s syndrome).2 More recently, a group from the Institute of Neurology, Queen Square, London,3 have reported a significant reduction in cerebral blood flow (CBF) in patients with Hct values in the upper range of normal (47 per cent to 53 per cent). They subsequently found the CBF increased by a mean of 50 per cent in these patients following repeated venesection, along with a decrease in the incidence of T.I.A.‘s. A significant reduction in whole blood viscosity was felt to be responsible for these findings.” Although the hypothesis that reduced Hct -+ reduction in blood viscosity -+ increase in CBF + improvement in symptoms is an attractive one, there are theoretical considerations which render it suspect. For example, the viscosity of whole blood is influenced by many variables aside from Hct. Also of importance are the flexibility of red blood cells, aggregation of cellular elements, rate of blood flow, vessel bore, and plasma protein and fibrinogen concentrations. In addition, it has been shown that the shear rate dependency of viscosity varies directly with the Hct. Since the Hct in the microcirculation has been found to be less than the venous Hct, and since viscosity plays a lesser role in smaller vessels, blood viscosity in the microcirculation may have a negligible effect on flow rates.4 This may be of particular importance in the cerebral circulation, where the vessels determining flow are of small diameter. Also, the main factors in determining flow in the microcirculation appear to be the deformability of red blood cells and the occurrence of emboli or cellular aggregates, and not viscosity.’ From an experimental point of view, it has been found that viscosity elevations up to five times normal have little effect on CBF in dogs” with existing CBF changes explained by alterations in 0, carrying capacity.’ Finally, it is felt by many investigators that physiologically significant changes in blood viscosity do not occur below Hct values of 0.55” Epidemiological evidence has also been obtained relating to the Hct-cerebrovascular disease relationship. Data from the Framingham study9 revealed a significant correlation between Hct (within the normal range) and risk of cerebral infarction. However, when hypertension was taken into account, the residual risk associated with elevated Hct was not signifi-
404
March,
1979,
Vol.
97, No.
3
blood flow cant.‘O Studies of hemoglobin and ischemic heart disease revealed a similar correlation, but these also were not significant when the data were adjusted for hypertension.‘0 A small but significant negative correlation has recently been observed between cerebrovascular disease mortality rate and increasing altitude in the United States.” Although other factors may be involved, the finding of lower stroke mortality at higher altitudes (with correspondingly higher Hcts) is not consistent with the proposed Hct-viscosity-cerebrovascular disease relationship. To date there is no evidence linking elevated Hct within the normal range with coronary artery or cerebrovascular disease on an independent basis. While the CBF impairment reported by the British group may not be related to viscosity as suggested, it is an intriguing finding. The most essential question is the effect of Hct changes on flow in diseased vessels. It is likely that the normal flows maintained with elevated viscosity reported in animal experiments are due to metabolic control mechanisms intrinsic to the cerebral circulation.” It is possible that in patients with pre-existing cerebrovascular disease, the relatively small viscosity changes associated with high Hct3 produce CBF alterations because of defective autoregulation. However, the finding of lower CBF with Hct’s from 47 per cent to 53 per cent is surprising and certainly would not be expected from analysis of the factors discussed above. Further studies of the Hct-CBF relationsliip would be expected to settle this important issue. This could easily be done utilizing CBF data already collected. The clinical question of phlebotomy (recommended by Thomas and colleagues” for patients at risk for occlusive vascular disease with Hct’s consistently above 46 per cent) is of potentially great importance. There have already been suggestions both on empirical and experimental grounds for judicious phlebotomy in patients at risk for coronary artery disease with high Hct’s in the normal range.‘“‘I While definitive evidence supporting venesection in such patients is presently lacking, carefully controlled double-blind prospective studies designed to answer these questions are clearly indicated. Robert P. Friedland, M.D.* Department of Neurology University of California, Davis V. A. Hospital 150 Muir Road Martinez, Calif. 94553 Steven Grant, M.D. Department of Medical Oncology Yale University School of Medicine New Haven, Conn. 06510 *Dr.
Friedland’s work has been supported of Health Grant No. NS 03356.
in part
by a National
Institutes
0002-8703/79/030404
+ 02$00.20/O 0 1979 The
C. V. Mosby
Co.
