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Hemophilia A
Updated: Jan 14, 2019
 Author: Douglass A Drelich, MD; Chief Editor: Srikanth Nagalla, MBBS, MS,
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Pathophysiology
Factor VIII production, processing, and structure
Primary sites of factor VIII (FVIII) production are thought to be the vascular
endothelium in the liver and the reticuloendothelial system. Liver
transplantation corrects FVIII deficiency in persons with hemophilia.
FVIII messenger RNA has been detected in the liver, spleen, and other
tissues. [2] Studies of FVIII production in transfected cell lines have shown that
following synthesis, FVIII moves to the lumen of the endoplasmic reticulum,
where it is bound to several proteins that regulate secretion, particularly
immunoglobulin binding protein, from which it has to dissociate in an energy-
dependent process.
Cleavage of FVIII's signal peptide and the addition of oligosaccharides also
occur in the endoplasmic reticulum. The chaperone proteins, calnexin and
calreticulin, enhance both FVIII secretion and degradation.
A part of the factor FVIII protein in the endoplasmic reticulum is degraded
within the cell. The other part enters the Golgi apparatus, where several
changes occur to produce the heavy and light chains and to modify the
carbohydrates. The addition of sulfates to tyrosine residues of the heavy and
light chains is necessary for full procoagulant activity, with the sulfated region
playing a role in thrombin interaction. This posttranslational sulfation of
tyrosine residues impacts the procoagulant activity of factor VIII and its
interaction with von Willebrand factor (vWF).
von Willebrand factor
FVIII circulates in plasma in a noncovalently bound complex with vWF, which
plays significant roles in the function, production, stabilization, conformation,
and immunogenicity of FVIII. [3] VWF has been termed FVIII-related antigen
(FVIII-R); related terminology for FVIII is FVIII-coagulant (FVIII-C).
VWF appears to promote assembly of the heavy and light chains of FVIII and
more efficient secretion of FVIII from the endoplasmic reticulum. It also directs
FVIII into the Weibel-Palade bodies, which are the intracellular storage sites
for vWF.
In plasma, vWF stabilizes FVIII and protects it from degradation. In the
presence of normal vWF protein, the half-life of FVIII is approximately 12
hours, whereas in the absence of vWF, the half-life of FVIII-C is reduced to 2
hours. [4, 5, 6]
The clotting cascade
The role of the coagulation system is to produce a stable fibrin clot at sites of
injury. The clotting mechanism has two pathways: intrinsic and extrinsic. See
the image below.
 Coagulation Cascade

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The intrinsic system is initiated when factor XII is activated by contact with
damaged endothelium. The activation of factor XII can also initiate the
extrinsic pathway, fibrinolysis, kinin generation, and complement activation.
In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa
converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor
XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can
bind phospholipids. Then, factor X is activated on the cell surface; activation
of factor X involves a complex (tenase complex) of factor IXa, thrombin-
activated FVIII, calcium ions, and phospholipid.
In the extrinsic system, the conversion of factor X to factor Xa involves tissue
factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released
from the damaged cells and is thought to be a lipoprotein complex that acts as
a cell surface receptor for factor VII, with its resultant activation. TF also
adsorbs factor X to enhance the reaction between factor VIIa, factor X, and
calcium ions. Factor IXa and factor XII fragments can also activate factor VII.
In the common pathway, factor Xa (generated through the intrinsic or extrinsic
pathways) forms a prothrombinase complex with phospholipids, calcium ions,
and thrombin-activated factor Va. The complex cleaves prothrombin into
thrombin and prothrombin fragments 1 and 2.
Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and
factor XIII. Fibrinopeptides A and B, the results of the cleavage of peptides A
and B by thrombin, cause fibrin monomers to form and then polymerize into a
meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-
linking of adjacent fibrin strands.
Because of the complex interactions of the intrinsic and extrinsic pathways
(factor IXa activates factor VII), the existence of only one in vivo pathway with
different mechanisms of activation has been suggested. See the image below.

