7.4: White Blood Cells

White blood cells play a key role in immunity by destroying bacteria and other foreign substances. They defend the body against infections and tumors.

Leukemia and AIDS involve white blood cells. We see, again, the familiar theme of too much or too little as a problem. In leukemia, there’s an uncontrolled production of white blood cells. The overwhelming abundance of white blood cells, causes a potentially fatal disruption of normal body processes.

AIDS: Acquired Immunodeficiency Syndrome: Acquired from an infection rather than a genetic defect; Immunodeficiency because white blood cells are infected and destroyed; and a Syndrome (set of symptoms occurring together in a disease). Besides destroying white blood cells, AIDS can damage the nervous system and cause unusual diseases, like a pneumonia caused by Pneumocystis carnii (a microbe that’s ordinarily harmless) and Kaposi’s sarcoma, a rare cancer.

Platelets

Platelets are small disk-shaped structures (small plates) that can be thought of as sentries on the lookout and at the ready for any injury to a blood vessel. They immediately gather at an injury, temporarily plugging a leak until a clot can form by normal clotting mechanisms.

Injuring a blood vessel’s inner lining exposes an underlying layer. Platelets have proteins on their surface that attach to this normally unexposed layer. Because of this feature, platelets normally cluster only at the site of damage. At the injury, the platelets release a variety of substances, including those needed to clot blood. They also release substances that constrict injured blood vessels and promote healing.

Aspirin lessens the platelets’ ability to cluster. This alteration lasts for the life of the platelet (less than a week), so blood donors are asked if they’ve taken aspirin within the past week. If so, the blood won’t be used to replace surgical losses. Surgery patients need blood that clots well (to stem the bleeding). Conversely, aspirin is commonly prescribed to people who have had inappropriate clotting (as in a previous heart attack).

Plasma Proteins

Antibodies

Many kinds of proteins are dissolved in the plasma of blood. Among them are antibodies made in response to infection (or vaccination). We make the antibodies when we’re exposed to a foreign agent, and usually continue to make them to protect against any subsequent infections by the same agent. Thus, the presence or absence of specific antibodies in a blood sample can reveal whether we’ve ever been infected with (or vaccinated against) a particular microbe.

The development of vaccines was a major breakthrough in preventive medicine. Some vaccines have microbes (dead or alive) that are similar to the disease-causing ones—similar in that they cause us to make protective antibodies, but dissimilar in that they don’t cause the disease. Some vaccines have only harmless part(s) of the microbe. If, for example, we make protective antibodies in response to a particular protein on the surface of a microbe, that protein alone might be used in a vaccine.

Two milestones in preventive medicine involved the smallpox vaccine: the first safe and effective vaccine and the eradication of a horrible disease that had plagued mankind for centuries.

The first smallpox vaccine was the cowpox virus. English physician Edward Jenner had heard that dairy maids who’d been infected with cowpox virus (from cowpox blisters on nipples of cows they milked) didn’t get smallpox.

In 1796, he tested the hypothesis that infection with cowpox virus confers immunity to smallpox. Using the fluid from a cowpox blister (on a dairy maid’s hand), he infected a healthy boy (Jim Phipps) by way of two slight incisions on Jim’s arm. Seven weeks later, and again several months later, he tried (unsuccessfully, thank goodness) infecting Jim with smallpox by applying fluid from a smallpox blister and then making several slight punctures and incisions on Jim’s arms.

Smallpox as a disease was eradicated worldwide in 1977, so the vaccine is no longer needed.* This first and only eradication of an infectious disease was made possible by an effective vaccine, a major effort by the World Health Organization, and by the fact that humans are the only natural host of the smallpox virus. This accomplishment is impressive. In 1967, smallpox killed about two million people.

Using mass surveillance and immunization campaigns, the World Health Organization together with other governments and organizations such as Rotary International have been working toward eradicating polio. On a single day in 1997, volunteers vaccinated 134 million children in India. In Turkey, the Rotary talked soap manufacturers into adding vaccination announcements to their commercials. Where there’s war, doctors have negotiated cease-fires to immunize children.

Scientists are working on an AIDS vaccine. One obstacle is that the proteins on the surface of HIV (the virus that causes AIDS) differ and change (mutate). In other words, there are many strains of HIV (unlike many other viruses that have only a few strains), and a vaccine against one strain may not be effective against others.

