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.
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