Introduction of Hemophilia.
The word “hemophilia” is a combination of Greek words for “blood” and “love,” a way to say “love to bleed” people with hemophilia, or rather it’s hard to stop bleeding.
That is because the cycle called fantasize, meaning simply to interrupt blood supply, is compromised. Normally, after a cut and damage to the endothelium, or inner lining of blood vessel walls, there’s immediate vasoconstriction or narrowing of the blood vessel which limits the amount of blood flow.
Then, some platelets adhere to the damaged vessel wall, and become activated and then recruit additional platelets to form a plug. The formation of this platelet plug is called primary hemostasis.
After that, the coagulation cascade is activated. First off the blood has a set of clotting factors – most of which are proteins synthesized by the liver, that are inactive and simply float around the blood.
The coagulation cascade begins when one of these proteins gets proteolytically cleaved – activating it. 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 the activation of the protein fibrinogen (Factor I) to fibrin, which deposits and polymerizes to form a mesh around the platelets.
While these measures leading to fibrin reinforcement of the platelet plug form the mechanism called secondary hemostasis and outcome in a hard clot at the injuries and illnesses location. In most cases of hemophilia, there is a decrease in the amount or function of one or more of the clotting factors that make secondary hemostasis less effective and allows more bleeding to occur.
The coagulation cascade can get started in two ways. The first route is called the extrinsic pathway, which ends after endothelium damage reveals the tissue component.
Tissue factor turns inactive factor VII inactivate 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. Factor Xa, with Factor Va as a cofactor, turnsfactor II (also called prothrombin) into factor IIa or 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 factorXIIIa 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 VIIa, which then activates factor XI to factor XIa, which then activates factor IX to factor Xa.
Factor IXa and factor VIIa work together to activate factor X to factor Xa, from which point it follows the same fate as before. 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 contains all of the key parts needed to understand hemophilia. An insufficient concentration or decreased activity of any coagulation factor can cause hemophilia, except factor XII deficiency, which is asymptomatic.
Hemophilia B :
Hemophilia usually refers to inherited deficiencies– either quantitative or qualitative — of coagulation factors. By far the most common of these are deficiencies of factor VIII which gives rise to factor VIIa and is stabilized by another factor called von Willebrand factor, called hemophilia A (or classic hemophilia), and 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 VWF deficiency, factor VIII gets broken down faster and can become deficient, too.
Hemophilia of Causes.
Some acquired causes of hemophilia are liver failure since the liver synthesizes factors I, II, V, VII, VIII, IX, X, XI, and XIII, vitamin k deficiency which is needed by the liver to synthesize and release factors II, VII, IX, and X, autoimmunity against a clotting factor, and disseminated intravascular coagulation which consumes coagulation factors.
The mutated genes in hemophilia A and B, calledF8 and F9, are on the X chromosome, and both conditions are X-linked recessive, so it usually affects men, since they only have one X chromosome and therefore an 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.
Signs and Symptoms Hemophilia.
So 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 VIIa and IXa work together in the coagulation cascade to activate factor X.
They can both cause easy bruising (or ecchymosis); hematomas (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 – blood in the urine; severe nosebleeds; and hemarthrosis (or bleeding into joint spaces).
A dangerous complication is bleeding into the brain, which can cause a stroke or increased intracranial pressure. The severity of the symptoms depends on the severity of the underlying mutation, which determines the activity of the factor.
Hemophilia of Diagnosis.
Diagnosis of hemophilia A and B usually starts with lab tests including a platelet count which is usually normal, a prothrombin (PT)time, and a partial thromboplastin (PTT) time. The PT tests extrinsic and common pathways, meaning factors VII, X, V, II (prothrombin), and I (fibrinogen), whereas the PTT tests the intrinsic and common pathways, meaning factors XII, XI, IX, VIII, X, V, II, and I.
Since factors VIII and IX are part of the intrinsic pathway, PT is normal and PTT is prolonged in hemophilia A and B. To confirmhemophilia A or B, tests to look at specific factor activities, and mutation testing of the genes encoding them, can be done.
Treatment for hemophilia A and B are treated with injections of the missing or nonfunctional clotting factor. Unfortunately, if the patient has a severe deficiency, where intrinsic production of the factor is absent or very low, the supplemental factor can be seen as foreign by the immune system, producing antibodies that try to eliminate the injected clotting factors, which are called inhibitors.
Inhibitors diminish the treatment’s effectiveness over time, and can sometimes cause a severe allergic reaction – anaphylaxis. For hemophilia A, desmopressin, also called AVP (1-diamino-8-D-arginine vasopressin) is helpful for patients with mild, quantitative factor VIII deficiency.
Desmopressin stimulates VWF release from endothelial cells, which promotes the stabilization of the residual factor VIII. Finally, it’s best for individuals with hemophilia to avoid contact sports and medicines that promote bleeding, like aspirin.
OK – Quick recap – Hemophilia is a bleeding disorder that is caused by an impaired coagulation cascade. Hemophilia A is caused by mutations in the genes for factors VIII and B is caused by, mutations in the genes for factor IX, and are the most common genetic hemophilias. They’re treated by supplementing the missing clotting factor.