Annotations REFERENCES
1.
2.
3.
4. 5. 6. 7.
8.
Nicolaides, A. N., Harbourne, T., Bowers, R., Kidner, P. H., and Besterman, E. M.: Blood viscosity, red-cell flexibility, haematocrit, and plasma-fibrinogen in patients with angina, Lancet 2:943, 1977. Burge, P. S., Johnson, W. S., and Prankerd, T. A. J.: Morbidity and mortality in pseudopolycythaemia, Lancet 1:1266, 1975. Thomas, D. J., Marshall, J., Ross Russel, R. W., Wetherley-Mein, G., DuBoulay, G. H., Pearson, T. C., Symon, L., and Zilkha, E.: Effect of haematocrit on cerebral blood-flow in man, Lancet 2:941, 1977. Editorial: Haemorheology, blood-flow and venous thrombosis, Lancet 2:113, 1975. Dintenfass, L.: Hyperviscosity in disease, Lancet 1:327, 1978. Haggendal, E. and Norback, B.: Effect of viscosity on cerebral blood flow, Acta Chir. Stand. 364:13, 1966. Haggendal, E., Nilsson, N. J., and Norback, B.: Effect of blood corpuscle concentration on cerebral blood flow, Acta Chir. Stand. 364:3, 1966. Leblond, P. F.. and Weed, R. I.: The peripheral blood in
Nonbacterial myocardial
thrombotic infarction
9.
10.
11.
12.
13. 14.
endocarditis
and
Nonbacterial thrombotic endocarditis (NBTE), an entity characterized by bland fibrin-platelet thrombus on cardiac valves and the absence of microorganisms or valve destruction, may be the cause of significant morbidity and mortality as a result of major arterial embolization. NBTE is no longer regarded as a pathologic curiosity, occurring in about 1.6 per cent of adult deaths.’ It is associated with a variety of diseases, most commonly malignant tumors. Adenocarcinomas, particularly mucin-secreting types, predominate in most series.‘, ? The pathogenesis of NBTE is not clear; disseminated intravascular coagulation and thrombotic phenomena are not infrequently encountered, suggesting a pathogenetic role of coagulation abnormalities (hypercoagulable state) in some cases.” ’ Coronary embolism with myocardial infarction is one of the dreaded complications and was found in 6.7 per cent and 9 per cent of patients with NBTE in two recent studies.‘. ’ Thromboembolism, usually of the intramyocardial arteries, without myocardial infarction, is found more frequently but is not judged to be of clinical significance. All patients described so far have had underlying malignant neoplasms, characteristically of epithelial origin. This complication of NBTE has been reported in patients of both sexes with ages ranging from the third to the eighth decade. Pathologically, the vegetations of NBTE are small, measuring less than 10 mm. and usually situated on the closure or free margins of the valves. As may be expected, most verrucae are located on the mitral and aortic valves. The pathologic alterations in the hearts of patients with myocardial infarction associated with NBTE are not distinctive. The heart may be normal or moderately enlarged. An underlying cardiac disease such as rheumatic valvulitis may be present. The
0002-8703/79/030405
+ 02$00.20/O
0 1979 The
C. V. Mosby
polycythaemia vera and myelofibrosis, Clinics Haematol. 4:353, 1975. Kannel, W. B., Gordon, T., Wolf, P. A., and McNbmara, P.: Hemoglobin and the risk of cerebral infarction: The Framingham Study, Stroke 3:409, 1972. Abu-Zeid, H. A. H., Choi, N. W., Maini, K. K., Ping-Hwa, H.. and Nelson. N.: Relative role of factors associated with cerebral infarction and cerebral hemorrhage, Stroke 8: 106, 1977. Gordon, R. S., Kahn, H. A., and Forman, S.: Altitude and CBVD death rates show apparent relationship, Stroke 8:274, 1977. Olesen, J.: Cerebral blood flow, methods for measurement, regulation, effects of drugs and changes in disease, Acta Neurol. Stand. 5O(Suppl. 57):31, 1974. Burch, G. E., and DePasquale, N. P.: Hematocrit, viscosity and coronary blood flow, Dis. Chest 48:225, 1965. Erslev, A. J.: Erythrocyte disorders, in Williams, W. J., Beutler, E., Erslev, A. J., and Rundles, R. W., editors: Textbook of Hematology, New York, 1977, McGraw-Hill Book Company, Inc., p. 255.
