FEDERAL UNIVERSITY OF HEALTH SCIENCES,

ILA-ORANGUN
COLLEGE OF MEDICINE
FACULTY OF BASIC MEDICAL SCIENCES
DEPARTMENT OF PHYSIOLOGY

COAGULATION
DISORDERS
PHS 301 – Pathophysiology I
300 Level Lecture Scheduled for MBBS Students

Dr. A. A .Adeosun
 COAGULATION
DISORDERS
Result from either congenital or acquired
deficiencies of clotting factors.
Acquired deficiencies are most common and involve
several factors simultaneously.

Vitamin K is required for the synthesis of

prothrombin and clotting factors VII, IX, and X, and its
deficiency causes a severe coagulation defect.
 COAGULATION DISORDERS
The liver synthesizes several coagulation factors and also
removes many activated coagulation factors from the
circulation.
Thus, hepatic parenchymal diseases are common causes
of complex hemorrhagic diatheses.

Disseminated intravascular coagulation

Also called: DIC, consumptive coagulopathy: also may
lead to multiple concomitant factor deficiencies.
Rarely, autoantibodies may cause acquired deficiencies
limited to a single factor.
COAGULATION DISORDERS
• Hereditary deficiencies of many coagulation factors
also have been identified.
• Hemophilia A (a deficiency of factor VIII) and
hemophilia B (Christmas disease, a deficiency of
factor IX) are X-linked traits,
• Whereas other deficiencies are autosomal recessive
disorders.
Deficiencies of Factor
VIII–von Willebrand
Factor Complex
• Hemophilia A and von Willebrand disease are
caused by qualitative or quantitative defects
involving the factor VIII–vWF complex.
• Factor VIII is an essential cofactor for factor IX,
which activates factor X in the intrinsic coagulation
pathway.
• Circulating factor VIII binds noncovalently to vWF.
Deficiencies of Factor VIII–von
Willebrand Factor Complex
• Endothelial cells are the major source of plasma
vWF, whereas most factor VIII is synthesized in the
liver.
• vWF is found in the plasma (in association with
factor VIII), in platelet granules, in endothelial cells
within cytoplasmic vesicles called Weibel-Palade
bodies, and in the subendothelium, where it binds
to collagen.
 Deficiencies of Factor VIII–von
Willebrand Factor Complex
• When endothelial cells are stripped away by
trauma or injury, subendothelial vWF is
exposed and binds platelets, mainly through
glycoprotein Ib and to a lesser degree through
glycoprotein IIb/IIIa.
• The most important function of vWF is to
facilitate the adhesion of platelets to damaged
blood vessel walls, a crucial early event in the
formation of a hemostatic plug.
Deficiencies of Factor VIII–von
Willebrand Factor Complex
• Inadequate platelet adhesion is believed to
underlie the bleeding tendency in von
Willebrand disease.
• In addition to its role in platelet adhesion,
vWF also stabilizes factor VIII; thus, vWF
deficiency leads to a secondary deficiency of
factor VIII.
Deficiencies of Factor VIII–von
Willebrand Factor Complex
• The various forms of von Willebrand disease
are diagnosed by measuring the quantity,
size, and function of vWF.
• vWF function is assessed using the ristocetin
platelet agglutination test.
Deficiencies of Factor VIII–von
Willebrand Factor Complex
• Ristocetin somehow “activates” the bivalent
binding of vWF and platelet membrane
glycoprotein Ib, creating interplatelet “bridges” that
cause platelets to clump (agglutination), an event
that can be measured easily.
• Thus, ristocetin-dependent platelet agglutination
serves as a useful bioassay for vWF.
von Willebrand Disease
• von Willebrand disease is transmitted as an
autosomal dominant disorder.
• It usually presents as spontaneous bleeding
from mucous membranes, excessive bleeding
from wounds, and menorrhagia.
• It is underrecognized, as the diagnosis requires
sophisticated tests and the clinical
manifestations often are quite mild.
von Willebrand Disease

• It is prevalent, particularly in persons of

European descent.
• People with von Willebrand disease have
compound defects in platelet function and
coagulation, but in most cases only the
platelet defect produces clinical findings.
von Willebrand Disease

• The exceptions are rare in patients with

homozygous von Willebrand disease, in
whom there is a concomitant deficiency of
factor VIII severe enough to produce features
resembling those of hemophilia.
von Willebrand Disease

The effects of the causative mutations vary,

allowing von Willebrand disease to be divided
into several subtypes:
Type 1 is the classic and most common variant
of von Willebrand disease.
• It is an autosomal dominant disorder in which
the quantity of circulating vWF is reduced.
von Willebrand Disease
Type II is divided into several subtypes
characterized by the selective loss of high–
molecular-weight multimers of vWF.
• Because these large multimers are the most
active form, there is a functional deficiency of
vWF.
Hemophilia A—Factor VIII
Deficiency
• Hemophilia A is the most common hereditary cause
of serious bleeding.
• It is an X-linked recessive disorder caused by
reduced factor VIII activity.
• It primarily affects males.
• Much less commonly, excessive bleeding occurs in
heterozygous females, presumably due to
preferential inactivation of the X chromosome
carrying the normal factor VIII gene (unfavorable
lyonization).
Hemophilia A—Factor VIII
Deficiency
• Approximately 30% of cases are caused by new
mutations; in the remainder, there is a positive
family history.
• Severe hemophilia A is observed in people with
marked deficiencies of factor VIII (activity levels <
1% of normal).
Hemophilia A—Factor VIII
Deficiency
• Milder deficiencies may only become apparent in
the face of trauma or other hemostatic stressses.
• In about 10% of patients,the factor VIII
concentration is normal by immunoassay, but the
coagulant activity is low because of a mutation in
factor VIII that causes a loss of function.
Hemophilia A—Factor VIII
Deficiency
• In symptomatic cases there is a tendency
toward easy bruising and massive hemorrhage
after trauma or operative procedures.
• In addition, “spontaneous” hemorrhages
frequently are encountered in tissues that
normally are subject to mechanical stress,
particularly the joints, where recurrent bleeds
(hemarthroses) lead to progressive deformities
that can be crippling.
Hemophilia A—Factor VIII
Deficiency
• Petechiae are characteristically absent.
• Specific assays for factor VIII are used to
confirm the diagnosis of hemophilia A.
• Typically, patients with hemophilia A have a
prolonged PTT that is corrected by mixing
the patient’s plasma with normal plasma.
• Specific factor assays are then used to
confirm the deficiency of factor VIII.
Hemophilia A—Factor VIII
Deficiency
• In approximately 15% of those with severe
hemophilia A, replacement therapy is
complicated by the development of
neutralizing antibodies against factor VIII,
probably because factor VIII is seen by the
immune system as a “foreign” antigen.
Hemophilia A—Factor VIII
Deficiency
• Hemophilia A is treated with factor VIII
infusions.
• Factor VIII was prepared from human plasma,
carrying with it the risk of transmission of viral
diseases.
• The availability and widespread use of
recombinant factor VIII and more highly
purified factor VIII concentrates have now
eliminated the infectious risk of factor VIII
replacement therapy.
Hemophilia B—Factor IX
Deficiency
• Severe factor IX deficiency is an X-linked
disorder that is indistinguishable clinically
from hemophilia A but is much less common.
• The PTT is prolonged.
• The diagnosis is made using specific assays of
factor IX.
• It is treated by infusion of recombinant factor
IX.
Thank You