Bleeding Disorders: Abnormalities of

Coagulation Factors
 INTRODUCTION
• Bleeding disorders due to coagulation factor deficiencies
present as spontaneous large ecchymoses, hematomas or
prolonged bleeding following laceration or any surgical
procedure.
• The patient typically complains of continuous oozing for days
after a tooth extraction.
• Hemarthrosis
• Bleeding into the gastrointestinal and urinary tracts is also
common.
COAGULATION DISORDERS
 HEREDITARY COGULATION DISORDERS

• Deficiency usually involves a single clotting factor resulting in

bleeding disorder.
• The three common hereditary disorders are:-
– Hemophilia A (deficiency of factor VIII)
– Hemophilia B (deficiency of factor IX)
– Von Willebrand disease (Deficiency of vWF)

(Deficiency of factor XI is also known as hemophilia C)

 VON WILLEBRAND DISEASE
• Most common inherited group of bleeding disorders.
• It has variable clinical picture and modes of inheritance.
• In most cases, it is transmitted as an autosomal dominant
disorder.
• They are grouped into two major categories: -

Quantitative deficiency of vWF: -

• Type 1 and type 3 von Willebrand diseases are associated with a

decreased quantity of circulating vWF.
• Type 1 is an autosomal dominant, relatively mild disorder and
constitutes about 75% of all cases.
• Type 3 is an autosomal recessive disorder. It is the least
common type and is a severe disorder associated with extremely
low levels of functional vWF.
Qualitative defects in vWF:

• Type 2 von Willebrand disease accounts for 25% of all cases and
is characterized by qualitative defects in vWF.
• It is inherited as an autosomal dominant disorder.
• There are several subtypes:
– Type 2a is the most common of type 2 in which vWF is
expressed in normal amounts, but has defective assembly of
multimers.
– Type 2b is caused by synthesis of an abnormal vWF with
increased affinity for platelets which results in
thrombocytopenia.
 CLINICAL FEATURES

• Bleeding manifestations are mild and remain undetected in

most cases.
• Common symptoms are spontaneous bleeding from mucous
membranes (e.g. epistaxis), excessive bleeding from wounds
or menorrhagia.
 LABORATORY FINDINGS
• Platelet count: Normal.
• Bleeding time: Prolonged.
• Clotting time: Prolonged.
• Tourniquet test (Hess test): This is positive due to defect in
platelet adhesion.
• PT: Normal
• APTT: Normally, vWF stabilizes factor VIII by binding to it.
A deficiency of vWF gives rise to a secondary decrease in
factor VIII levels and prolonged APTT.
• vWF assay: The plasma level of active vWF is decreased.
• Platelet function test:
– Function of vWF is assessed by ristocetin aggregation test.
– Ristocetin induces multivalent vWF multimers to bind platelet
glycoprotein Ib-IX and results in bridging of platelets to each
other.
– The resultant aggregation of platelets is measured by
aggregometer.
– The degree of ristocetin-dependent platelet aggregation is a
measure of vWF activity.
– Defective ristocetin-induced platelet aggregation is
diagnostic of vWF.
HEMOPHILIA A (CLASSIC HAEMOPHILIA)

• Hemophilia A is the most common hereditary X - linked

recessive disease with a reduction in the amount or activity
of factor VIII due to mutation in the gene for factor VIII.
• It is associated with life threatening bleeding due to both
inadequate coagulation.
• About 30% of hemophiliacs have no family history and may
be due to acquired mutations.
• Factor VIII serves as a cofactor for factor IX in the activation
of factor X in the coagulation cascade.
 MODE OF INHERITANCE

