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The omnipotent platelet part II: Further observations
Medical Hypotheses (1997) 49, 15-17 © Pearson Professional Ltd 1997
The omnipotent platelet Part I1: Further observations L. A. STEINBERG Chestnut Hill Medical Center, 25 Boylston Street, Suite 312, Chestnut Hill, MA 02167, USA (Tel: +I 617 734 1394; Fax: +1 617 738 0001)
Abstract - - Observation of platelet responses during acute injury or pathology can provide important information. The initial response is thrombocytopenia followed by thrombocytosis. In the case of injury with negative X-ray and appropriate thrombocytosis, a bone scan is indicated. The platelet responds like a sedimentation rate, which indicates the course of the injury or pathology.
The platelet resembles the sedimentation rate in being a guide to acute and healing major pathology. In the first few days, there is thrombocytopenia (1-3) to gradual-increase to normal levels and thrombocytosis in 10-20 days (1). The amount of decrease and the subsequent quantity of increase according to my observations suggest the magnitude of the pathology. At the same time, an increased platelet size may also occur (1,9) (Table 1).
The platelet has been noted to be directed to the site of the pathology. Fracture healing begins immediately following injury when growth factors including TGF Beta 1 and platelet-derived growth factor (PDGF) are released into the fracture hematoma by the platelet inflammatory cells. TGF-Beta 1 and PDGF appear to have an influence on the initiation of fracture repair and the formation of cartilage and intramembraneous bone in the initiation of callus formation (4). Thiede et al noted that osteocalcin
Table 1 Examples of thrombocytopenia of hip and knee within 72 h post-op Patient
#1
#2
#3
#4
#5
Mean
Platelets pre-op * 1000
166
180
251
230
306
226.6
Platelets post-op (72 h)
79
98
190
161
232
152
Difference
87
82
61
69
74
74.6
Drop from pre-op
52.41%
45.56%
24.30%
30.00%
24.18%
32.92%
Date received 1 May 1996 Date accepted 24 October 1996
15
16
MEDICAL HYPOTHESES
messenger RNA (ocmRNA) is found in megakaryocytes and peripheral blood platelets (5). The literature denotes an increase in PDGF in acute arthritic joint of rheumatoid arthritis (6) and an increase in PDGF in the coronary sinus with unstable angina (7). As with other body functions, a signal is probably transmitted to the megakaryocyte to produce more platelets and this suggests to me that the platelet produced may be more specific for that particular injury or pathology, i.e. soft tissue or bone. Bass et al noted that megakaryocytes ploidy is increased in human coronary atherosclerosis and correlates with serum lipids. He hypothesized that hypercholesterolemia may induce increases in megakaryocytes ploidy and enhance the production of hyperfunctional platelets. He also observed that 'Megakaryocyte DNA content is increased in patients with coronary artery atherosclerosis' (8). Martin et al noted that the sudden death of a human being in an accident causes no change in the megakaryocyte. However, one who has a mild coronary infarction will show megakaryocytic change and often a large platelet. The platelet is the single most powerful predictor of reinfarction and death, and the reason for this, I am convinced, is the change to a new large hyper-reactive platelet species in the period before the infarction (9). This suggests to me that the platelet is responding to the pathology and not to the etiology. Stephen Ellis MD of the Cleveland Clinic Foundation, at the 68th Scientific Session of the American Heart Association, suggested that GPllb/llla receptor inhibition (which inhibits platelet activation) may provide prophylaxis in preventing restenosis and subacute thrombosis. Platelet membrane glycoproteins IIb and IIIa participate in the fibrinogen-mediated interaction of platelet membranes with one another and with artificial surfaces. These membrane glycoproteins also appear to play a role in calcium transport across the platelet membrane (10). Angioplasty patients who were treated with abcixmab (ReoPro) were significantly less likely to die or suffer a myocardial infarction (MI), so researchers brought an early halt to a trial called EPILOG
