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Bleeding Disorders:

Understanding the Pathogenesis


and Pathophysiology

Block of Hematopoietic & Lymphoreticular System


Faculty of Medicine University of Brawijaya
Dr. Saiful Anwar General Hospital
Objective
After this session, student can understand &
explain the pathogenesis & pathophysiology of:
 Immune thrombocytopenic purpura (ITP)
 Hemophilia
 Vitamin K deficiency bleeding (VKDB)
Pathogenesis and
Pathophysiology of
Immune Thrombocytopenic
Purpura (ITP)
Immune Thrombocytopenic Purpura
Immune thrombocytopenic purpura (ITP) is an autoimmune
disorder characterized by a low platelet count and
mucocutaneous bleeding.
Classification based on onset and duration of illness:
• Acute ITP (usually in childhood)
• Chronic ITP (usually in adult)
Normal Hemostasis
How does bleeding start and stop?

Bleeding

Primary
Vasoconstriction
Hemostasis

Platelet plug
Secondary
Blood clot Hemostasis
Normal Primary Hemostasis

Hoffbrand AV, Pettit JE, Moss PA. Essential Haematology. 4th ed. 2001
Pathogenesis of ITP
Specific platelet autoantibodies binding to the
platelets

• Autoantibody-mediated platelet destruction
• Suboptimal platelet production
Pathogenesis of ITP
Autoantibody-mediated platelet destruction

Cines DB, Blanchette VS. N Engl J Med 2002


Pathogenesis of ITP
Autoantibody-mediated platelet destruction

Glycoprotein IIb/IIIa are recognized by autoantibodies,


while antibodies recognizing glycoproteins Ib/IX have not
been formed at this stage  antibody-coated platelet

Cines DB, Blanchette VS. N Engl J Med 2002


Pathogenesis of ITP
Autoantibody-mediated platelet destruction

Autoantibody-coated platelets will bind to antigen


presenting cells (APCs), i.e. macrophages, through Fc
receptors  activated macrophage  internalized and
degraded platelet

Cines DB, Blanchette VS. N Engl J Med 2002


Pathogenesis of ITP
Autoantibody-mediated platelet destruction

The destruction of platelets within antigen-presenting


cells may generate a succession of neoantigens,
resulting in sufficient antibody production

Cines DB, Blanchette VS. N Engl J Med 2002


Pathogenesis of ITP
Autoantibody-mediated platelet destruction

Cines DB, Blanchette VS. N Engl J Med 2002


Pathogenesis of ITP
Suboptimal platelet production
The activated APCs

Th cells costimulation
by CD154 & CD40

New peptides are presented

Produce cytokines & activate
B cells

Produce platelet autoantibody

Suppressed megakaryocite
maturation & platelet production
Pathogenesis and
Pathophysiology of
Hemophilia
Hemophilia
Hemophilia is congenital-
inherited bleeding
disorder caused by a
deficiency of coagulation
factor VIII or factor IX
Hemophilia A:
Factor VII deficiency
Hemophilia B:
Factor IX deficiency
The Inheritance of Hemophilia
• Acquired hemophilia
• Congenital inherited
(x-linked recessive)

Hemophilia is a long-life
disease !!
Etiology & Pathogenesis

Inherited x-linked recessive:


genetic abnormalities

Hemophilia A Hemophilia B

The gene for FVIII (F8C) The gene for FIX (F9)
located within the Xq28 located within the Xq27
region; contains 2332 region; contains 415
amino acids amino acids
Normal Hemostasis
How does bleeding start and stop?

Bleeding

Primary
Vasoconstriction
Hemostasis

Platelet plug
Secondary
Blood clot Hemostasis
Normal Secondary Hemostasis
The classic coagulation cascade model
Intrinsic pathway Extrinsic pathway

Common pathway

Hoffman M, Dargaud Y. J Thromb Haemost 2012.


Normal Secondary Hemostasis
The modern coagulation model

Initiation Amplification

Propagation
Hoffman M, Dargaud Y. J Thromb Haemost 2012.
Secondary Hemostasis Disorders

Hemophilia A (FVIII deficiency)


Hemophilia B (FIX deficiency)
Hemophilia with inhibitor

WFH Guidelines 2013.


Pathogenesis of Hemophilia
The classic coagulation cascade model
Intrinsic pathway Extrinsic pathway

Common pathway

Hoffman M, Dargaud Y. J Thromb Haemost 2012.


Pathogenesis of Hemophilia
The modern coagulation model

Initiation Amplification

Propagation
Hoffman M, Dargaud Y. J Thromb Haemost 2012.
Pathophysiology of Hemophilia
Hemophilia (secondary hemostatic disorder):
• Bleeding tendency
• Most internal bleeding: joints, muscles, GIT,
genitourinary tact or intracranial
• The severity of bleeding is generally correlated with
the clotting factor level

Characteristics of laboratory findings:


• Clotting time (CT) prolonged
• aPTT is prolonged; normal aPTT does not exclude
mild or moderate hemophilia
• BT, PT & platelet count normal
Pathophysiology of Hemophilia
The common sites of bleeding in hemophilia
Pathophysiology of Hemophilia
Joint bleeding is primary manifestation
Inhibitors in Hemophilia
What is an inhibitor?
Alloantibody (IgG4) which neutralize (i.e. binds to an active
site) FVIII/FIX and affect the circulation or clearance of
FVIII/FIX.
The most serious complication associated with the using of
FVIII or FIX concentrates.
Antibodies against
A2 domain in FVIII

Antibodies against
C2 domain

DiMichele DM. World Federation of Hemophilia 2008.


