Blood Clotting…and Not Clotting

Over a gallon of blood circles your body every 45 seconds, under pressure, in a network of arteries, veins and capillaries. Any leaks in the system must be plugged and repaired. Some ruptures are emergencies requiring outside help, but most are fixed handily by a well calibrated system of physical and chemical reactions in your body. You watch this process every time you cut yourself shaving or slicing tomatoes, but it also happens microscopically, all over your body, when blood vessels are damaged internally by trauma or infection or chronic degenerative changes in the walls of arteries.

How clotting happens

Hemostasis, the first step in controlling bleeding, involves mechanical measures like pressure, cautery or stitches to stop blood flow from damaged blood vessels. Hemostasis alone is ineffective and must to be accompanied by blood clotting, a process triggered by blood platelets, which are tiny little disc shaped cell fragments that accumulate at the site of blood vessel injury. About a trillion platelets circulate in the blood, speeding by over 10,000 square feet endothelial cells that line the inside walls of blood vessels. When damage exposes collagen and other proteins in the endothelial cells and surrounding tissues, platelets gather to plug the defect, while secreting chemicals that draw white blood cells to the scene. An orderly sequence of chemical reactions, known as the clotting cascade, then produces in a stringy mass of sticky protein called fibrin, which fills the gaps between the platelets. Over the next few days to weeks, as healing proceeds, the clot gradually dissolves and disappears in a process called lysis. Your scab falls off to reveal new skin underneath.

Balance between clotting and not clotting

Blood also must not clot to carry out its normal function of transporting oxygen and carbon dioxide and nutrients and waste. If blood clots occur inside blood vessels, they block blood flow and cause damage in surrounding tissues. Health problems like strokes and heart attacks, and clots in the heart, lungs and leg veins occur because local conditions like inflammation and slow blood flow trigger the clotting process. For example, when atrial fibrillation causes failure of atrial pumping, blood pools in the recesses of the upper chambers of the heart and clots may form. Slow and turbulent blood flow in arteries narrowed by inflamed cholesterol plaques sets off the clotting process. Immobilization, bed rest or even prolonged sitting can promote clot formation in the leg veins.

Manipulation of the clotting system

Health problems like these, as well as the need to hasten clotting in some medical situations, drive attempts to manipulate the clotting system. Infusions of platelets and other blood products correct bleeding in the operating room and in medical conditions that lead to poor clotting, but, more commonly, medical problems require suppressing the blood clotting response. Most people are familiar with anti-clotting drugs, called “anticoagulants,” that interfere with one or more of the chemical processes in the clotting cascade. They are used for common heart problems like atrial fibrillation, leg vein clots and after heart valve replacements to prevent the foreign valve materials from triggering clotting. Most people are also familiar with “antiplatelet” drugs like aspirin used to help prevent heart attacks and strokes by interfering with the ability of platelets to start the clotting process.

Pharmacological aid in breaking down clots

A third type of intervention employing “thrombolytic” drugs aims to dissolve clots that have already formed.Thrombolytic drugs are used in hospitals, in the acute setting of clots that have caused heart attacks and strokes. When injected into arteries, they dissolve clot and restore blood flow though the problem area of the blood vessel that triggered the clotting process, or through an artery in the brain that has been suddenly blocked by a clot that traveled there from the heart.

Blood “thinners”

Anticoagulant drugs are often incorrectly called blood thinners, but they do not change the thickness of blood. They block reactions in the clotting cascade. Heparin, when injected intravenously, causes the most direct and immediate interference, so doctors opt for this choice (or other similar drugs if a patient is allergic to heparin) when stopping clot formation is urgent. The insertion of an artificial heart valve, which will trigger clot formation on its surface, the presence of leg clots which may break off and travel to the lungs, or the onset of atrial fibrillation call for prompt blocking of clot formation, while the transition is made to oral anticoagulant drugs.