(Evaluation of PTCA to Improve Long-term Outcomes by c7E3 Glycoprotein IIb/IIIa Receptor Blockade). Abcixmab
Abcixmab is a monoclonal antibody fragment that blocks the final common pathway of platelet aggregation involving the platelet GIIb/IIIa receptor. The literature notes that platelets contain the calciumbinding protein calmodulin, which is presumed to function as a carrier in some calcium-regulated processes (11,12). As noted by Schroeder et al in regard to the calcium, it may explain why calcium channel blockers are beneficial prior to cardiac transplant (13). The action of 'calcium channel blockers' including nifedipine, verapamil, and diltiazem, in blocking the transmembrane flux of calcium in response to platelet agonists at least partially explains their inhibition of platelet aggregation and secretion (14). The platelet is known to possess properties involved in clotting PDGF and calcification. It is plausible in effecting repair, and it may also adversely affect that particular tissue. After an MI, coronary artery bypass graft (CABG), or angioplasty, the platelet's provision of PDGF may also result in angiogenesis and an increase in calcium transport. I have observed platelet activity in fracture, bone surgery, CABG, angioplasty with and without stint insertion, acute congestive failure, acute renal shutdown and malignancy. Some examples of nonosseous pathology are given below and the patients' respective platelet levels in Table 2. Patient #1. An 81-year-old female with acute congestive failure who underwent aortic valve replacement; Patient #2. A 80-year-old male on whom a CABG was performed; Patient #3. A 71-year-old female who had suffered an MI with cardiac rupture, which was repaired with superglue; Patient #4. A 66-year old male with acute aneuria who underwent dialysis.
Table 2 Platelet levels of four patients with non-osseous pathology Platelets pre admission
Platelets 72 h post op
Platelets post op
Patient #l Patient #2 Patient #3
210 000 214 000 224 000
58 000 99 000 55 000
Patient #4*
83 000
12 days post op: 199 000 9 days post op: 274 000 10 days post op: 512 000 23 days post op: 385 000 23 days post dialysis: 240 000
64 000/dialysis
*Patient #4 was not a surgical patient and underwent only dialysis.
17
THE OMNIPOTENT PLATELET (PART II)
Table 3
Platelets levels of four patients with traumatic injuries
Age
Sex
Platelet count
Days post injury
Diagnosis by subsequent bone scan & X-ray
92 96 74 90
F F F F
649 000 550 000 459 000 544 000
13 days 15 days 13 days 10 days
Fracture of the sacrum Fracture of 2 ribs, 2 vertebrae, sacrum Fracture of sacro-iliac joint Fracture of foot
As with electron spin resonance, a bone scan is indicated if the platelets are increased (10-20 days) following injury with ongoing pain and a negative X-ray. I have observed this in ten patients over the past three years. The four patients shown in Table 3 were admitted to hospital with traumatic injuries. X-ray on admission was negative in involved areas. During the 10-15 day period post injury, the platelets elevated. At that time, a bone scan and repeat X-ray were performed and the patient was found to be positive for fracture.
3.
4. 5.
6.
Conclusions 1. The number of platelets in response to acute injury or pathology can mimic the sedimentation rate. 2. The response may not always be beneficial, especially with soft tissue. 3. The increase in thrombocytosis and prolonged thrombocytosis suggests prognosis. 4. Persistent pain following injury and despite a negative X-ray with thrombocytosis (10-20 days) is indicative of fracture. 5. The literature continues to contain many reports of these various platelet activities. 6. The question remains of whether the Ghon complex of tuberculosis, microcalcification of breast, calcific tendonitis and calcification in blood vessels is related to platelet response.
7. 8. 9. 10. 11.
12. 13.
