When fasting (meaning, in this case, not eating any carbohydrates), the pancreas releases a polypeptide hormone, glucagon, that stimulates gluconeogenesis in the liver (1). Glucagon functions via a regulating bifunctional enzyme (1). The enzyme dephosphorylated acts as phophofructokinase-2 (PFK-2) and glucagon induces phosphorylation to produce fructose bisphosphatase-2 (FBPase-2) (1). The suppression of PFK-2 and increased activity of FBPase-2 reduces concentration of fructose 2,6-biphosphate (1).
Fructose 2,6-biphosphate’s presence regulates glycolysis and gluconeogenesis (1). It is the key positive modulator for glycolytic enzyme phophofructokinase (PFK) (not same as PFK-2), and PFK’s increased activity stimulates glycolysis by suppressing activity of fructose biphophatase (not same as FBase-2) (1). The reduced presence of fructose 2,6-biphosphate and, thus, increased activity of gluconeogenesis restores blood glucose levels successfully (1).
Phew! Now on to dessert.
In response to restored blood glucose levels from gluconeogenesis or when breaking a fast, the picture is reversed. The presence of glucose stimulates the pancreas to release insulin (1). Insulin reduces fructose 2,6-biphosphate via dephosphorylation of phosphofructokinase-2, and positively affects activity of glycogen synthase (also through dephosphorylation) stimulating glycogenesis (1).
So just remember, dessert equals dephosphorylation and phasting equals phosphorylation!
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
Saturday, February 28, 2009
Sunday, February 22, 2009
Why can't we convert fat to glucose?
As evident by many sugar-laden soda pop "potbellies" of North America, lipogenesis can obviously occur from drinking and eating too much sugar (1). Wouldn’t it be just grand to reverse the process and be able to lose all that fat via gluconeogenesis? Unfortunately mammals do not have the ability to synthesize glucose from fats (1).
The fact is that once glucose is converted to acetyl coA there is no method of getting back to glucose. The pyruvate dehydrogenase reaction that converts pyruvate to acetyl CoA is not reversible (1p252). Because lipid metabolism produces acetyl CoA via beta-oxidation, there can be no conversion to pyruvate or oxaloacetate that may have been used for gluconeogenesis (1p252). Further, the two carbons in the acetyl CoA molecule are lost upon entering the citric acid cycle (1p252). Thus, the acetyl CoA is used for energy (1p252).
There are some fatty acids that have an odd number of carbon atoms that can be converted to glucose, but these are not common in the diet (1p253). Maybe they should be made more common. Do they taste good?
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
The fact is that once glucose is converted to acetyl coA there is no method of getting back to glucose. The pyruvate dehydrogenase reaction that converts pyruvate to acetyl CoA is not reversible (1p252). Because lipid metabolism produces acetyl CoA via beta-oxidation, there can be no conversion to pyruvate or oxaloacetate that may have been used for gluconeogenesis (1p252). Further, the two carbons in the acetyl CoA molecule are lost upon entering the citric acid cycle (1p252). Thus, the acetyl CoA is used for energy (1p252).
There are some fatty acids that have an odd number of carbon atoms that can be converted to glucose, but these are not common in the diet (1p253). Maybe they should be made more common. Do they taste good?
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
When to use a ketogenic diet
Normally what you need before you can start up aerobic respiration in the mitochondria is a multienzyme complex known as pyruvate dehydrogenase complex—of which the main enzyme is pyruvate decarboxylase. The complex acts on pyruvate, produced from glycolysis, in an oxidative decarboxylation reaction to produce acetyl-coA, which then enters the citric acid cycle (1).
What happens when pyruvate dehydrogenase is deficient? An actual genetic deficiency is rare, but it is the most common mitochondria-associated neurodegenerative disorder (2). When it does occur it significantly effects energy metabolism, poor use of glucose and build-up of lactic acid (2). Along with probable neurological impairments, too much glucose can exacerbate the problem leading to hyperglycemia and diabetes (2).
Diabetics , in essence, can also be described as a condition where pyruvate dehydrogenase complex activity is reduced(3-5). The lack of insulin to bring glucose into cells may be a factor, leading to little activity, or a nutritional deficiency of a vitamin such as thiamine (vitamin B-1) due to poor diet or starvation may lead to decreased production of the complex (3-5). In these cases, just as genetic deficiency, inefficient use of glucose results in hyperglycemia.