Oral anticoagulant drugs take a few days to slow the speed of blood clotting. Of the oral drugs available for blocking clotting, coumadin is the oldest and most frequently used because its anticoagulant effects can be stopped quickly, if necessary. The ability to reverse anti-clotting effects is important if the anticoagulated patient develops a bleeding problem or is at risk of falling or other injury. Coumadin’s effects are reversed by intravenous injection of Vitamin K. People taking coumadin must have their blood checked regularly to monitor the rate at which the blood clots, and adjust doses accordingly. Other newer oral anticoagulants are popular because they do not require testing, but are more expensive and their effects cannot be reversed as quickly. Intramuscular drugs are available for home use, usually when anticoagulation is a temporary treatment.

Drugs that make platelets less sticky

Antiplatelet drugs like aspirin and persantin are often prescribed to prevent clot formation in the coronary arteries, though the evidence about their benefits is mixed. Far more common, however, is the unsuspected antiplatelet effect encountered by people using many over the counter products, particularly non-steroidal anti-inflammatory drugs (NSAIDS) used for pain, and some supplements like fish oil. Aspirin and NSAIDS are implicated in stomach bleeding episodes and in heavy menstrual bleeding.

In addition to its role in repairing leaks and keeping blood running freely through the vast network of blood vessels in the body, the complex chemistry of the blood clotting system is revealing itself to be intricately involved in other aspects healing and in immune-mediated inflammatory states (such as COVID-19). The attempt to immunize against the SARS-COV2 virus has also focused attention on blood clotting, with the antigen chosen to stimulate antibody formation triggering serious adverse events involving both clotting and bleeding, as well as unsuspected clot formation in very small blood vessels. Knowledge is accumulating rapidly and, as it does, expect to see blood platelets revealed as much more than pieces of cells used to plug holes and the clotting system more closely related to the inflammatory system.

Posted by medical plaintalk

Physician turned medical writer.

Iron: Too Little and Too Much

Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy.
Paracelsus. Swiss-German physician (1493-1541)

Iron is present in abundant quantities in the earth’s core and crust, in the sun, the stars and meteorites – and inside all living things. In humans, iron carries oxygen to all the body’s cells, carries carbon dioxide back to the lungs, enables many chemical reactions related to energy production, and binds oxygen inside for use in muscle cells. It is a vital nutrient – a substance that must be part of the diet, but also one which the body cannot excrete except by losing blood and skin cells. Both too little iron and too much iron present us with problems.

Where the body puts iron

Iron is absorbed from food in the upper part of the small intestine. Specialized proteins
carry it in the blood and store it in the liver and other organs. Ten percent of total body
iron is attached to myoglobin in muscles, 25 percent is stored in the liver and in specialized cells throughout the body, and the major portion, 65 percent, is bound to hemoglobin inside red blood cells. Hemoglobin-bound iron is constantly recycled as old red blood cells are destroyed and new ones are made.

Iron absorption from food – a tightly regulated process

Iron must be bound to proteins or it excites free radical damage in cells. When all of the protein binding sites for hemoglobin in the body are filled, the liver sends a signal to the small intestine to decrease the amount of iron taken in from food. This regulation of iron absorption is a very sensitive and tightly regulated process in which a message is sent to the intestines conveying how much iron is already in the body. That amount determines how much or how little iron is absorbed from food. This feedback loop is necessary because, beyond minor blood loss and regular shedding of skin and bowel cells, the body has no way to get rid of extra iron. Most health problems related to iron come from too little iron in the diet, from too much iron, delivered intravenously in the form of blood transfusions, or from genetic defects in the feedback loop that tells the intestines how much iron to take in.

Too Little Iron

Deficiency of iron in the body causes weakness, fatigue, and shortness of breath because of inability to carry enough oxygen in the blood and failure to produce required energy. Skin and nail beds are pale because mature red blood cell production is limited (iron deficiency anemia). Dizziness and fainting upon standing up can occur.
Iron deficiency comes about because dietary iron is insufficient to make up normal losses of iron through menstrual blood loss , or abnormal losses that might occur chronically, such as from an unsuspected stomach inflammation, an intestinal tumor or abnormally heavy menstrual bleeding.