• Hemophilia is transmitted as sex - linked recessive disease

• Male are affected and females are usually carriers
• The genes for factor VIII are located on the long arm of the X-
chromosome.
• Hemophilia does not clinically manifest when there is a
normal copy of X-chromosome.
• Males with a defective factor VIII gene (hemophiliac gene) on
their single X chromosome (XH) suffer from hemophilia.
• Heterozygous females are carriers and do not express the full
clinical disease because of the paired normal X-chromosome.
• However, females with two copies of the defective XH
chromosome may rarely suffer from hemophilia
 CLINICAL FEATURES
• Clinical severity depends on the level of factor VIII activity
with normal range expressed as 50 – 150%.
• Moderate to severe deficiency of factor VIII presents with
easy bruising and massive bleeding following trauma or
operative procedures.
• Hemarthrosis may be seen.
• Recurrent bleeding into the joints will lead to crippling
deformities.
• Patient may also present with spontaneous or post-traumatic
bleeding into soft tissues.
Normal range for factor VIII levels are 50% -150%
 LABORATORY FINDINGS

• Bleeding time: Normal.

• Clotting time: Prolonged.
• Platelet count: Normal.
• Prothrombin time: Normal.
• Activated partial thromboplastin time (APTT): Increased
(normal 30–40 seconds)Prolongation of APTT is dependent
upon the severity of deficiency of factor VIII.
• Factor VIII assay: Decreased.
 COMPLICATIONS OF HEMOPHILIA

1. Deforming arthritis and contractures:

– Deforming arthritis due to repeated bleeding into the joints.
– Organization and fibrosis of intramuscular hematomas results in
contractures of involved muscles.
2. Anemia: Excessive, spontaneous or repeated bleeding may
result in anemia.
 CAUSES OF DEATH
• Severe deficiency of factor VIII may result in
spontaneous, fatal intracranial hemorrhage.
• Rarely, prolonged bleeding following surgical procedures
may be fatal.

TREATMENT
• Factor VIII replacement therapy consisting of Factor VIII
concentrates or plasma cryopreceipitates.
 Hemophilia B (Christmas Disease)

• Due to factor IX deficiency

• Clinically indistinguishable from hemophilia A.
• It is also inherited as an X-linked recessive trait and presents
with variable clinical severity.
• Assay of factor IX should be done to diagnose Christmas
disease (named after the first patient).
 CLINICAL FEATURES
• Clinical features are usually milder than those of hemophilia A.
• In both the diseases, hemarthrosis is the common presentation.
• Treatment is by infusion of purified or recombinant factor IX.

LABORATORY FINDINGS

– Similar to hemophilia A
– Bleeding time: Normal.
– Clotting time: Prolonged.
– Platelet count: Normal.
– Prothrombin time: Normal.
– Activated partial thromboplastin time (APTT): Increased (normal
30–40 seconds).
– Factor IX assay: Factor IX is decreased.
SUMMARY OF LABORATORY TESTS IN HEREDITARY
COAGULATION DISORDERS
 Vitamin K Deficiency

• Vitamin K is a fat-soluble vitamin and requires bile for its

absorption.
• Vitamin K is required by liver for the production of 6 vitamin
K dependent factors II, VII, IX, X, protein C and protein S.
• Deficiency of vitamin K results in release of the above
coagulation factors in incomplete and inactive form from the
liver.
• Vitamin K deficiency may develop when absorption is
defective as in obstructive jaundice, pancreatic disease or
small bowel disease.
• In neonates, vitamin K levels are low and are due to liver cell
immaturity, lack of gut bacterial synthesis of the vitamin and
low concentrations of the vitamin in breast milk.
• Liver immaturity along with low level of vitamin K may
produce life-threatening hemorrhage during the first week of
life known as hemorrhagic disease of the newborn.
• The bleeding manifestations show a dramatic response to
parenteral vitamin K therapy.

• The oral anticoagulant drug warfarin is a vitamin K antagonist.