References 14. 1. Steinberg L. The omnipotent platelet. Medical Hypotheses 1996; 46: 188-190. 2. Thuruer R L, Lytle B W, Cosgrove D M, Loop F D. Auto-
transfusion following cardiac operations: a randomized, prospective study. Ann Thorac Surg 1979; 27(6): 500-507. Warkentin T E, Levine M N, Hirsh J e t al. Heparin-induced thombocytopenia in patients treated with low-molecular weight heparin or unfractioned heparin. N Engl J Med 1995; 332: 1330-1335. Bolander M E. Regulation of fracture repair by growth factors. Dept of Orthopedics, Mayo Clinic, Rochester MN. Proc Soc Exp Biol Med 1992; 200(2): 165-170. Thiede M A, Smock S L, Petersen D N e t al. Department of Cardiovascular and Metabolic Diseases. Central Research Div, Pfizer Inc., Presence of Messenger Ribonucleic Acid Encoding Osteocalcin, a Marker of Bone Turnover. In: Bone Marrow Megakaryocytes and Peripheral Blood Platelets. Endocrinology 1994; 135(3): 929-937. Weissbarthe E, Baruth B, Mielke H, Liman W, Deicher H. Platelets as target cells in rheumatoid arthritis and systemic lupus erythematosus: a platelet specific immunoglobulin inculding the release factor. Rheumatol Int 1982; 2: 67-73. Ogawa H, Ogawa A, Yasue H et al. Plasma platelet derived growth factor levels in unstable angina pectoris. Am J Cardiol 1992; 69: 453-456. Bath P N, Gladwin AM, Carden N, Martin J F. Megakaryocyte DNA content is increased in patients with coronary artery atherosclerosis. Cardiovasc Res 1994; 8: 1348-1352. Martin J F, Bath P M W, Burr M L. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409-1411. Bennett J S, Vilalre G. Exposure of platelet flbrinogen receptors by ADP and epinephrine. J Clin Invest 1979; 64: 1393. Young N H, Crawford N. Isolation from blood platelets and polymorph of a Ca2+-dependent regulator protein (CDR) which activates cyclic nucleotide phosphodiesterase. Thromb Haemostas 1979; 42: 81. Levine S N, Steiner A L, White K G C II. Identification and distribution of the calcium-dependent regulator protein in human platelet preparations. Thumb Haemostas 1979; 42:81. Shroeder J S. Calcium blockade prevents coronary artery disease. Stamford University Study presented at the Joint 12th World Congress of Cardiology and the 15th Congress of the European Society of Cardiology, 1994. Ware J A, Johson P C, Smith M, Salzman E W. Inhibition of platelet aggregation and cytoplasmic calcium response by calcium antagonists: studies with aequorin and quin 2. Circ Res 1986; 59: 39-42.
The omnipotent platelet Part I1: Further observations L. A. STEINBERG Chestnut Hill Medical Center, 25 Boylston Street, Suite 312, Chestnut Hill, MA 02167, USA (Tel: +I 617 734 1394; Fax: +1 617 738 0001)
Abstract - - Observation of platelet responses during acute injury or pathology can provide important information. The initial response is thrombocytopenia followed by thrombocytosis. In the case of injury with negative X-ray and appropriate thrombocytosis, a bone scan is indicated. The platelet responds like a sedimentation rate, which indicates the course of the injury or pathology.
The platelet resembles the sedimentation rate in being a guide to acute and healing major pathology. In the first few days, there is thrombocytopenia (1-3) to gradual-increase to normal levels and thrombocytosis in 10-20 days (1). The amount of decrease and the subsequent quantity of increase according to my observations suggest the magnitude of the pathology. At the same time, an increased platelet size may also occur (1,9) (Table 1).