Inhibitors in Hemophilia
Mechanisms of inhibitor formation

Key NS. British Journal of Haematology 2004.


Inhibitors in Hemophilia
Risk factors for inhibitor formation

Genetic risk factors


•Genetic mutation: the highest risk is found for null mutations (i.e. large
deletions, nonsense mutations and the intron 22 inversion)
•Family history of an inhibitor
•Race/ethnicity: African or Hispanic
•Immune response traits: explored immunologic factors include the
major histocompatibility complex class II system and polymorphisms of
cytokines (interleukins, TNF-α)

Environmental risk factors


•Intensity of the first factor VIII exposure: surgical procedure, high
frequency treatment
•Inconclusive factors further study is needed:
- Source of factor VIII: plasma-derived vs recombinant FVIII
- Early prophylaxis: to prevent inhibitor formation

Witmer C, Young G. Ther Adv Hematol 2013.


Inhibitors in Hemophilia
What are problems?
• Inhibitors do not increase mortality, but associated with
significant morbidity (higher rate of bleeding, increased
disability & a decreased QoL) and also higher medical
care expenditure per individual.
• Low titers (<5 BU) may indicate transient inhibitor
formation, but patients with high titers (≥5 BU) tend to
have persistent inhibitors

DiMichele DM. World Federation of Hemophilia 2008; Gringeri A, et al. Blood 2003.
Pathogenesis and
Pathophysiology of
Vitamin K Deficiency
Bleeding (VKDB)
Vitamin K
 A fat-soluble vitamin that can be absorbed from the
GI tract in the presence of bile salts.
 Is required for the production of coagulation factor (FII,
FVII, FIX and FX) in the liver.
 Inadequate intake of vitamin K can result in
deficiency in a short period of time because of:
- the short half-life of these factors, and
- the small amounts of vitamin K that can be
stored in the body.
Several Forms of Vitamin K
• Vitamin K1 (Phylloquinone): green leafy vegetables

• Vitamin K2 (Menaquinone): intestinal bacteria

• Vitamin K3 (Menadione): synthetic form


Functions of Vitamin K
Coenzyme for the synthesis of prothrombin & blood clotting
factors in the liver
• Prothrombin and clotting factors are protein in nature
• Synthesis of prothrombin, clotting factors VII, IX, X
require carboxylation of their glutamic acid (Glu)
residue
• Mature prothrombin and clotting factors contain g-
carboxyglutamate (Gla) after carboxylation reaction
• Vitamin K is essential for the carboxylase enzyme
involved
• Dihydroquinone form of vitamin K is essential for this
reaction
Vitamin K Cycle
Vitamin K Cycle

Vitamin K γ-glutamyl
carboxylase (GGCX)
Vitamin K Cycle

Vitamin K γ-glutamyl
carboxylase (GGCX)

Vitamin K dependent
proteins
Vitamin K Dependent Proteins
• Coagulation factors:
- Factor II (prothrombin)
- Factor VII (proconvertin)
- Factor IX (thromboplastin component)
- Factor X (Stuart factor)
• Protein C & protein S
• Protein Z
Functions of Vitamin K
Prothrombin – platelet interaction
•Carboxylated prothrombin contains two carboxylate
groups  bind to Ca2+ forming prothrombin-Ca complex
•The complex then binds to phosholipids on the surface of
platelets (important for blood clotting)
•Converting prothrombin to thrombin & initiating clot
formation
Vitamin K Deficiency Bleeding
Synonym: Vitamin K Deficiency Bleeding (VKDB),
Hemorrhagic Disease of the Newborn (HDN)
Risk factors for VKDB:
• Prolonged antibiotic therapy & gastrointestinal
infections with diarrhea  destroy the bacterial flora
leading to vitamin K deficiency
• Most common in newborn infants
Vitamin K Deficiency Bleeding
Why are newborns vulnerable to deficient in vitamin K ?
• Placenta transfer of vitamin K is very limited
• Vitamin K1 (Phylloquinone) levels in umbilical cord
blood is very low
• The storage of vitamin K in neonate liver is also
limited
• Breast milk is poor source of vitamin K
• GI tract is sterile at birth  gut-related microbial
source of vitamin K is low
Pathogenesis of VKDB

Vitamin K γ-glutamyl
carboxylase (GGCX)

Vitamin K dependent
proteins
Pathogenesis of VKDB

Hoffbrand AV, et al. 2001; Cantor AB. 2009.


Classification of VKDB
Classification by causes
1. Idiopathic
2. Secondary
- poor intake of milk
- malabsorption of vitamin K
- antagonism of vitamin K by drugs
- hepatobiliary disease (predominantly cholestasis)
Classification by age at onset
1. Early VKDB
2. Classical VKDB
3. Late VKDB
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