Hemophlia

 Hemophilia results from mutations at the factor VIII or IX loci on the X

chromosome and each occurs in mild, moderate, and severe forms.
 A similar level of deficiency of factor VIII or IX results in clinically
indistinguishable disease because the end result is deficient activation of
factor X by the factor Xase complex (FVIIIa/FIXa/calcium and phospholipid).
 Hemophilia A is an X-linked, recessive disorder caused by the deficiency of
functional plasma clotting factor VIII (FVIII), which may be inherited or arise
from spontaneous mutation.
 Hemophilia B, or Christmas disease, is an inherited, X-linked, recessive
disorder that results in the deficiency of functional plasma coagulation factor
IX.

Pathophysiology
Pathophysiologies for both hemophilia A and B are as follows:

Hemophilia A
 Primary sites of factor VIII (FVIII) production are thought to be the vascular
endothelium in the liver and the reticuloendothelial system.
 FVIII deficiency, dysfunctional FVIII, or FVIII inhibitors lead to the disruption
of the normal intrinsic coagulation cascade, resulting in excessive
hemorrhage in response to trauma and, in severe cases, spontaneous
hemorrhage.
 Human synovial cells synthesize high levels of tissue factor pathway
inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which
predisposes hemophilic joints to bleed.
 This effect may also account for the dramatic response of activated factor VII
(FVIIa) infusions in patients with acute hemarthroses and FVIII inhibitors.
  Bleeding into a joint may lead to synovial inflammation, which predisposes
the joint to further bleeds; a joint that has had repeated bleeds (by one
definition, at least 4 bleeds within a 6-month period) is termed a target joint.
 Approximately 30% of patients with severe hemophilia A develop
alloantibody inhibitors that can bind FVIII; these inhibitors are typically
immunoglobulin G (IgG), predominantly of the IgG4 subclass, that
neutralizes the coagulant effects of replacement therapy.
Hemophilia B
 Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to
disruption of the normal intrinsic coagulation cascade, resulting in
spontaneous hemorrhage and/or excessive hemorrhage in response to
trauma.
 Hemorrhage sites include joints (eg, knee, elbow), muscles, central nervous
system (CNS), GI system, genitourinary (GU) system, pulmonary system,
and cardiovascular system.
 Factor IX, a vitamin K–dependent single-chain glycoprotein, is synthesized
first by the hepatocyte; the precursor protein undergoes extensive
posttranslational modification before being secreted into the blood.
 The intrinsic system is initiated when factor XII is activated by contact with
damaged endothelium.
 In the extrinsic system, the conversion of factor X to factor Xa involves tissue
factor (TF), or thromboplastin; factor VII; and calcium ions.
 FVIII and FIX circulate in an inactive form; when activated, these 2 factors
cooperate to cleave and activate factor X, a key enzyme that controls the
conversion of fibrinogen to fibrin.
 Therefore, the lack of either of these factors may significantly impair clot
formation and, as a consequence, result in clinical bleeding.

Statistics and Incidences
Hemophilia is slowly progressing among pediatric patients in all parts of the globe.

 Hemophilia A is the most common X-linked genetic disease and the second
most common factor deficiency after von Willebrand disease (vWD).
 The worldwide incidence of hemophilia A is approximately 1 case per 5000
males, with approximately one-third of affected individuals not having a
family history of the disorder.
 In the United States, the prevalence of hemophilia A is 20.6 cases per
100,000 males; in 2016, the number of people in the United States with
hemophilia was estimated to be about 20,000.
 Hemophilia A occurs in all races and ethnic groups.
 Because hemophilia is an X-linked, recessive condition, it occurs
predominantly in males; females usually are asymptomatic carriers.
 The incidence of hemophilia B is estimated to be approximately 1 case per
25,000-30,000 male births.
 The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals,
with 44% of those having severe disease.
  Hemophilia B is much less common than hemophilia A. Of all hemophilia
cases, 80-85% are hemophilia A, 14% are hemophilia B, and the remainder
are various other clotting abnormalities.
 Hemophilia B occurs in all races and ethnic groups.

Causes
The causes of both hemophilia A and B are apparently from a genetic form.

 Genetics. Hemophilia A is caused by an inherited or acquired a genetic

mutation that results in dysfunction or deficiency of factor VIII, or by an
acquired inhibitor that binds factor VIII; Hemophilia B is an X-linked recessive
disease caused by an inherited or acquired mutation in the factor IX gene or
by an acquired factor IX inhibitor.

Clinical Presentation
Hemophilia is suggested by a history of hemorrhage disproportionate to trauma or of
spontaneous hemorrhage, or a family history of bleeding problems.