^{*Ironically, smallpox virus (and anthrax) is a threat as a biological weapon by terrorists or in warfare. High- security depots in Russia and the U.S. are the only known and legitimate sources of the smallpox virus today. These were to be destroyed but weren’t, mostly because of fear that there may be unknown (illegitimate) sources. If used as biological weapons, the legitimate depots of the virus could then be used to make and test vaccines.}

Albumin

Albumin is the most abundant protein in blood plasma and has many functions, e.g., it helps transport substances like bile components in the blood and helps regulate the pH of blood by acting as a buffer (Chap. 3). Albumin also holds liquid in the plasma (imagine transparent sponges holding water). When there isn’t enough albumin, some of the fluid moves out of blood vessels into the surrounding tissue, causing edema (swelling from excess tissue fluid). A number of diseases can cause low plasma-albumin, as can the severe dietary protein deficiency common among children in some low-income countries. These children can’t make enough albumin, and they look “puffy” with their bellies and faces swollen from edema.

Clotting Factors

Proteins needed for blood clotting are in the blood plasma. Clotting involves more than a dozen clotting factors. Lacking even one can cause life-threatening bleeding from minor injuries. Hemophiliacs genetically lack one and get it from a plasma-extract.* Some clotting factors are now made by biotechnology (Chap. 10). Hemophiliacs avoid taking aspirin—they are especially dependent on the clustering of platelets to prevent bleeding.

Forming a blood clot involves a complex series of reactions in which enzymes are activated; these, in turn, activate other enzymes. Calcium and vitamin K are required (as shown below in a small segment of the clotting process) to form thrombin, the enzyme that catalyzes the final reaction that forms the blood clot (fibrin).† (“Pre-prothrombin,” prothrombin, thrombin, and fibrinogen are proteins dissolved in blood plasma.)

Good sources of vitamin K include green leafy vegetables (plants use K for photosynthesis) and liver (where K is stored). Vitamin K deficiency is uncommon because intestinal bacteria make ample amounts under normal circumstances.

As mentioned in earlier chapters, a vitamin K injection is given routinely to newborns in the U.S. because there are no bacteria in the intestine at birth. A vitamin K deficiency is occasionally seen in people who ingest antibiotics for a long time, or have diseases where there’s chronic malabsorption of dietary fat (K is a fat-soluble vitamin).

Drugs that hamper K activity are prescribed as anticoagulants for those who want to reduce their ability to form blood clots (e.g., people who’ve had a previous heart attack). Dicumarol and warfarin (Coumadin®) are two such drugs. Dicumarol is found naturally in spoiled sweet clover. When animals feed on this clover, the dicumarol can cause a hemorrhagic disease in the animals called sweet clover disease.

Warfarin is also a very effective rat poison. When rats’ food is laced with warfarin, they die from internal hemorrhage. Warfarin (or dicumarol) can thus be a lifesaving drug or the cause of a fatal hemorrhage. It’s all in the dose.

There are newer (and much more expensive) anticlotting drugs, e.g., Eliquis that inhibits another clotting factor.

There’s always enough calcium in the plasma for the clotting process because very little is needed and bone holds a huge reserve. Calcium’s importance in blood clotting can be demonstrated in a test tube. If calcium is removed from a blood sample, it doesn’t clot. One way to keep it from clotting is to collect it into a tube that has oxalic acid. Oxalic acid combines with the calcium in the blood, making it unavailable in the clotting process.**

There’s a fine balance between clotting and the prevention of clotting. We need a clot to stop bleeding, but if a clot forms when it isn’t needed, it can impair the normal flow of blood and even cause a life-threatening heart attack, stroke, or blood clot in the lung (pulmonary embolism).

Sometimes, a clot forms because of impaired circulation. For example, as mentioned earlier, blood can pool in leg veins when a person stands or sits still for a long time. The “sluggishness” (reduced circulation) of blood in these veins can cause a clot to form. The clot might then be carried in the bloodstream to block a blood vessel elsewhere.