Who becomes iron deficient?

Dietary iron deficiency is very common, especially in people who restrict calories, avoid meat or have poor diets. Women of childbearing age, children and the elderly of both sexes are the most at risk. Dietary deficiency can also be aggravated by increased need for iron, as in pregnancy and childhood growth. While many foods contain iron, it is better absorbed from animal sources like beef, chicken liver, fish and mollusks than from plant based sources like spinach and beans. Iron absorption also requires an acid environment, which acid relieving drugs block.

Iron deficiency in post-menopausal women or in men of any age group always raises suspicion of low grade, unsuspected blood loss, which usually comes from the gastrointestinal tract. Causes are gastritis (often from use of anti-inflammatory drugs), ulcers, colitis, diverticulitis, tumors and rare vascular malformations are all causes. Black, tarry and metallic smelling stool is often a clue.

Replenishing iron stores

Treatment of iron deficiency requires improving diet and finding and correcting sources of blood loss. Iron is better absorbed by the stomach from food than it is from pills. Red meat is the best source. But iron supplements are necessary when iron deficiency has caused symptoms. Several different versions of iron supplements may have to be tried – ferrous sulfate is the most commonly prescribed, but can be hard on the stomach. Ferrous gluconate may cause less nausea and stomach upset. Ferrous fumarate contains more iron per pill. The addition of Vitamin C to the diet helps absorption of iron supplements and iron can also be delivered by injection if dietary methods and oral suuplements fail.

Too Much Iron

Iron overload is called hemochromatosis and its symptoms come from damage to the cells in which iron is stored once the normal iron binding proteins can hold no more. The damage is very slow and cumulative and the liver and the heart bear the brunt. Testicles and thyroid gland are also storage sites. Skin storage may cause the patient to look inappropriately tanned, but weakness, lassitude, weight loss, shortness of with breath and abdominal pain typically bring the patient to the doctor.

Transfusion-related iron overload

Hemochromatosis can be caused by repetitive transfusions of blood. Transfusion related hemochromatosis afflicts patients with bone marrow diseases such as myelofibrosis and multiple myeloma. Repeated transfusions are the treatment for severe anemia in these patients and each unit of packed red blood cells delivers enough iron for six months. Iron overload begins to develop quickly.

Hereditary hemochromatosis

Hemochromatosis can also be caused by a genetic problem in which too much iron is absorbed. This hereditary version of hemochromatosis occurs in about 5 in 1000 people in the US. Caucasians are more susceptible than other races. While men and women are affected equally, men typically develop symptoms in their 30s or 40s, a decade or two earlier than women, because women are able to shed iron on a monthly basis until menopause.

Hemochromatosis is treated by regular bleeding, performed in the same way that blood donations are collected. But bleeding is not suitable treatment for patients whose severe anemia is the problem that forces them to receive repeated blood transfusions. The only option for them is chelation of the iron with drugs that bind iron in the blood and carry it out of the body, a difficult and time consuming process, but one that lengthens survival time. A new oral drug may soon make the process easier. At this time in medical history though, using iron as a remedy is easier than treating iron as a poison.

Posted by medical plaintalk

Physician turned medical writer.

Sickle Cell Anemia: Side Effect of the Battle with Malaria

One of the milestones in the history of molecular biology and genetic diseases occurred in 1949, when Lines Pauling ( 1901-1994; 1953 Nobel Prize in Chemistry) discovered that sickle cell anemia, an inherited blood disorder, was caused by a single change in the structure of a single protein in hemoglobin, the complex molecule which carries oxygen in everyone’s red blood cells. For the first time, a hereditary disease was shown to be the result of a miniscule change in DNA that leads cells to make slightly different proteins. In sickle cell anemia, the tiny substitution in the hemoglobin protein changes the way the molecule shapes itself three-dimensionally and this change causes all of the misery and illness associated with sickle cell anemia (also known as sickle cell disease).

