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 inner lining of blood vessel walls, there’s an 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 activation of the protein
fibrinogen (Factor I) 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 that makes secondary
hemostasis less effective and allows more bleeding to occur. The 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
activate 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, turns
factor 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 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. 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 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 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 VIIIa 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. 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, called
F8 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 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. 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 VIIIa 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. 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 confirm
hemophilia 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 severe deficiency,
where intrinsic production of the factor is absent or very low, 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
DDAVP (1-deamino-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. Thanks for watching, you can help support
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