A ketogenic diet is used to manage the disease of pyruvate dehydrogenase deficiency (2). And it’s important to understand why this higher-fat, adequate protein, low-carb diet works for possible use with diabetes. It is because production of acetyl-coA can come from lipid metabolism via beta-oxidation as well as from amino acids isoleucine, lysine, phenylalanine, tyrosine and leucine (other amino acids are formed into pyruvate) (1p252).
There is plenty of research available showing that a ketogenic diet can help to control blood sugar (6-10). As a short-term therapy, the diet has had success even with children with Type II diabetes (11). But what of the side effects? As we know from critiques of the Atkin’s diet, a ketogenic diet produces fast weight loss through polyuria, but comes back with water retention from refeeding of carbohydrates (12) . The diet increases plasma cholesterol, uric acid, and may even cause hypokalemia (12). Further, you suffer nausea, fatigue, and hypotension (12). One must weigh the goods and bads of a ketogenic diet and make modifications as necessary.
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Henwood MJ, Thornton PS, Preis CM, Chee C, Grimberg A. Reconciling diabetes management and the ketogenic diet in a child with pyruvate dehydrogenase deficiency. J Child Neurol 2006;21:436-9.
3. Koivisto VA, Yki-Jarvinen H. Changes in muscle glucose metabolism in type 1 diabetes. Ann Med 1990;22:201-5.
4. Beltramo E, Berrone E, Tarallo S, Porta M. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol 2008;45:131-41.
5. Hutson NJ, Kerbey AL, Randle PJ, Sugden PH. Regulation of pyruvate dehydrogenase by insulin action. Prog Clin Biol Res 1979;31:707-19.
6. Westman EC, Yancy WS, Jr., Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond) 2008;5:36.
7. Feinman RD, Makowske M. Metabolic syndrome and low-carbohydrate ketogenic diets in the medical school biochemistry curriculum. Metab Syndr Relat Disord 2003;1:189-97.
8. Nuttall FQ, Schweim K, Hoover H, Gannon MC. Effect of the LoBAG30 diet on blood glucose control in people with type 2 diabetes. Br J Nutr 2008;99:511-9.
9. Dashti HM, Mathew TC, Khadada M et al. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem 2007;302:249-56.
10. Henwood MJ, Thornton PS, Preis CM, Chee C, Grimberg A. Reconciling diabetes management and the ketogenic diet in a child with pyruvate dehydrogenase deficiency. J Child Neurol 2006;21:436-9.
11. Willi SM, Martin K, Datko FM, Brant BP. Treatment of type 2 diabetes in childhood using a very-low-calorie diet. Diabetes Care 2004;27:348-53.
12. Hirschel B. [Dr. Atkins' dietetic revolution: a critique]. Schweiz Med Wochenschr 1977;107:1017-25.
What happens when pyruvate dehydrogenase is deficient? An actual genetic deficiency is rare, but it is the most common mitochondria-associated neurodegenerative disorder (2). When it does occur it significantly effects energy metabolism, poor use of glucose and build-up of lactic acid (2). Along with probable neurological impairments, too much glucose can exacerbate the problem leading to hyperglycemia and diabetes (2).
Diabetics , in essence, can also be described as a condition where pyruvate dehydrogenase complex activity is reduced(3-5). The lack of insulin to bring glucose into cells may be a factor, leading to little activity, or a nutritional deficiency of a vitamin such as thiamine (vitamin B-1) due to poor diet or starvation may lead to decreased production of the complex (3-5). In these cases, just as genetic deficiency, inefficient use of glucose results in hyperglycemia.
A ketogenic diet is used to manage the disease of pyruvate dehydrogenase deficiency (2). And it’s important to understand why this higher-fat, adequate protein, low-carb diet works for possible use with diabetes. It is because production of acetyl-coA can come from lipid metabolism via beta-oxidation as well as from amino acids isoleucine, lysine, phenylalanine, tyrosine and leucine (other amino acids are formed into pyruvate) (1p252).
There is plenty of research available showing that a ketogenic diet can help to control blood sugar (6-10). As a short-term therapy, the diet has had success even with children with Type II diabetes (11). But what of the side effects? As we know from critiques of the Atkin’s diet, a ketogenic diet produces fast weight loss through polyuria, but comes back with water retention from refeeding of carbohydrates (12) . The diet increases plasma cholesterol, uric acid, and may even cause hypokalemia (12). Further, you suffer nausea, fatigue, and hypotension (12). One must weigh the goods and bads of a ketogenic diet and make modifications as necessary.