 Spontaneous hemorrhage. Approximately 30-50% of patients with severe

hemophilia present with manifestations of neonatal bleeding (eg, after
circumcision); other neonates may present with severe hematoma and
prolonged bleeding from the cord or umbilical area or at sites of blood draws
or immunizations.
 Hematuria. In the genitourinary tract, gross hematuria may occur in as many
as 90% of patients.
 General symptoms. Weakness and orthostasis may occur.
 Musculoskeletal. Tingling, cracking, warmth, pain, stiffness, and refusal to
use the joint among children are common.
  Central nervous system. Headache, stiff neck, vomiting, lethargy, irritability,
and spinal cord syndromes may occur.
 Genitourinary.  Symptoms may be painless; there may be hepatic/splenic
tenderness and peritoneal signs.

Assessment and Diagnostic Findings

The diagnosis of hemophilia A and B is established by measuring the following:

 Chromogenic assay. This assay is considered by some to be more

accurate, as it measures the level of plasma factor VIII activity but it is less
widely available in clinical laboratories in the United States.
 Laboratory studies. Laboratory studies for suspected hemophilia include a
complete blood cell count, coagulation studies, and a factor VIII (FVIII)
assay.
 CT scans. Head CT scans without contrast are used to assess for
spontaneous or traumatic intracranial hemorrhage.
 MRI. Perform magnetic resonance imaging (MRI) on the head and spinal
column for further assessment of spontaneous or traumatic hemorrhage;
MRI is also useful in the evaluation of the cartilage, synovium, and joint
space.
 Ultrasonography. Ultrasonography is useful in the evaluation of joints
affected by acute or chronic effusions.
 Testing for inhibitors. Laboratory confirmation of a FVIII inhibitor is
clinically important when a bleeding episode is not controlled despite infusion
of adequate amounts of factor concentrate.
 Carrier testing. Screening for carrier status can be performed by measuring
the ratio of FVIII coagulant activity to the concentration of von Willebrand
factor (vWF) antigen; a ratio that is less than 0.7 suggests carrier status.
 Radiography. Radiography for joint assessment is of limited value in acute
hemarthrosis; evidence of chronic degenerative joint disease may be visible
on radiographs in patients who have been untreated or inadequately treated
or in those with recurrent joint hemorrhages.

Medical Intervention
The treatment of hemophilia may involve prophylaxis, management of bleeding
episodes, treatment of factor VIII (FVIII) inhibitors, and treatment and rehabilitation of
hemophilia synovitis.

 Prehospital care. Rapid transport to definitive care is the mainstay of

prehospital care; prehospital care providers should apply aggressive
hemostatic techniques, assist patients capable of self-administered factor
therapy, and gather focused historical data if the patient is unable to
communicate.
 Emergency department care. Use aggressive hemostatic techniques;
correct coagulopathy immediately; include a diagnostic workup for
hemorrhage, but never delay indicated coagulation correction pending
 diagnostic testing; acute joint bleeding and expanding, large hematomas
require adequate factor replacement for a prolonged period until the bleed
begins to resolve, as evidenced by clinical and/or objective methods; life-
threatening bleeding episodes are generally initially treated with FVIII levels
of approximately 100%, until the clinical situation warrants a gradual
reduction in dosage.
 Factor VIII  and FIX concentrates. Various FVIII and FIX concentrates are
available to treat hemophilia A and B; besides improved hemostasis,
continuous infusion decreases the amount of factor used, which can result in
significant savings; obtain factor level assays daily before each infusion to
establish a stable pattern of replacement regarding the dose and frequency
of administration.
 Desmopressin. Desmopressin vasopressin analog, or 1-deamino-8-D-
arginine vasopressin (DDAVP), is considered the treatment of choice for mild
and moderate hemophilia A; DDAVP stimulates a transient increase in
plasma FVIII levels; DDAVP may result in sufficient hemostasis to stop a
bleeding episode or to prepare patients for dental and minor surgical
procedures.
 Management of bleeding. Immobilization of the affected limb and the
application of ice packs are helpful in diminishing swelling and pain; early
infusion upon the recognition of initial symptoms of a joint bleed may often
eliminate the need for a second infusion by preventing the inflammatory
reaction in the joint; prompt and adequate replacement therapy is the key to
preventing long-term complications.
 Treatment of patients with inhibitors. Inhibitors are antibodies that
neutralize factor VIII (FVIII) and can render replacement therapy ineffective;
the treatment of patients with inhibitors of FVIII is difficult; assuming no
anamnestic response, low-titer inhibitors (ie, concentrations below 5
Bethesda units [BU]) occasionally can be overcome with high doses of factor
VIII; there is no established treatment for bleeding episodes in patients with
high-titer inhibitors.
 Prophylactic factor infusions. The main goal of prophylactic treatment is to
prevent bleeding symptoms and organ damage, in particular to joints; in
December 2013, the US Food and Drug Administration (FDA) expanded the
indication for anti-inhibitor coagulant complex (Feiba NF) to include routine
prophylaxis in patients with hemophilia A or B who have developed
inhibitors; approval was based on data from a pivotal phase III study in which
a prophylactic regimen resulted in a 72% reduction in median annual bleed
rate compared with on-demand treatment.
 Pain management. Hemophilic chronic arthropathy is associated with pain;
narcotic agents have been used, but frequent use of these drugs may result
in addiction; nonsteroidal anti-inflammatory drugs may be used instead
because their effects on platelet function are reversible and because these
drugs can be effective in managing acute and chronic arthritic pain;
avoid aspirin because of its irreversible effect on platelet function.
  Activity. Generally, individuals with severe hemophilia should avoid high-
impact contact sports and other activities with a significant risk of trauma;
however, mounting evidence suggests that appropriate physical activity
improves overall conditioning, reduces injury rate and severity, and improves
psychosocial functioning.
 Gene therapy. With the cloning of FVIII and advances in molecular
technologies, the possibility of a cure for hemophilia with gene therapy was
conceived; ex vivo gene therapy, in which cells to be transplanted are
genetically modified to secrete factor VIII and then are reimplanted into the
recipient; in vivo gene therapy, in which a vector (typically a virus altered to
include FVIII DNA) is directly injected into the patient; and nonautologous
gene therapy, in which cells modified to secrete FVIII are packaged in
immunoprotected devices and implanted into recipients.
 Radiosynovectomy. In patients who develop synovitis from joint bleeds,
intra-articular injection of radioisotopes to ablate the synovium
(radiosynovectomy) can be used to decrease bleeding, slow progression of
cartilage and bone damage, and prevent arthropathy.
Pharmacologic Intervention
Medications of choice for patients with hemophilia are:

