Hemophilia

The word “hemophilia” is a combination of the Greek words for “blood” and “love”, a way of saying that people with hemophilia “love to bleed”, or rather that it’s hard to stop bleeding. This is because the process called hemostasis, literally meaning to stop the flow of blood, is impaired.

Normally, after a cut and damage to the endothelium, or the inner lining of blood vessel walls, there’s an immediate vasoconstriction or narrowing of the blood vessel which limits the amount of blood flow. After that some platelets adhere to the damaged vessel wall, and become activated and then recruit additional platelets to form a plug. The formation of the platelet plug is called primary hemostasis.

After that, the coagulation cascade is activated. First off in the blood there’s a set of clotting factors, most of which are proteins synthesized by the liver, and usually these are inactive and just floating around the blood. The coagulation cascade starts when one of these proteins gets proteolytically cleaved. This active protein then proteolytically cleaves and activates the next clotting factor, and so on. This cascade has a great degree of amplification and takes only a few minutes from injury to clot formation. The final step is activation of the protein fibrinogen to fibrin, which deposits and polymerizes to form a mesh around the platelets. So these steps leading up to fibrin reinforcement of the platelet plug make up the process called secondary hemostasis and results in a hard clot at the site of the injury.

In most cases of hemophilia there is a decrease in the amount or function of one or more of the clotting factors which makes secondary hemostasis less effective and allows more bleeding to happen.

Now, that coagulation cascade can get started in two ways. The first way is called the extrinsic pathway, which starts when tissue factor gets exposed by the injury of the endothelium. Tissue factor turns inactive factor VII into activated factor VIIa (a for active), and then tissue factor goes on to bind the newly formed factor VIIa to form a complex that turns factor X into active factor Xa with the help of calcium. Factor Xa, with Factor Va as a cofactor, turns factor II (which is also called prothrombin) into factor IIa, also called thrombin. Thrombin then turns factor I (or fibrinogen), which is soluble, into factor Ia (or fibrin), which is insoluble and precipitates out of the blood at the site of injury. Thrombin also turns factor XIII into factor XIIIa which cross links the fibrin to form a stable clot. The second way is called the intrinsic pathway, and it starts when platelets near the blood vessel injury activate factor XII into factor XIIa, which then activates factor XI to factor XIa, which then activates factor IX to factor IXa. And factor IXa and factor VIIIa work together to activate factor X to factor Xa, and from that point it follows the same fate as before, so both the extrinsic and intrinsic pathways basically converge on a single final path called the common pathway. Believe it or not, this is a somewhat simplified version of the coagulation cascade; but, it has all of the key parts needed to understand hemophilia.

Now, an insufficient concentration or decreased activity of any coagulation factor can cause hemophilia, except factor XII deficiency which is asymptomatic. Hemophilia usually refers to inherited deficiencies of coagulation factors, which could be either quantitative or qualitative. By far the most common of these are deficiencies of factor VIII which gives rise to factor VIIIa and is stabilized by another factor called von Willebrand factor, and this deficiency is called hemophilia A (or classic hemophilia). Another common deficiency is deficiency of factor IX, called hemophilia B (which used to be called Christmas disease, named after the first patient who had it, not the holiday). Now, a mimic of hemophilia A is von Willebrand disease, which is an inherited problem with primary hemostasis caused by a deficiency of von Willebrand factor. So in severe von Willebrand factor deficiency, factor VIII gets broken down faster and can become deficient, too.

As opposed to inherited forms of hemophilia, one acquired causes of hemophilia is liver failure since the liver synthesizes factors I, II, V, VII, VIII, IX, X, XI, and XIII. Also, vitamin k deficiency can cause hemophilia, since vitamin k is needed by the liver to synthesize and release factors II, VII, IX, and X. Another cause is autoimmunity against a clotting factor, and finally there’s disseminated intravascular coagulation which consumes coagulation factors.

Now, the mutated genes in hemophilia A are called F8, and in hemophilia B they’re called F9, and these are both on the X chromosome, meaning both conditions are X-linked recessive, so it usually affects men, since they only have one X chromosome and therefore only copy of the F8 and F9 genes. Women with one mutated gene copy have a remaining healthy copy, so they don’t get hemophilia unless X-chromosome inactivation turns off the normal copy in the majority of cells. But generally, women are carriers, while men are symptomatic with the disease.

Signs and symptoms hemophilia A and B are nearly clinically identical, which makes sense since factors VIIIa and IXa work together in the coagulation cascade to activate factor X. Both of these can cause easy bruising (or ecchymosis); as well as hematomas (which are collections of blood outside the blood vessels) that are often deep in muscles; prolonged bleeding after a cut or surgical procedure, for example circumcision; oozing after tooth extractions; gastrointestinal bleeding; hematuria, which is blood in the urine; severe nosebleeds; and hemarthrosis (or bleeding into joint spaces).