Hemoglobin fails to stack and fold itself normally

Hemoglobin molecules carry oxygen from the lungs to the rest of the body, and pick up carbon dioxide to be expelled on the next pass through the lungs. Hemoglobin molecules are stacked neatly inside red blood cells which, under a microscope, look like plump, oval discs, flattened in their mid-sections. To hold and release oxygen and carbon dioxide, the hemoglobin molecules change their shapes, folding and unfolding in response to changes in the acidity of the blood. In sickle cell disease, hemoglobin does not stack neatly or fold correctly, and it distorts the shape of the red blood cells, damaging their membranes. Instead of flattened ovals, red blood cells containing sickle cell hemoglobin assume odd and spiky shapes which are reminiscent of sickles.

Abnormally shaped red blood cells cause trouble

Distorted, sickled red blood cells are shorter-lived than normal red blood cells, causing anemia , or low red blood cell counts, with symptoms of fatigue, weakness and shortness of breath. The abnormally shaped cells also get stuck in small blood vessels of many organs, causing pain and organ damage, and symptoms like strokes, abdominal pain, joint pain and swelling. Episodes of pain and other symptoms are called sickle cell crises, last for about a week, and often require hospitalization and narcotics. The spleen can become severely damaged and non-functional in patients with sickle cell disease. The spleen is an important part of the immune system and, without it, sickle cell patients can be subject to life threatening infections. They require prophylactic antibiotics and careful attention to immunizations. Sickle cell crises are triggered by stress, dehydration, infections and illness and the damage they cause can shorten life. Modern diagnosis and treatment have raised life expectancy of sickle cell patients to over age fifty, an improvement of almost a decade compared to the past. Some babies with sickle cell disease have been successfully treated with bone marrow transplants.

A common genetic trait

In certain parts of the world, 10-40% of the population carry one copy of the mutated gene that codes for the abnormal hemoglobin of sickle cell anemia. Those carriers are said to have sickle cell trait, and they do not suffer from sickle cell disease, which appears only if two copies of the gene are present. But since children get half their genes from each parent, if two carriers of the sickle cell trait get together and have children, the odds are that 25% of their children will be born with two copies of the gene and have sickle cell disease, 25% will have normal hemoglobin, and fifty percent will carry a single copy of the gene, without symptoms. These are the same odds that are associated with other recessive traits, such as blue eyes or red hair, that require two copies of a given gene for expression of the trait carried by the gene.

The trait has an upside – in malaria infections

Why would a genetic trait be so common when it can lead to a disease that causes illness and premature death? The geography associated with sickle cell trait provides one answer. Sickle cell trait is common in groups of people who come from the belt of the earth around the equator where malaria is or was at one time endemic: sub-Saharan Africa, India, the Mediterranean and Arabian Gulf countries, and Central and South America. What is the relationship between malaria and sickle cell trait? The malaria parasite lives in red blood cells, which are full of hemoglobin. The parasite feeds on hemoglobin as a necessary part of its lifecycle. But something about the hemoglobin produced by the abnormal gene makes carriers of the sickle cell trait less likely to succumb to malaria in infancy and less subject to severe malarial symptoms at older ages. The sickle cell trait thus confers a survival advantage on people from malarial regions of the earth, and it has persisted in the population despite the disadvantage it produces when a child inherits two copies of the sickle cell gene. Paradoxically, two copies of the gene do not protect against malarial symptoms because the infection triggers sickle cell crises.

Sickle cell disease affects as many as one in 400-500 of African Americans in the United States, and about 1 in 36,000 Hispanic Americans. About 90,000-100,000 people in the US have the disease. The sickle cell trait is present in one out of every 12 African Americans and one of every 100 Hispanic Americans. In France sickle cell disease is now the leading genetic disease because of emigration from Africa and the Caribbean. Over a long period of time, as these populations live and reproduce in regions where malaria is not a significant threat, the trait may disappear since it will no longer be conferring a survival advantage. In the meantime, researchers hope to better understand how sickle cell hemoglobin tames the malaria parasite and to use the knowledge in the battle against this ancient disease.

Posted by medical plaintalk

Physician turned medical writer.

No more posts.