 Factor VIII. Factor VIII (FVIII) is the treatment of choice for acute or potential
hemorrhage in hemophilia A; recombinant FVIII concentrate is generally the
preferred source of factor VIII; prophylactic administration of FVIII is often
recommended for pediatric patients with severe disease.
 Antifibrinolytic agents. Antifibrinolytic agents, such as aminocaproic acid
and tranexamic acid, are especially useful for oral mucosal bleeds but are
contraindicated as initial therapies for hemophilia-related hematuria
originating from the upper urinary tract because they can cause obstructive
uropathy or anuria.
 Factor IX. Factor IX is the treatment of choice for acute hemorrhage or
presumed acute hemorrhage in hemophilia B. Recombinant factor IX is the
preferred source for replacement therapy.
 Coagulation factor VIIa. These agents can activate coagulation factor X to
factor Xa as well as coagulation factor IX to IXa.
 Coagulation factors. FVIII concentrates replace deficient FVIII in patients
with hemophilia A, with the goal of achieving a normal hematologic response
to hemorrhage or preventing hemorrhage; recombinant products should be
used initially and subsequently in all newly diagnosed cases of hemophilia
that require factor replacement; agents that bypass FVIII activity in the
clotting cascade (eg, activated FVII) are used in patients with FVIII inhibitors.
 Antihemophilic agents. These agents are used to control bleeding in
hemophilia B or FIX deficiency and to prevent and/or control bleeding in
patients with hemophilia A and inhibitors to FVIII.
 Monoclonal antibodies. Monoclonal antibodies are used to bind to one
specific substance in the body (eg, molecules, antigens); this binding is very
versatile and can mimic, block, or cause changes to enact precise
 mechanisms (eg, bridging molecules, replacing or activating enzymes or
cofactors, immune system stimulation).
 Vasopressin-related. Desmopressin transiently increases the FVIII plasma
level in patients with mild hemophilia A.

Nursing Interventions and implications:

 Physical examination. Assess for joint swelling and ability to move affected
limb; Assess for limited ROM, contractures, and bony changes in the joints
when bleeding has stopped.
 Relieve pain. Immobilize joints and apply elastic bandages to the affected
joint if indicated; elevate affected and apply a cold compress to active
bleeding sites, but must be used cautiously in young children to prevent skin
breakdown.
 Maintain optimal physical mobility. Provide gentle, passive
ROM exercise when the child’s condition is stable; educate on preventive
measures, such as the application of protective gear and the administration
of factor products; and refer for physical therapy, occupational therapy, and
orthopedic consultations, as required.
 Assist in the coping of the family. Encourage family members to verbalize
problem areas and develop solutions on their own; encourage family
members to express
feelings, such as how they deal with the chronic needs of a family member
and coping patterns that help or hinder adjustment to the problems.
 Prevent bleeding. Monitor hemoglobin and hematocrit levels; assess for
inhibitor antibody to factor VIII; anticipate or instruct in the need for
prophylactic treatment before high-risk situations, such as invasive
diagnostic or surgical procedures, or dental work; and provide replacement
therapy of deficient clotting factors.
 Prevent injury. Utilize appropriate toys (soft, not pointed
or small sharp objects); for infants, may need to use padded bed rail sides
on crib; avoid rectal temperatures; provide appropriate oral hygiene (use of
a water irrigating device; use of a soft toothbrush or softening the toothbrush
with warm water before brushing; use of sponge-tipped toothbrush); and
avoid contact sports such as football, soccer, ice hockey, karate.