The platelet has been noted to be directed to the site of the pathology. Fracture healing begins immediately following injury when growth factors including TGF Beta 1 and platelet-derived growth factor (PDGF) are released into the fracture hematoma by the platelet inflammatory cells. TGF-Beta 1 and PDGF appear to have an influence on the initiation of fracture repair and the formation of cartilage and intramembraneous bone in the initiation of callus formation (4). Thiede et al noted that osteocalcin
Table 1 Examples of thrombocytopenia of hip and knee within 72 h post-op Patient
#1
#2
#3
#4
#5
Mean
Platelets pre-op * 1000
166
180
251
230
306
226.6
Platelets post-op (72 h)
79
98
190
161
232
152
Difference
87
82
61
69
74
74.6
Drop from pre-op
52.41%
45.56%
24.30%
30.00%
24.18%
32.92%
Date received 1 May 1996 Date accepted 24 October 1996
15
16
MEDICAL HYPOTHESES
messenger RNA (ocmRNA) is found in megakaryocytes and peripheral blood platelets (5). The literature denotes an increase in PDGF in acute arthritic joint of rheumatoid arthritis (6) and an increase in PDGF in the coronary sinus with unstable angina (7). As with other body functions, a signal is probably transmitted to the megakaryocyte to produce more platelets and this suggests to me that the platelet produced may be more specific for that particular injury or pathology, i.e. soft tissue or bone. Bass et al noted that megakaryocytes ploidy is increased in human coronary atherosclerosis and correlates with serum lipids. He hypothesized that hypercholesterolemia may induce increases in megakaryocytes ploidy and enhance the production of hyperfunctional platelets. He also observed that 'Megakaryocyte DNA content is increased in patients with coronary artery atherosclerosis' (8). Martin et al noted that the sudden death of a human being in an accident causes no change in the megakaryocyte. However, one who has a mild coronary infarction will show megakaryocytic change and often a large platelet. The platelet is the single most powerful predictor of reinfarction and death, and the reason for this, I am convinced, is the change to a new large hyper-reactive platelet species in the period before the infarction (9). This suggests to me that the platelet is responding to the pathology and not to the etiology. Stephen Ellis MD of the Cleveland Clinic Foundation, at the 68th Scientific Session of the American Heart Association, suggested that GPllb/llla receptor inhibition (which inhibits platelet activation) may provide prophylaxis in preventing restenosis and subacute thrombosis. Platelet membrane glycoproteins IIb and IIIa participate in the fibrinogen-mediated interaction of platelet membranes with one another and with artificial surfaces. These membrane glycoproteins also appear to play a role in calcium transport across the platelet membrane (10). Angioplasty patients who were treated with abcixmab (ReoPro) were significantly less likely to die or suffer a myocardial infarction (MI), so researchers brought an early halt to a trial called EPILOG
(Evaluation of PTCA to Improve Long-term Outcomes by c7E3 Glycoprotein IIb/IIIa Receptor Blockade). Abcixmab
Abcixmab is a monoclonal antibody fragment that blocks the final common pathway of platelet aggregation involving the platelet GIIb/IIIa receptor. The literature notes that platelets contain the calciumbinding protein calmodulin, which is presumed to function as a carrier in some calcium-regulated processes (11,12). As noted by Schroeder et al in regard to the calcium, it may explain why calcium channel blockers are beneficial prior to cardiac transplant (13). The action of 'calcium channel blockers' including nifedipine, verapamil, and diltiazem, in blocking the transmembrane flux of calcium in response to platelet agonists at least partially explains their inhibition of platelet aggregation and secretion (14). The platelet is known to possess properties involved in clotting PDGF and calcification. It is plausible in effecting repair, and it may also adversely affect that particular tissue. After an MI, coronary artery bypass graft (CABG), or angioplasty, the platelet's provision of PDGF may also result in angiogenesis and an increase in calcium transport. I have observed platelet activity in fracture, bone surgery, CABG, angioplasty with and without stint insertion, acute congestive failure, acute renal shutdown and malignancy. Some examples of nonosseous pathology are given below and the patients' respective platelet levels in Table 2. Patient #1. An 81-year-old female with acute congestive failure who underwent aortic valve replacement; Patient #2. A 80-year-old male on whom a CABG was performed; Patient #3. A 71-year-old female who had suffered an MI with cardiac rupture, which was repaired with superglue; Patient #4. A 66-year old male with acute aneuria who underwent dialysis.
Table 2 Platelet levels of four patients with non-osseous pathology Platelets pre admission
Platelets 72 h post op
Platelets post op
Patient #l Patient #2 Patient #3
210 000 214 000 224 000
58 000 99 000 55 000
Patient #4*
83 000
12 days post op: 199 000 9 days post op: 274 000 10 days post op: 512 000 23 days post op: 385 000 23 days post dialysis: 240 000
64 000/dialysis
*Patient #4 was not a surgical patient and underwent only dialysis.