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Henwood MJ, Thornton PS, Preis CM, Chee C, Grimberg A. Reconciling diabetes management and the ketogenic diet in a child with pyruvate dehydrogenase deficiency. J Child Neurol 2006;21:436-9.
3. Koivisto VA, Yki-Jarvinen H. Changes in muscle glucose metabolism in type 1 diabetes. Ann Med 1990;22:201-5.
4. Beltramo E, Berrone E, Tarallo S, Porta M. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol 2008;45:131-41.
5. Hutson NJ, Kerbey AL, Randle PJ, Sugden PH. Regulation of pyruvate dehydrogenase by insulin action. Prog Clin Biol Res 1979;31:707-19.
6. Westman EC, Yancy WS, Jr., Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond) 2008;5:36.
7. Feinman RD, Makowske M. Metabolic syndrome and low-carbohydrate ketogenic diets in the medical school biochemistry curriculum. Metab Syndr Relat Disord 2003;1:189-97.
8. Nuttall FQ, Schweim K, Hoover H, Gannon MC. Effect of the LoBAG30 diet on blood glucose control in people with type 2 diabetes. Br J Nutr 2008;99:511-9.
9. Dashti HM, Mathew TC, Khadada M et al. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem 2007;302:249-56.
10. Henwood MJ, Thornton PS, Preis CM, Chee C, Grimberg A. Reconciling diabetes management and the ketogenic diet in a child with pyruvate dehydrogenase deficiency. J Child Neurol 2006;21:436-9.
11. Willi SM, Martin K, Datko FM, Brant BP. Treatment of type 2 diabetes in childhood using a very-low-calorie diet. Diabetes Care 2004;27:348-53.
12. Hirschel B. [Dr. Atkins' dietetic revolution: a critique]. Schweiz Med Wochenschr 1977;107:1017-25.
Focusing on the heart of the No. 1 and No. 3 killer
Almost half of us will die of a heart attack or stroke; in fact, it’s likely many of us have been developing a type of cardiovascular disease already (1). Just being male increases your risk, and if you happen to be a male, sedentary, obese smoker then you’re in real trouble (1). Adding these risk factors up doesn’t triple your chances, it multiplies them seven-fold (1)!
In light of American Heart Month, don’t forget to donate to cardiovascular disease research—spend with a clear conscience for clear arteries—but although the American Heart Association badly needs your funding, your cash is best suited for a pair of tennis shoes (1).
The conclusion on getting a heart attack is that the problem isn’t the heart, and in stroke, the brain isn’t at fault either (1). By far the greatest culprit is the accumulated thickening of thick sludge in scattered patches in your blood vessels that eventually merge to form large plaques (1). These atheromas represent atherosclerosis (1).
There’s no sign to us that plaque development is occurring (1). We feel no pain or any other symptoms (1). But our blood vessels are narrowing, called stenosis, more and more as they become hardened, due to calcification, and obstructed (1). The volume of blood delivered to tissues lessens (1). Eventually you might notice skin wounds heal slowly especially in the legs, and reduced blood flow to the brain is causing memory loss and confusion (1). The narrowing will sap your energy and ischemic heart disease results (1). Elevated blood pressure from hypertension worsens the problem and taxes the heart (1).
As blood swirls around plaque, splashing up against vessel walls, resulting endothelial damage might lead to a thromboembolic event (1). As platelets activate as well as a cascade of coagulation, an internal blood clot, or thrombus, can narrow the lumen further and consolidate the stenosis and ischemia (1). Another possibility is an aneurysm from blood flow pushing out a weakened vessel wall like a balloon (1). Usually thrombosis is the final case of fatal myocardial infarction (1).
Where hyperlipidemia, if you are obese, and hypercholesterolemia play roles are in contributing ingredients of plaque (1). LDL cholesterol makes multiple contributions to plaque development (1). When it is oxidized by free radicals and taken up by smooth muscle and macrophages, it leaves fats (intended to go to muscle and adipose tissue) to create foam cells that create thickening (1). The oxidized LDL then causes stimulation of plaque through growth factor production, promoting connective tissue desposition, and attracting monocytes that adhere to and modify endothelial surface (1). Further the LDL itself damages the endothelium causing inflammation (1).
In diabetes, sugars that circle LDL and bind to it in a process known as glycation then allows LDL to easily bind to endothelia (1). This in effect leads to more aggressive attraction of macrophages and promotion of connective tissue deposition enlarging the atheroma and inactivating nitric oxide, which is necessary for vasodilation (1).
