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Applied Physiology of Applied Physiology of Bleeding DisordersBleeding Disorders
Dr.B.Gowri Shankar MD pg
Prof.Dr.G.Sundaramurthy’s unit(M 7).
Hemostasis
• Blood must be fluid
• Must coagulate (clot) at appropriate time– Rapid– Localized– Reversible
Thrombosis…inappropriate coagulation
3 Major systems involved
• Vessel wall– Endothelium
– ECM = BM (type 4 collagen + other proteins)
• Platelets• Coagulation cascade
– Coagulation factors (proteins)• Names and numbers
• Active and inactive forms (zymogens)
Antithrombogenic Thrombogenic
Vessel injury
(Favors fluid blood) (Favors clotting)
Antithrombotic Properties of the Endothelium
• Anti-platelet properties– Covers highly thrombogenic basement
membrane– Uninjured endothelium does not bind platelets– PGI2 (prostacyclin) and NO from uninjured
endothelium inhibit platelet binding– ADPase counters the platelet aggregating
effects of ADP
Antithrombotic Properties of the Endothelium
Anticoagulant properties
*HEPARIN-LIKE MOLECULES: activate anti-thrombin III (inactivates active proteases)
*THROMBOMODULIN: changes specificity of thrombin (activates protein C , which
inactivates factors Va and VIIIa
*Endothelial cells produce tPA which activates fibrinolysis via plasminogen to plasmin
Prothrombotic Properties of the Endothelium•Synthesis of von Willebrand factor
•Release of tissue factor
•Production of plasminogen activator inhibitors (PAI)
•Membrane phospholipids bind and facilitate activation of clotting factors via Ca bridges
Platelet Response to Agonists
Platelets - unstimulated Addition of ADP
(mild stimulation)
Addition of thrombin
(strong stimulation )Characteristic discoid shape
Shape change (elongation and crescents) and Fila form process formation (arrows)
Increased spreading, Fila form process extension (arrows) and aggregate formation (stars)
PLATELET
Coagulation Cascade
• Enzymatic cascade (amplification)• Several serine proteases
– Produced by liver (most)
– Require Vit K (several)
• 3 protein cofactors (not enzymes)• Requires Ca 2+
• Localized to site of injury • Reversible (via production of plasmin)
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
Fibrinogen Fibrin
Fibrinogen FibrinThrombin
Fibrinogen FibrinThrombin
Prothrombin
XaVa
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
Hemophilia A
Deficiency of/nonfunctional VIII
Hemophilia BDeficiency of /nonfunctional IX
Why do they bleed?
Hemophilia C
Deficiency of/nonfunctional XI
Thrombin (IIa)
Prothrombin (II)
Xa
VIIa
TF
IXa
Revised Coagulation Pathway (Tissue Factor Pathway)
IX
NB: production of IXaInteraction of intrinsic and extrinsic pathways
Tissue Factor Pathway Inhibitor
• Kunitz-type protease inhibitor (kringles)• 34 and 41 KD forms in plasma (C-term
truncation)• Directly inhibits Xa• Inhibits VIIa-TF complex in a [Xa]-dependent
manner• Bound to LDL, HDL and Lp (a)• ~10% present in platelets (endothelium also)
Thrombin (IIa)
Prothrombin (II)
Xa
VIIa
TF
IXa
Tissue Factor Pathway Inhibitor
IX
TFITFPI
NB: Inhibition of Xa and VIIa
Proposed Mechanism of Tissue Factor Pathway Inhibitor (TFPI) Activity
F-Xa
Endothelium
Tissue factorF-VIIa
TFPI
F-Xa
TFPITFPI
F-Xa
Physiologic Inhibitors of coagulation
• Antithrombin III (serpin)• Activated Protein C + protein S
– Inactivates Va and VIIIa (via proteolysis)– NB: Factor V Leiden
• Thrombomodulin (EC glycoprotein)– Binds to thrombin– Decreases ability to produce fibrin– Increases ability to activate Protein C
Proposed Mechanism of AT III-Heparin System
HeparinThrombin Antithrombin
Lysine sites
Serine site
Argininesite
H
Th
H
AT III
AT III
Th
Proposed Mechanism of Thrombomodulin, Protein C and Protein S (TM-PC-PS) System
Thrombin
Prothrombin
Protein C
Thrombomodulin
Thrombin
F-Xa
Activatedplatelet
PS
F-Va
x
Ca++
Ca++
ActivatedProtein C
Role of vitamin K
Some clotting factors require a post-translational modification before they are active in clotting
These factors are II, VII, IX, X, proteins C and S
This PTM involves the addition of a COO- to certain Glu residues in the clotting factors
This PTM results in the formation of several -carboxy glutamates = Gla
This PTM requires vitamin K
Role of vitamin K
• Vit K is altered in carboxylation Rx and must be regenerated before reuse
• Regeneration involves 2 reductases which convert vit K epoxide to vit K
• Vit K antagonists inhibit these reductases