Co.
intramyocardial or coronary arteries or both frequently contain thromboemboli. Histologically, multiple acute infarcts of different ages are usual. A single area of infarction may result when the embolus lodges in a coronary artery or a large intramyocardial artery. This was described in three of six cases published recently.’ The pathologic diagnosis should be accepted only in the presence of extensive occlusion of coronary arteries or their branches and in the absence of significant atherosclerosis or other diseases of coronary arteries. The antemortem diagnosis of NBTE-associated myocardial infarction is difficult but not impossible.” Most patients have concomitant neurologic symptoms probably secondary to cerebral embolism. These symptoms may mask the chest pain that would alert physicians to the diagnosis of myocardial infarction. Severe symptoms and signs resulting from embolization to other organs-kidneys, spleen, the gastrointestinal tract-may further complicate the clinical picture. The diagnosis under these conditions would depend on a high index of suspicion. It is suggested that, in the patient at risk (with carcinomatosis or other disseminated malignant neoplasms), there should be intermittent monitoring with noninvasive techniques such as electrocardiograms, cardiac enzyme studies and screening for evidence of disseminated intravascular coagulation, venous thrombosis or hypercoagulable state by determining platelet counts, partial thromboplastin time, prothrombin time, and levels of blood fibrinogen and fibrin split products. The latter, in combination with nonspecific signs such as changing murmurs and purpuric skin lesions”, ’ may indicate the presence of NBTE, thus increasing the potential for the diagnosis of myocardial infarction. In most patients, the clinical status and the severity of the underlying diseases would preclude coronary angiography, coronary
American
Heart
Journal
405
Hematocrit,
viscosity
and cerebral
The relationship between elevated hematocrit (Hct) and brain disease has been of interest for some time. There is an increased incidence of strokes and transient ischemic attacks (T.I.A.‘s) in patients with polycythemia Vera, although platelet function abnormalities may play a critical role in this disorder. The concept that a pure erythrocytosis may be significant in a variety of disease states has recently received much attention. For example, it has been reported that Hct elevations may be related to intermittent claudication and ischemic heart disease.’ In addition, it has been claimed that there is a sixfold elevation in mortality rate in patients with pseudopolycythemia (Geisbtick’s syndrome).2 More recently, a group from the Institute of Neurology, Queen Square, London,3 have reported a significant reduction in cerebral blood flow (CBF) in patients with Hct values in the upper range of normal (47 per cent to 53 per cent). They subsequently found the CBF increased by a mean of 50 per cent in these patients following repeated venesection, along with a decrease in the incidence of T.I.A.‘s. A significant reduction in whole blood viscosity was felt to be responsible for these findings.” Although the hypothesis that reduced Hct -+ reduction in blood viscosity -+ increase in CBF + improvement in symptoms is an attractive one, there are theoretical considerations which render it suspect. For example, the viscosity of whole blood is influenced by many variables aside from Hct. Also of importance are the flexibility of red blood cells, aggregation of cellular elements, rate of blood flow, vessel bore, and plasma protein and fibrinogen concentrations. In addition, it has been shown that the shear rate dependency of viscosity varies directly with the Hct. Since the Hct in the microcirculation has been found to be less than the venous Hct, and since viscosity plays a lesser role in smaller vessels, blood viscosity in the microcirculation may have a negligible effect on flow rates.4 This may be of particular importance in the cerebral circulation, where the vessels determining flow are of small diameter. Also, the main factors in determining flow in the microcirculation appear to be the deformability of red blood cells and the occurrence of emboli or cellular aggregates, and not viscosity.’ From an experimental point of view, it has been found that viscosity elevations up to five times normal have little effect on CBF in dogs” with existing CBF changes explained by alterations in 0, carrying capacity.’ Finally, it is felt by many investigators that physiologically significant changes in blood viscosity do not occur below Hct values of 0.55” Epidemiological evidence has also been obtained relating to the Hct-cerebrovascular disease relationship. Data from the Framingham study9 revealed a significant correlation between Hct (within the normal range) and risk of cerebral infarction. However, when hypertension was taken into account, the residual risk associated with elevated Hct was not signifi-
404
March,
1979,
Vol.