When smoking, carbon monoxide that replaces oxygen in hemoglobin, causing hypoxia may also be atherogenic by promoting smooth muscle proliferation and LDL accumulation (1). Plus, the nicotine has vasoconstrictive effects, narrowing blood vessels further (1).
Reducing risk factors is the solution. In conclusion, by knowing more about how cardiovascular disease develops, we can help to prevent heart attacks and stroke. While lowering cholesterol is not justified by scientific research, reducing calories to avoid obesity is strongly supported, more so when saturated fat is reduced. Stopping the cigarette habit helps, and so does keeping blood pressure in check (1). Getting in shape, even with moderate exercise, by far can quickly yield results including a reduced heart rate of 10 beats a minute saving your heart more than 5 million beats a year that cause wear and tear (1). The goal is to avoid developing atherosclerosis further and leading a longer, healthier life.
Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
In light of American Heart Month, don’t forget to donate to cardiovascular disease research—spend with a clear conscience for clear arteries—but although the American Heart Association badly needs your funding, your cash is best suited for a pair of tennis shoes (1).
The conclusion on getting a heart attack is that the problem isn’t the heart, and in stroke, the brain isn’t at fault either (1). By far the greatest culprit is the accumulated thickening of thick sludge in scattered patches in your blood vessels that eventually merge to form large plaques (1). These atheromas represent atherosclerosis (1).
There’s no sign to us that plaque development is occurring (1). We feel no pain or any other symptoms (1). But our blood vessels are narrowing, called stenosis, more and more as they become hardened, due to calcification, and obstructed (1). The volume of blood delivered to tissues lessens (1). Eventually you might notice skin wounds heal slowly especially in the legs, and reduced blood flow to the brain is causing memory loss and confusion (1). The narrowing will sap your energy and ischemic heart disease results (1). Elevated blood pressure from hypertension worsens the problem and taxes the heart (1).
As blood swirls around plaque, splashing up against vessel walls, resulting endothelial damage might lead to a thromboembolic event (1). As platelets activate as well as a cascade of coagulation, an internal blood clot, or thrombus, can narrow the lumen further and consolidate the stenosis and ischemia (1). Another possibility is an aneurysm from blood flow pushing out a weakened vessel wall like a balloon (1). Usually thrombosis is the final case of fatal myocardial infarction (1).
Where hyperlipidemia, if you are obese, and hypercholesterolemia play roles are in contributing ingredients of plaque (1). LDL cholesterol makes multiple contributions to plaque development (1). When it is oxidized by free radicals and taken up by smooth muscle and macrophages, it leaves fats (intended to go to muscle and adipose tissue) to create foam cells that create thickening (1). The oxidized LDL then causes stimulation of plaque through growth factor production, promoting connective tissue desposition, and attracting monocytes that adhere to and modify endothelial surface (1). Further the LDL itself damages the endothelium causing inflammation (1).
In diabetes, sugars that circle LDL and bind to it in a process known as glycation then allows LDL to easily bind to endothelia (1). This in effect leads to more aggressive attraction of macrophages and promotion of connective tissue deposition enlarging the atheroma and inactivating nitric oxide, which is necessary for vasodilation (1).
When smoking, carbon monoxide that replaces oxygen in hemoglobin, causing hypoxia may also be atherogenic by promoting smooth muscle proliferation and LDL accumulation (1). Plus, the nicotine has vasoconstrictive effects, narrowing blood vessels further (1).
Reducing risk factors is the solution. In conclusion, by knowing more about how cardiovascular disease develops, we can help to prevent heart attacks and stroke. While lowering cholesterol is not justified by scientific research, reducing calories to avoid obesity is strongly supported, more so when saturated fat is reduced. Stopping the cigarette habit helps, and so does keeping blood pressure in check (1). Getting in shape, even with moderate exercise, by far can quickly yield results including a reduced heart rate of 10 beats a minute saving your heart more than 5 million beats a year that cause wear and tear (1). The goal is to avoid developing atherosclerosis further and leading a longer, healthier life.
Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
Saturday, February 21, 2009
Contraceptive use and increased risk of thrombosis?
It's interesting to note that contraceptives can increase risk of thrombosis. A report in 1980 showed that two women who died of myocardial infarction did not smoke or have hyperlipidemia, hypertension or atherosclerosis; the only connection was an oral contraceptive (1). I'd like to learn more about why this would happen.