Note that blood returning to the heart from the legs goes through the lungs to be oxygenated before it goes to the coronary arteries and brain (Figure 7.1). This is why a clot formed in the leg is more likely to block a blood vessel in the lung than in the heart or brain.

As a preventive measure, people with narrowed arteries are often advised to get up and walk around occasionally during a long, cramped, airplane flight. Likewise, patients recovering from surgery are encouraged to take walks (despite the discomfort) in the hospital corridor soon after surgery. Many years ago, the common practice was for patients to lie in their hospital beds for a week or more after surgery.

As expected, plasma also has substances that help prevent clotting and help dissolve any clots that do form. This “anti-clot” system is also complex (though not as complex as clotting). One substance that triggers the breakdown of clots is tissue plasminogen activator (TPA). Activase is TPA made by biotechnology (Chap. 10) and sold as a drug.

Activase can be injected into the bloodstream to rapidly dissolve the clot in a patient with a heart attack or stroke caused by a clot blocking an artery. The sooner the clot is dissolved to clear the blockage, the less the heart or brain damage and the better the chance of recovery. An injection of Activase also, of course, increases the risk of bleeding in the brain or elsewhere. Activase isn’t selective. It acts on any clot it encounters.

^{*The plasma came from blood pooled from about 2,000-200,000 donors. Thus, many hemophiliacs were inadvertently infected with HIV before it was known that it could be transmitted in blood, making AIDS their leading cause of death.
†Danish scientist Henrik Dam discovered Vitamin K (from the Danish word koagulation). He and Edward Doisy (who determined the structure of vitamin K) shared a Nobel Prize in 1943.
**Oxalic acid was mentioned earlier in this chapter as a substance found in some foods (e.g., spinach) that can combine with iron (as with calcium) and prevent the absorption of that iron from the intestine.}

Lipoproteins

Fat (lipid) alone would clump together in plasma (plasma is water-based; fat doesn’t dissolve in water), so it’s combined with protein (which can dissolve). These lipid-protein packages are called lipoproteins. They’re ball-shaped—a core of fat surrounded by a protein-containing outer layer.

Lipoproteins are grouped by how dense they are (how heavy they are for their size). Fat is less dense (lighter) than protein, so the fattier a lipoprotein, the lower its density (Table 7-2).

Table 7-2: Composition of Plasma Lipoproteins

Chylomicrons are the fattiest, biggest, and least dense. High-Density Lipoproteins (HDL) are the leanest, smallest, and most dense. Think of lipoproteins as fat-carrying vehicles that “ride” the blood to transport fat throughout the body.

Chylomicrons* originate in the intestine and transport fat from food (food fat is mainly triglycerides, as discussed in Chap. 5). As expected, chylomicrons increase in the plasma after eating a meal. If the meal is fatty, the abundant chylomicrons give plasma a cloudy appearance and, in a blood sample, they rise to form a layer of fat above the plasma.

As chylomicrons travel through the capillaries, an enzyme in the capillary lining breaks apart the chylomicron’s triglycerides into fatty acids and glycerol, which then move out of the capillaries for use by nearby tissues. After unloading much of their triglycerides in this way, chylomicrons are taken up by the liver, where they’re repackaged into lipoproteins called VLDL.

VLDL (Very Low Density Lipoprotein) is rich in triglycerides, and delivers them to tissues in much the same way as chylomicrons. As VLDL makes its deliveries, it becomes smaller and more dense (removing fat increases the proportion of the more-dense protein). The proportion of cholesterol also goes up as triglycerides are selectively removed.

At this stage, VLDL is taken up by the liver, which alters the protein portion, turning it into a lipoprotein called LDL (Low-Density Lipoprotein). LDL is mostly cholesterol and delivers cholesterol for use in making cell membranes, sex hormones, etc.

HDL (High-Density Lipoprotein) is mostly protein, but also is rich in cholesterol. But in contrast to LDL, it generally delivers cholesterol to the liver, where it can be made into bile acids and secreted into the intestine for use in digestion. The relationship of these lipoproteins to heart disease will be discussed in the next chapter.

^{*They’re called chylomicrons because dietary fat comes into the blood mainly as a fluid called chyle, and the size of lipoproteins is measured in microns. Chylomicrons are about 0.1 microns wide (HDL are about 0.01 microns wide).}