• Vit K-dependent PTM provides sites on modified coag factors for Ca bridging
Non-physiologic inhibitors of coagulation
• Vitamin K antagonists (in vivo only)
• Ca chelators (in vitro only)– EDTA– Citrate– Oxalate
* Heparin (in vivo and in vitro)
Clot removal
Fibrin Fibrin Split Products (FSP)Plasmin
Fibrinolysis
Fibrin Fibrin Split Products (FSP)Plasmin
Plasminogen
tPA
Fibrinolysis
Inhibitors of fibrinolysis
• Plasminogen activator inhibitors (PAIs)
2-antiplasmin (serpin)
Pathophysiology of DIC loss of localization of coagulation process caused by abnormalities in any of four
major components of hemostasis1. vascular integrity2. platelets3. coagulation cascade4. clot lysis
Pathophysiology of DIC
Disruption of Vascular Integrity vascular endothelial
damage can initiate coagulation and DIC causes platelet
adhesion and aggregation
vasculitis (infectious, systemic lupus)
burns dissecting aortic
aneurysms
Pathophysiology of DIC
Abnormal Platelet Function
Pathophysiology of DIC
Abnormal Platelet Function altered platelet aggregation causes DIC
platelets coated with immune complexes or bacteria aggregate without vascular injury
immune complex disease pregnancy toxemia (immune complexes) viraemia sepsis or bacteremia
diffuse platelet consumption and destruction
Pathophysiology of DIC
Clotting Factor Abnormalities
Pathophysiology of DIC
I. Abnormal Factor Activation intravascular tissue phospholipid causes
abnormal activation of clotting factors provides surface for factor activation
massive trauma necrotic tumor red cell hemolysis of any cause obstetric complications: retained dead fetus,
placental abruption, amniotic fluid embolus
Pathophysiology of DIC
I. Abnormal Factor Activation widespread activation of coagulation leads
to formation of fibrin coagulation factors consumed
concentrations of fibrinogen and labile cofactors (V and VIII) decline first
used once and destroyed serine proteases capable of catalyzing multiple reactions
Pathophysiology of DIC
II. Abnormal Factor Control hemostasis controlled by antithrombin (AT)
and protein C antithrombin inhibits active serine proteases protein C regulates thrombin formation
deficiencies lead to excess clot formation and factor consumption precipitate or exacerbate DIC
Pathophysiology of DIC
Accelerated Fibrinolysis
fibrinolysis → fibrin split products (FSPs) also called fibrin degradation products (FDPs)
clearance mechanisms may be overwhelmed FSPs normally cleared by Kupffer cells
excess FSPs cause decreased clot formation coat platelets and inhibit aggregation inhibit fibrin cross-linking
Pathophysiology of DIC
Accelerated Fibrinolysis urokinase lyses
fibrin clots catalyzes synthesis
of plasmin from plasminogen
leads to excess FSP production
promotes DIC prostate disease,
urinary tract surgery
Heparin Induced Thrombocytopenia
HIT(heparin-induced thrombocytopenia)
HAT(heparin-associated thrombocytopenia)
White- clot syndrome
HIT An immunoglobulin-mediated adverse
drug reaction characterized by: platelet activation thrombocytopenia thrombotic complications
Pathogenesis of HIT Most commonly caused by IgG antibodies
(designated HIT-IgG) that activate platelets through their Fc receptors
Antigenic Heparin/PF4 Complex
antigen in HIT is a complex of “-” charged heparin polysaccharide and “+” charged protein tetramer (platelet factor 4 or PF4)
PF4 - released from platelet storage granules during platelet activation
unfractionated heparin wraps around PF4 to a greater extent than LMWH
Effects on the coagulation system
Binding of heparin to PF4 neutralizes the anti-coagulant effect of heparin
Immune complexes composed of heparin, PF4, and IgG binds to platelet Fc receptors, resulting in strong platelet activation, and ultimate increase in thrombin generation
10/98 medslides.com 55
Iceberg Model
Multiplethrombosis
(white clot syndrome)0.01-0.1%
Isolated thrombosis30-80% of below groups
Asymptomatic thrombocytopenia30-50% of below group
HIT - IgG seroconversion 0-10%
Warkentin TE, et al. 1994;75-127
Pathophysiology of Drug-induced thrombocytopenia Certain drugs(quinine, quinidine, sulfa
antibiotics) link non-covalently to platelet membrane glycoproteins
very rarely, IgG antibodies are produced that recognize these drug-glycoprotein complexes
macrophages remove the complexes causing severe thrombocytopenia
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