• It inhibits the synthesis of coagulation factors II, VII, IX and
X and is associated with a risk of hemorrhage.
 Liver Disease

• Liver synthesizes virtually all the clotting factors

• Severe liver disease is associated with a hemorrhagic
diathesis.
• Liver disease if associated with hypersplenism may cause
thrombocytopenia

Other Causes

• Disseminated intravascular coagulation which involves

deficiency of several coagulation factors.
 INHIBITORS OF COAGULATION FACTORS

• Acquired inhibitors of coagulation factors (circulating

anticoagulants) are usually autoantibodies.
• Most of these circulating anticoagulants are against factor
VIII and vWF.
• In hereditary coagulation disorders, therapeutic
administration of plasma concentrates containing the
deficient factor, especially hemophilia, may stimulate
production of circulating anticoagulants.

• The anticoagulants can also develop in patients with

autoimmune disorders like systemic lupus erythematosus
and rheumatoid arthritis.
 DISSEMINATED INTRAVASCULAR
COAGULATION

• Disseminated intravascular coagulation (DIC) is a widespread

thrombohemorrhagic disorder in which a combination of
thrombosis and hemorrhage develops as a secondary
complication of wide variety of disorders.
 ETIOLOGY AND PATHOGENESIS

• Disseminated intravascular coagulation is not a primary disease

but develops as a process secondary to several diverse
diseases.
• DIC could result from pathologic activation of the extrinsic or
intrinsic pathways of coagulation or the impairment of clot-
inhibiting mechanisms.
• Even though in acute DIC, the clinical manifestation is
widespread hemorrhage, it is primarily a thrombotic/coagulative
disorder.
MECHANISM OF THROMBI/CLOT FORMATION
Two major mechanisms that initiate the thrombotic process of
DIC are:
1. Entry of procoagulant (thromboplastic) substances into
the circulation.
2. Widespread endothelial injury.
ENTRY OF PROCOAGULANT SUBSTANCES INTO THE CIRCULATION

• The basic process starts with the entry of procoagulant

substances into the circulation.
• The source of procoagulant substance in majority of cases is
tissue factor.
• The placenta and uterine contents are rich sources of tissue
factor.
• Tissue factor gains access to blood by tissue injury.
• Tissue injury may be induced by tissue destruction due to
trauma, burns, surgery, sepsis or malignancy.
• In sepsis, TNF induces endothelial cells to express tissue
factor on their cell surfaces.
• In some, the source of procoagulants may be other than tissue
factor.
• The examples include mucus (released from certain
adenocarcinomas) and cytoplasmic granules (e.g. acute
promyelocytic leukemia cells).
• Tissue factor activates the coagulation system and results in
widespread (disseminated) deposition of fibrin-platelet
thrombi.
 WIDESPREAD ENDOTHELIAL INJURY

• Endothelial injuries expose the thrombogenic subendothelial

matrix leading to activation of both platelets and coagulation
pathway and thrombi formation.

• In sepsis, TNF promotes the adhesion of leukocytes to

endothelial cells and reactive oxygen species and preformed
proteases from leukocytes can damage endothelial cells.
• Widespread endothelial injury may also result from
– Deposition of immune complexes (e.g. SLE)
– Temperature extremes (e.g. burns, heat stroke)
– Microbial infection (e.g. meningococci).
 CONSEQUENCES OF THROMBI
FORMATION
• Both procoagulant substances and endothelial injury activate
coagulation resulting in fibrin-platelet thrombi formation (clot) in
the microvasculature (arterioles, capillaries and venules
throughout the body)
• In the process, clotting factors, fibrin and platelets are consumed.
• Hence, it is also referred to as consumptive coagulopathy or
defibrination syndrome.
• In acute DIC, coagulation factors and platelets are consumed in
excess rate than the synthetic capacity of liver and bone marrow
megakaryocytes respectively.
• Widespread deposition of fibrin-thrombi within the microcirculation
leads to:

Ischemic necrosis:
• Thrombi are found in the microvasculature of any organ especially in
the brain, heart, lungs and kidney.
• Microvascular obstruction leads to widespread ischemic changes with
micro-infarcts or large areas of infarction.
• Multiorgan failure develops as a result of ischemic necrosis of
vulnerable organs.