1. Loire R, Touboul P, Gressard A, Rondepierre D, Tabib A. [Oral contraceptive and coronary thrombosis. Two clinicopathological cases]. Arch Mal Coeur Vaiss 1980;73:432-7.
1. Loire R, Touboul P, Gressard A, Rondepierre D, Tabib A. [Oral contraceptive and coronary thrombosis. Two clinicopathological cases]. Arch Mal Coeur Vaiss 1980;73:432-7.
Anticoagulants a factor for thrombosis?
Next time you're on a long car trip, check your legs to see if one is redder or warmer than the other. Or if your calf or thigh begins to ache. These could be symptoms of deep vein thrombosis, especially if you're genetically predisposed. Inactivity can cause the condition and blood thinners like heparin or warfarin are generally used as treatment (1).
But while we understand that hypercoagulation can be a factor for thrombosis, it’s important to note that anticoagulants can also potentially cause thrombosis. Oral anticoagulants can increase severity of bleeding, which can exacerbate intracerebral hemorrhage leading to significantly higher risk of a thromboembolic events (2).
Exercise and take your fish oil softgels!
References
1. WebMD. Deep vein thrombosis: Topic overview. Available at: http://www.webmd.com/heart-disease/tc/deep-vein-thrombosis-topic-overview.
2. Goldstein JN, Fazen LE, Wendell L et al. Risk of thromboembolism following acute intracerebral hemorrhage. Neurocrit Care 2009;10:28-34.
But while we understand that hypercoagulation can be a factor for thrombosis, it’s important to note that anticoagulants can also potentially cause thrombosis. Oral anticoagulants can increase severity of bleeding, which can exacerbate intracerebral hemorrhage leading to significantly higher risk of a thromboembolic events (2).
Exercise and take your fish oil softgels!
References
1. WebMD. Deep vein thrombosis: Topic overview. Available at: http://www.webmd.com/heart-disease/tc/deep-vein-thrombosis-topic-overview.
2. Goldstein JN, Fazen LE, Wendell L et al. Risk of thromboembolism following acute intracerebral hemorrhage. Neurocrit Care 2009;10:28-34.
What are the factors leading up to thrombosis?
When a blood vessel is injured, a coagulation cascade is activated to form an organized clot to retain moisture and begin a healing process. Unlike a clot, a thrombus occurs in the blood vessel as a result of endothelial damage, altered blood flow or a hypercoagulation state that triggers platelet activation and a coagulation cascade (1). About one in 1,000 adults develop thrombosis annually (2).
Endothelial damage
Contributing to risk of thrombosis, endothelial damage can occur from hemodynamic stress (normal wear and tear). Hemodynamic stress is accentuated by conditions such as hypertension or infection (1). The stress eventually strips away endothelial cells exposing subendothelial collagen (1). This may occur, for example, on endocardial surface (1). The change can lead to platelet adherence, activation, aggregation and eventually a thrombus (1). Endothelial damage may occur from iatrogenic disease (a disease result of medical or surgical intervention) such as can be caused by an intravenous needle. Endothelial damage can also occur from trauma such as from an auto accident, a fall, or by radiation, high cholesterol or smoking (1).
Altered blood flow
The abnormal pattern of blood flow leads to thrombosis because it increases platelet contact with endothelium (1). It can occur from reduction in rate or turbulence, principally caused by cardiac damage or increased blood viscosity (1). At times, also, reduced venous blood flow is due to weakened vein walls, varicose veins, which disrupts functioning of leaflet valves (1). A malformed heart can cause blood flow turbulence that may create a thrombus in a cardiac chamber, called a mural thrombus (1). Lastly, a tumor causing inflammation or swelling can compress a vessel causing turbulence (1). Increased pressure from arterial pressure can eventually push out a weakened arterial wall causing a pouchlike bulge called an aneurysim (1). Blood swirls into the aneurism, platelets smash against the endothelium and thrombosis follows (1).
Blood Hypercoagulation
Hypercoagulation is suspected when turbulent blood flow or endothelial damage don’t appear the case in thrombosis (1). Genetic defects can lead to malfunction and overproduction of coagulation promoters or lack of coagulation inhibitors (1). A deficiency, for example of PG-I(2), a coagullaation inhibitor, leads to the liver overproducing clotting factors (1). Those with such “thrombophilic disorders” can applaud the discovery of factor V Leiden since its occurrence is most common in these disorders and subject to intense research (3).