97, No.
3
blood flow cant.‘O Studies of hemoglobin and ischemic heart disease revealed a similar correlation, but these also were not significant when the data were adjusted for hypertension.‘0 A small but significant negative correlation has recently been observed between cerebrovascular disease mortality rate and increasing altitude in the United States.” Although other factors may be involved, the finding of lower stroke mortality at higher altitudes (with correspondingly higher Hcts) is not consistent with the proposed Hct-viscosity-cerebrovascular disease relationship. To date there is no evidence linking elevated Hct within the normal range with coronary artery or cerebrovascular disease on an independent basis. While the CBF impairment reported by the British group may not be related to viscosity as suggested, it is an intriguing finding. The most essential question is the effect of Hct changes on flow in diseased vessels. It is likely that the normal flows maintained with elevated viscosity reported in animal experiments are due to metabolic control mechanisms intrinsic to the cerebral circulation.” It is possible that in patients with pre-existing cerebrovascular disease, the relatively small viscosity changes associated with high Hct3 produce CBF alterations because of defective autoregulation. However, the finding of lower CBF with Hct’s from 47 per cent to 53 per cent is surprising and certainly would not be expected from analysis of the factors discussed above. Further studies of the Hct-CBF relationsliip would be expected to settle this important issue. This could easily be done utilizing CBF data already collected. The clinical question of phlebotomy (recommended by Thomas and colleagues” for patients at risk for occlusive vascular disease with Hct’s consistently above 46 per cent) is of potentially great importance. There have already been suggestions both on empirical and experimental grounds for judicious phlebotomy in patients at risk for coronary artery disease with high Hct’s in the normal range.‘“‘I While definitive evidence supporting venesection in such patients is presently lacking, carefully controlled double-blind prospective studies designed to answer these questions are clearly indicated. Robert P. Friedland, M.D.* Department of Neurology University of California, Davis V. A. Hospital 150 Muir Road Martinez, Calif. 94553 Steven Grant, M.D. Department of Medical Oncology Yale University School of Medicine New Haven, Conn. 06510 *Dr.
Friedland’s work has been supported of Health Grant No. NS 03356.
in part
by a National
Institutes
0002-8703/79/030404
+ 02$00.20/O 0 1979 The
C. V. Mosby
Co.
Annotations REFERENCES
1.
2.
3.
4. 5. 6. 7.
8.
Nicolaides, A. N., Harbourne, T., Bowers, R., Kidner, P. H., and Besterman, E. M.: Blood viscosity, red-cell flexibility, haematocrit, and plasma-fibrinogen in patients with angina, Lancet 2:943, 1977. Burge, P. S., Johnson, W. S., and Prankerd, T. A. J.: Morbidity and mortality in pseudopolycythaemia, Lancet 1:1266, 1975. Thomas, D. J., Marshall, J., Ross Russel, R. W., Wetherley-Mein, G., DuBoulay, G. H., Pearson, T. C., Symon, L., and Zilkha, E.: Effect of haematocrit on cerebral blood-flow in man, Lancet 2:941, 1977. Editorial: Haemorheology, blood-flow and venous thrombosis, Lancet 2:113, 1975. Dintenfass, L.: Hyperviscosity in disease, Lancet 1:327, 1978. Haggendal, E. and Norback, B.: Effect of viscosity on cerebral blood flow, Acta Chir. Stand. 364:13, 1966. Haggendal, E., Nilsson, N. J., and Norback, B.: Effect of blood corpuscle concentration on cerebral blood flow, Acta Chir. Stand. 364:3, 1966. Leblond, P. F.. and Weed, R. I.: The peripheral blood in
Nonbacterial myocardial
thrombotic infarction
9.
10.
11.
12.