17
THE OMNIPOTENT PLATELET (PART II)
Table 3
Platelets levels of four patients with traumatic injuries
Age
Sex
Platelet count
Days post injury
Diagnosis by subsequent bone scan & X-ray
92 96 74 90
F F F F
649 000 550 000 459 000 544 000
13 days 15 days 13 days 10 days
Fracture of the sacrum Fracture of 2 ribs, 2 vertebrae, sacrum Fracture of sacro-iliac joint Fracture of foot
As with electron spin resonance, a bone scan is indicated if the platelets are increased (10-20 days) following injury with ongoing pain and a negative X-ray. I have observed this in ten patients over the past three years. The four patients shown in Table 3 were admitted to hospital with traumatic injuries. X-ray on admission was negative in involved areas. During the 10-15 day period post injury, the platelets elevated. At that time, a bone scan and repeat X-ray were performed and the patient was found to be positive for fracture.
3.
4. 5.
6.
Conclusions 1. The number of platelets in response to acute injury or pathology can mimic the sedimentation rate. 2. The response may not always be beneficial, especially with soft tissue. 3. The increase in thrombocytosis and prolonged thrombocytosis suggests prognosis. 4. Persistent pain following injury and despite a negative X-ray with thrombocytosis (10-20 days) is indicative of fracture. 5. The literature continues to contain many reports of these various platelet activities. 6. The question remains of whether the Ghon complex of tuberculosis, microcalcification of breast, calcific tendonitis and calcification in blood vessels is related to platelet response.
7. 8. 9. 10. 11.
12. 13.
References 14. 1. Steinberg L. The omnipotent platelet. Medical Hypotheses 1996; 46: 188-190. 2. Thuruer R L, Lytle B W, Cosgrove D M, Loop F D. Auto-
transfusion following cardiac operations: a randomized, prospective study. Ann Thorac Surg 1979; 27(6): 500-507. Warkentin T E, Levine M N, Hirsh J e t al. Heparin-induced thombocytopenia in patients treated with low-molecular weight heparin or unfractioned heparin. N Engl J Med 1995; 332: 1330-1335. Bolander M E. Regulation of fracture repair by growth factors. Dept of Orthopedics, Mayo Clinic, Rochester MN. Proc Soc Exp Biol Med 1992; 200(2): 165-170. Thiede M A, Smock S L, Petersen D N e t al. Department of Cardiovascular and Metabolic Diseases. Central Research Div, Pfizer Inc., Presence of Messenger Ribonucleic Acid Encoding Osteocalcin, a Marker of Bone Turnover. In: Bone Marrow Megakaryocytes and Peripheral Blood Platelets. Endocrinology 1994; 135(3): 929-937. Weissbarthe E, Baruth B, Mielke H, Liman W, Deicher H. Platelets as target cells in rheumatoid arthritis and systemic lupus erythematosus: a platelet specific immunoglobulin inculding the release factor. Rheumatol Int 1982; 2: 67-73. Ogawa H, Ogawa A, Yasue H et al. Plasma platelet derived growth factor levels in unstable angina pectoris. Am J Cardiol 1992; 69: 453-456. Bath P N, Gladwin AM, Carden N, Martin J F. Megakaryocyte DNA content is increased in patients with coronary artery atherosclerosis. Cardiovasc Res 1994; 8: 1348-1352. Martin J F, Bath P M W, Burr M L. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409-1411. Bennett J S, Vilalre G. Exposure of platelet flbrinogen receptors by ADP and epinephrine. J Clin Invest 1979; 64: 1393. Young N H, Crawford N. Isolation from blood platelets and polymorph of a Ca2+-dependent regulator protein (CDR) which activates cyclic nucleotide phosphodiesterase. Thromb Haemostas 1979; 42: 81. Levine S N, Steiner A L, White K G C II. Identification and distribution of the calcium-dependent regulator protein in human platelet preparations. Thumb Haemostas 1979; 42:81. Shroeder J S. Calcium blockade prevents coronary artery disease. Stamford University Study presented at the Joint 12th World Congress of Cardiology and the 15th Congress of the European Society of Cardiology, 1994. Ware J A, Johson P C, Smith M, Salzman E W. Inhibition of platelet aggregation and cytoplasmic calcium response by calcium antagonists: studies with aequorin and quin 2. Circ Res 1986; 59: 39-42.