Other Risk factors
Apart from genetic predisposition, thrombosis risk increases with advancing age, being male, being obese, after surgery, trauma, cancer, immobilization, pregnancy and exogenous hormones (2;4).
Consequences
The sequela of thrombosis can resolve itself by being broken down or reduced, with the help of moderate exercise and cardiopulmonary fitness (1). A second consequence is organization where phagocytic digestion a couple or more days after the thrombus forms and with platelets and fibrin replaced by connective tissue; essentially the thrombus becomes part of the the vessel wall with endothelium formed over it and recanalization allows blood to flow through the thrombus (1). Propagation may occur when a thrombus enlarges, extends and continued coagulation produces a red cap that extends a significant distance (1). The major consequence is infarction, when ischemia forms a region of necrosis that completely occludes the lumen of a vessel (1). Infarction mainly can occur due to tissue vulnerability to hypoxia, pattern of vascular supply, capacity of oxygen delivery and the rate of occlusion (1).
Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol 2007;44:62-9.
3. Cushman M. Inherited risk factors for venous thrombosis. Hematology Am Soc Hematol Educ Program 2005;452-7.
4. Olson N, O'Meara ES, Jenny NS et al. Lipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults. Am J Hematol 2008;83:524-7.
Endothelial damage
Contributing to risk of thrombosis, endothelial damage can occur from hemodynamic stress (normal wear and tear). Hemodynamic stress is accentuated by conditions such as hypertension or infection (1). The stress eventually strips away endothelial cells exposing subendothelial collagen (1). This may occur, for example, on endocardial surface (1). The change can lead to platelet adherence, activation, aggregation and eventually a thrombus (1). Endothelial damage may occur from iatrogenic disease (a disease result of medical or surgical intervention) such as can be caused by an intravenous needle. Endothelial damage can also occur from trauma such as from an auto accident, a fall, or by radiation, high cholesterol or smoking (1).
Altered blood flow
The abnormal pattern of blood flow leads to thrombosis because it increases platelet contact with endothelium (1). It can occur from reduction in rate or turbulence, principally caused by cardiac damage or increased blood viscosity (1). At times, also, reduced venous blood flow is due to weakened vein walls, varicose veins, which disrupts functioning of leaflet valves (1). A malformed heart can cause blood flow turbulence that may create a thrombus in a cardiac chamber, called a mural thrombus (1). Lastly, a tumor causing inflammation or swelling can compress a vessel causing turbulence (1). Increased pressure from arterial pressure can eventually push out a weakened arterial wall causing a pouchlike bulge called an aneurysim (1). Blood swirls into the aneurism, platelets smash against the endothelium and thrombosis follows (1).
Blood Hypercoagulation
Hypercoagulation is suspected when turbulent blood flow or endothelial damage don’t appear the case in thrombosis (1). Genetic defects can lead to malfunction and overproduction of coagulation promoters or lack of coagulation inhibitors (1). A deficiency, for example of PG-I(2), a coagullaation inhibitor, leads to the liver overproducing clotting factors (1). Those with such “thrombophilic disorders” can applaud the discovery of factor V Leiden since its occurrence is most common in these disorders and subject to intense research (3).
Other Risk factors
Apart from genetic predisposition, thrombosis risk increases with advancing age, being male, being obese, after surgery, trauma, cancer, immobilization, pregnancy and exogenous hormones (2;4).
Consequences
The sequela of thrombosis can resolve itself by being broken down or reduced, with the help of moderate exercise and cardiopulmonary fitness (1). A second consequence is organization where phagocytic digestion a couple or more days after the thrombus forms and with platelets and fibrin replaced by connective tissue; essentially the thrombus becomes part of the the vessel wall with endothelium formed over it and recanalization allows blood to flow through the thrombus (1). Propagation may occur when a thrombus enlarges, extends and continued coagulation produces a red cap that extends a significant distance (1). The major consequence is infarction, when ischemia forms a region of necrosis that completely occludes the lumen of a vessel (1). Infarction mainly can occur due to tissue vulnerability to hypoxia, pattern of vascular supply, capacity of oxygen delivery and the rate of occlusion (1).
Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol 2007;44:62-9.
3. Cushman M. Inherited risk factors for venous thrombosis. Hematology Am Soc Hematol Educ Program 2005;452-7.
4. Olson N, O'Meara ES, Jenny NS et al. Lipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults. Am J Hematol 2008;83:524-7.
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