The hemostatic pathway. APC

= activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation
products; HC-II = heparin cofactor II; HMWK = high-molecular-weight
kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain
urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen
activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen
activator

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FVIII and factor IX 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 FVIII may
significantly alter clot formation and, as a consequence, result in clinical
bleeding.
Genetics
The gene for FVIII (F8C) is located on the long arm of chromosome X, within
the Xq28 region. The gene is unusually large, representing 186 kb of the X
chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains
2332 amino acids. See the image below.
 Structural domains of human
factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K,
Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound
coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-
dimensional density map derived by electron crystallography. Blood. Feb 15
2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler
E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY:
McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of
action of FVIIa. Presented at: Second Symposium on New Aspects of
Haemophilia Treatment; 1991; Copenhagen, Denmark.

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Approximately 40% of cases of severe FVIII deficiency arise from a large

inversion that disrupts the FVIII gene. Deletions, insertions, and point
mutations account for the remaining 50-60% of the F8C defects that cause
hemophilia A.
Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN
von Willebrand disease, in which the molecular defect resides in the FVIII-
binding domain of von Willebrand factor.
Hemophilia A
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.
Hemorrhage sites include joints (eg, knee, elbow); muscles; the central
nervous system (CNS); and the gastrointestinal, genitourinary, pulmonary,
and cardiovascular systems. Intracranial hemorrhage occurs most commonly
in patients younger than 18 years and can be fatal.
Hemorrhage into joints
The hallmark of hemophilia is hemorrhage into joints. This bleeding is painful
and leads to long-term inflammation and deterioration of the joint.
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. Commonly,
this occurs in knees.
Repeated hemarthroses lead to progressive synovial hypertrophy,
hemosiderin deposition, fibrosis, and damage to cartilage, with subchondral
bone-cyst formation. This results in permanent deformities, misalignment, loss
of mobility, and extremities of unequal lengths.
Inhibitors
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 neutralize the coagulant
effects of replacement therapy. However, the inhibitors do not fix complement
and do not result in the end-organ damage observed with circulating immune
complexes
Inhibitors occur at a young age (about 50% by age 10 years), principally in
patients with less than 1% FVIII. Both genetic and environmental factors
determine the frequency of inhibitor development. Specific molecular
abnormalities (eg, gene deletions, stop codon mutations, frameshift
mutations) are associated with a higher incidence of inhibitor development. In
addition, inhibitors are more likely to develop in black children. Missense
mutations are associated with a low risk of inhibitor development. [7]
The association of product used with the risk of inhibitor formation remains
controversial. In a study of 574 patients with severe hemophilia A, 177 of
whom developed inhibitors, the risks of inhibitor development were similar
with recombinant and plasma-derived FVIII products. No association was
found between the development of inhibitors and the von Willebrand factor
content of products, switching from a plasma-derived to a recombinant
product, or switching among brands of FVIII products. Unexpectedly,
however, inhibitors developed more often with second-generation full-length
recombinant products than with third-generation products. [8]
A study with 303 previously untreated or minimally treated children with
hemophilia demonstrated a increased risk of inhibitor formation in patients
who used recombinant products. [9] However, the European Medicines Agency
(EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded
that "there is no clear and consistent evidence of a difference in the incidence
of inhibitor development between the two classes of factor VIII medicines:
those derived from plasma and those made by recombinant DNA
technology." [10]
In the United States, levels of FVIII inhibitors are most often measured by the
Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of
antibody that destroys one half of the FVIII in an equal mixture of normal
plasma and patient plasma in 2 hours at 37°C. Inhibitor levels are described
as low titer or high titer, depending on whether they are less than or more than
5 BU, respectively; high-titer inhibitor levels are typically far higher than 5 BU.
The Nijmegen modification uses immunodepleted FVIII–deficient plasma
instead of an imidazole saline buffer to ensure pH control to prevent non–
antibody-mediated loss of FVIII-C activity during the prolonged 2-hour
incubation period. [11] The Bethesda assay tends to underestimate the titer of
VIII autoantibody because of its characteristics, in contrast to a hemophilic
antibody. [12] The Oxford assay is another modification of the Bethesda
inhibitor test.
Acquired hemophilia
Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in
persons without a history of FVIII deficiency. This condition can be idiopathic
(occurring in people >50 y), it can be associated with collagen vascular
disease or the peripartum period, or it may represent a drug reaction (eg, to
penicillin). High titers of FVIII autoantibodies may be associated with
lymphoproliferative malignancies. [13]

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