13. 14.
endocarditis
and
Nonbacterial thrombotic endocarditis (NBTE), an entity characterized by bland fibrin-platelet thrombus on cardiac valves and the absence of microorganisms or valve destruction, may be the cause of significant morbidity and mortality as a result of major arterial embolization. NBTE is no longer regarded as a pathologic curiosity, occurring in about 1.6 per cent of adult deaths.’ It is associated with a variety of diseases, most commonly malignant tumors. Adenocarcinomas, particularly mucin-secreting types, predominate in most series.‘, ? The pathogenesis of NBTE is not clear; disseminated intravascular coagulation and thrombotic phenomena are not infrequently encountered, suggesting a pathogenetic role of coagulation abnormalities (hypercoagulable state) in some cases.” ’ Coronary embolism with myocardial infarction is one of the dreaded complications and was found in 6.7 per cent and 9 per cent of patients with NBTE in two recent studies.‘. ’ Thromboembolism, usually of the intramyocardial arteries, without myocardial infarction, is found more frequently but is not judged to be of clinical significance. All patients described so far have had underlying malignant neoplasms, characteristically of epithelial origin. This complication of NBTE has been reported in patients of both sexes with ages ranging from the third to the eighth decade. Pathologically, the vegetations of NBTE are small, measuring less than 10 mm. and usually situated on the closure or free margins of the valves. As may be expected, most verrucae are located on the mitral and aortic valves. The pathologic alterations in the hearts of patients with myocardial infarction associated with NBTE are not distinctive. The heart may be normal or moderately enlarged. An underlying cardiac disease such as rheumatic valvulitis may be present. The
0002-8703/79/030405
+ 02$00.20/O
0 1979 The
C. V. Mosby
polycythaemia vera and myelofibrosis, Clinics Haematol. 4:353, 1975. Kannel, W. B., Gordon, T., Wolf, P. A., and McNbmara, P.: Hemoglobin and the risk of cerebral infarction: The Framingham Study, Stroke 3:409, 1972. Abu-Zeid, H. A. H., Choi, N. W., Maini, K. K., Ping-Hwa, H.. and Nelson. N.: Relative role of factors associated with cerebral infarction and cerebral hemorrhage, Stroke 8: 106, 1977. Gordon, R. S., Kahn, H. A., and Forman, S.: Altitude and CBVD death rates show apparent relationship, Stroke 8:274, 1977. Olesen, J.: Cerebral blood flow, methods for measurement, regulation, effects of drugs and changes in disease, Acta Neurol. Stand. 5O(Suppl. 57):31, 1974. Burch, G. E., and DePasquale, N. P.: Hematocrit, viscosity and coronary blood flow, Dis. Chest 48:225, 1965. Erslev, A. J.: Erythrocyte disorders, in Williams, W. J., Beutler, E., Erslev, A. J., and Rundles, R. W., editors: Textbook of Hematology, New York, 1977, McGraw-Hill Book Company, Inc., p. 255.
Co.
intramyocardial or coronary arteries or both frequently contain thromboemboli. Histologically, multiple acute infarcts of different ages are usual. A single area of infarction may result when the embolus lodges in a coronary artery or a large intramyocardial artery. This was described in three of six cases published recently.’ The pathologic diagnosis should be accepted only in the presence of extensive occlusion of coronary arteries or their branches and in the absence of significant atherosclerosis or other diseases of coronary arteries. The antemortem diagnosis of NBTE-associated myocardial infarction is difficult but not impossible.” Most patients have concomitant neurologic symptoms probably secondary to cerebral embolism. These symptoms may mask the chest pain that would alert physicians to the diagnosis of myocardial infarction. Severe symptoms and signs resulting from embolization to other organs-kidneys, spleen, the gastrointestinal tract-may further complicate the clinical picture. The diagnosis under these conditions would depend on a high index of suspicion. It is suggested that, in the patient at risk (with carcinomatosis or other disseminated malignant neoplasms), there should be intermittent monitoring with noninvasive techniques such as electrocardiograms, cardiac enzyme studies and screening for evidence of disseminated intravascular coagulation, venous thrombosis or hypercoagulable state by determining platelet counts, partial thromboplastin time, prothrombin time, and levels of blood fibrinogen and fibrin split products. The latter, in combination with nonspecific signs such as changing murmurs and purpuric skin lesions”, ’ may indicate the presence of NBTE, thus increasing the potential for the diagnosis of myocardial infarction. In most patients, the clinical status and the severity of the underlying diseases would preclude coronary angiography, coronary
American
Heart
Journal
405