Microangiopathic hemolytic anemia:

• Red blood cells trapped in the intravascular fibrin-thrombi deposits
undergo fragmentation as they squeeze through the narrowed
microvasculature.
• These red blood cells appear as schistocytes in blood smears in DIC.
MECHANISM OF HEMORRHAGIC DIATHESIS

• The fibrin-thrombi formed activate secondary fibrinolytic

system and plasmin is generated.
• The plasmin cleaves fibrinogen and fibrin and generates fibrin
degradation products (FDP).
• FDPs themselves have potent anticoagulant and antiplatelet
effect and contribute to the hemorrhagic/ bleeding diathesis.
• Thus, the bleeding diathesis in DIC are due to:
– Consumption of platelets
– Consumption of coagulation factors
– Activation of fibrinolytic system.
 MAJOR DISORDERS ASSOCIATED WITH DIC
Infection:
• It is the most common cause of DIC
• Associated with gram negative or gram-positive sepsis.
• Infection may directly or indirectly activate platelets through
release of toxins, TNF or immune complex formation.
Obstetric complications:
• The placenta and uterine contents are rich sources of tissue
factor and other procoagulants.
• In amniotic fluid embolism, patient develops acute fulminant
and often fatal DIC, whereas with a retained dead fetus it is of
subacute or chronic type DIC.
• Other obstetric conditions associated with DIC include
abruptio placentae, toxemia and septic abortion.
Neoplasms:
• Variety of malignant neoplasms like carcinoma of pancreas,
prostate, lung and mucin-secreting adenocarcinoma of
stomach in which thrombotic rather than bleeding
manifestations predominate.

Massive tissue injury:

• Tissue injury caused by trauma, surgery and shock can result
in DIC.
• Brain is a rich source of tissue factor, so traumatic brain injury
can cause acute DIC.
• In massive tissue injury, the major triggering factor is the
release of procoagulant tissue factor.
Vascular disorders:
• In aortic aneurysms, giant hemangiomas and other vascular
malformations, DIC is initiated locally in the abnormal
vasculature but can spread into the systemic circulation.

Miscellaneous
• Snake bite: Snake bites can induce DIC by introduction of
exogenous toxins and release of endogenous tissue factor
via tissue necrosis. Snake venom contains many substances
that can affect coagulation and endothelial permeability.
• Liver disease
 CLINICAL FEATURES
• DIC is a serious, often fatal, clinical condition which needs an
immediate diagnosis and management.
• Depending on the onset, DIC is divided into acute, subacute or
chronic forms.
• Low-grade DIC may be asymptomatic and can only be
diagnosed by laboratory findings.
• Bleeding is the most common clinical feature in acute DIC.
• It may manifest as ecchymoses, petechiae or bleeding from
mucous membranes or at the sites of venipuncture.
• Microvascular thrombi cause ischemic necrosis of the organ
with resultant dysfunction of the involved organ.
• The prognosis depends on the underlying disorder.
• Treatment is largely removal of the underlying cause and
replacement of clotting factors and platelets.
• Mortality is high in severe cases.
 LABORATORY FINDINGS IN DIC
Screening assays

• Platelet count: Decreased due to utilization of platelets in

microthrombi.
• Prothrombin time: Increased.
• APTT: Increased as a result of consumption and inhibition of
the function of clotting factors.
• Thrombin time (TT): Increased because of decreased
fibrinogen.
• Plasma fibrinogen: Decreased due to consumption in
microvascular coagulation
• Peripheral smear: Microangiopathic hemolytic anemia.
Confirmatory tests
• FDP (fibrin degradation products): Secondary fibrinolysis
results in generation of FDPs, which can be measured by latex
agglutination
• Also known as (D-dimer test): It is specific for diagnosing DIC.

>5 = compatible with overt DIC

<5 = repeat monitoring over 1-2 days
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