LO

1. Coagulation Cascade
 Hemostasis → menghentikan bleeding → spy damaged blood vessels maintain a
steady state of blood volume, pressure, and flow
 Three components of hemostasis → vasculature (endothelial cells and
subendothelial matrix), platelets, and blood proteins (clotting factors). 
 The general sequence of events in hemostasis 
a. vascular injury → leads to a transient arteriolar vasoconstriction (limit
blood flow)
b. Primary hemostasis : damage to the endothelial cell lining of the vessel →
exposes prothrombogenic subendothelial connective tissue matrix →
platelet adherence and activation and formation of a hemostatic plug to
prevent further bleeding
c. Secondary hemostasis : tissue factor, produced by the endothelium, +
secreted platelet factors and activated platelets → activate the clotting
(coagulation) system to form fibrin clots 
d. Fibrinolysis : the fibrin/platelet clot contracts → form a more permanent
plug, and regulatory pathways are activated (fibrinolysis) to limit the size of
the plug and begin the healing process.

 Platelets normally circulate freely, suspended in plasma, in an unactivated state.

 The role of platelets is :
o contribute to regulation of blood flow into a damaged site by induction of
vasoconstriction (vasospasm), 
o initiate platelet-to-platelet interactions → resulting in formation of a platelet
plug to stop further bleeding
o activate the coagulation (or clotting) cascade to stabilize the platelet plug, 
o initiate repair processes including clot retraction and clot dissolution
(fibrinolysis). 
 The normal platelet count ranges from 140,000 to 340,000/mm3. 
 If platelet counts drop below 100,000/mm3 → thrombocytopenic (abnormally low
numbers of platelets) → experience prolongation of normal clotting but is usually
not at risk for spontaneous major bleeding episodes unless the platelet count
falls below 20,000/mm3. 
 If platelet numbers are elevated → (thrombocytosis) the risk for spontaneous
blood clots (thrombosis), stroke, or heart attack is increased.
 platelet activation is controlled by endothelial cells lining the vessels. 
 Damage to the vessel → initiates a process of platelet activation; 
o increased platelet adhesion to the damaged vascular wall → activation
o activation → leading to secretion of chemicals from platelet granules,
which stimulate changes in platelet shape and biochemistry
o aggregation as platelet-vascular wall and platelet-platelet adherence
increases → leads to activation of the clotting system and development of
an immobilizing meshwork of platelets and fibrin
Primary Hemostasis
Adhesion
 At sites of vessel injury, platelets become adherent to the site of endothelial
damage where the subendothelial matrix is exposed and endothelial cells have
released vWF and decreased their antithrombotic activities 
 vWF has binding sites to which the fast-moving platelets attach → bridge
between platelets and the injured vessel wall
 Platelet adhesion is mostly mediated by the binding of platelet surface receptor
glycoprotein-Ib (GPIb) (in a complex with clotting factors IX and V) to von
Willebrand factor (vWF) 
 The vWF protein is found in the subendothelial matrix and is released by
endothelial cells and platelets. 
 This layer of stuck platelets → forms the foundation of a hemostatic platelet plug 

 Deficiencies in GPIb (Bernard-Soulier syndrome) or of vWF (von Willebrand
disease) → lead to highly defective hemostasis and congenital bleeding
disorders. 
 Platelet adhesion narrows the diameter of the blood vessel → resulting in
increasing shear forces (bs strip platelets off the vessel surface). 
 However, those same forces → induce conformational changes in the vWF
molecule → result in increased affinity with GPIb (stabilizing the adherent
platelet)

Activation
 interactions subendothelial matrix + exposure to inflammatory mediators
produced by the endothelium + COLLAGEN activates bound platelets →
platelets are activated → Normally platelets are disc-shaped and have a smooth
surface, but activated platelets reorganize their actin cytoskeletal elements to →
develop spiky processes (help them adhere to the collagen and other platelets)
 Platelets contain three types of granules: lysosomes, dense bodies, and alpha
granules
 contents of the dense bodies and alpha granules → important in hemostasis
 dense bodies contain → ADP, serotonin, and calcium. 
 ADP (adenosine diphosphate) → recruits and activates other platelets through
specific receptors, causing the surfaces of nearby circulating platelets to become
sticky so that they adhere to the first layer of aggregated platelets and are
activated → causes more platelets to pile on
 Serotonin → vasoactive amine that functions like histamine and increases
vasodilation and vascular permeability. 
 Calcium → necessary for adhesive interactions & intracellular signaling
mechanisms that control platelet activation.
 Alpha granules → contain clotting factors (e.g., fibrinogen, factor V), growth
factors (e.g., PDGF), and heparin-binding proteins (e.g., platelet factor 4) →
either promote or inhibit platelet activity and the eventual process of clot
formation. 
 PDGF → stimulates smooth muscle cells and promotes tissue repair. 
  Heparin- binding proteins → enhance clot formation at the site of injury.

Aggregation
 Platelets also initiate production of the prostaglandin derivative thromboxane-A2
(TXA2) 
 TXA2 promotes the degranulation of platelets, increases expression of platelet
fibrinogen receptors, and stimulates platelet aggregation by triggering the release
of even more ADP from the platelet granules
 ADP also stimulates → prostacyclin and nitric oxide from the normal
endothelium. Both these chemicals profoundly inhibit platelet aggregation → the
platelet plug is limited to the defect and does not spread to the nearby
undamaged vascular tissue
 TXA2 and ADP → give rise to functional fibrinogen receptors on the platelet. 
 The GPIIb-IIIa complex undergoes a conformational change during activation to
become → calcium-dependent receptor for fibrinogen → binds other matrix
proteins (e.g., fibronectin, fibrinogen, thrombo- spondin). 
 Although the GPIIb-IIIa complex is the most abundant aggregation receptor,
receptors for vWF (GPIb) and collagen (GPVI) also contribute to the process.
 The GPIIb-IIIa–fibrinogen pathway is essential for the formation of a thrombus
and as such is an important therapeutic target for blockage by antiplatelet drugs
 The aggregated platelet plug not only physically seals the break in the vessel but
also performs three other important roles. 
o The actin–myosin complex in the platelet cytoskeleton contracts to
compact and strengthen what was originally a fairly loose plug
o The platelet plug releases powerful vasoconstrictors that induce profound
constriction of the affected vessel to reinforce the initial vascular spasm
o The platelet plug releases other chemicals that enhance blood
coagulation, the next step of hemostasis.
 If blood vessel injury is minor, primary hemostasis is achieved by formation of the
platelet plug within 3 to 5 minutes of injury.
 prothrombinase complexes.
2. PT PTT  cari lebih dalam, + treatment kalo PT PTT abnormal

 PT evaluates clotting within the extrinsic and common coagulation pathways

 Causes of isolated prolonged PT
o Deficiency of or inhibitor to factor VII
o Mild decrease in common pathway factor(s)
o Medications: warfarin and other vitamin K antagonists, direct Xa inhibitors
o Liver disease (early / mild)
o DIC (early)
o Vitamin K deficiency
 aPTT evaluates clotting within the intrinsic and common coagulation pathways
 Causes of isolated prolonged aPTT
o Deficiency of or inhibitor to factors VIII, IX, or XI
o Deficiency of contact factors (factor XII, prekallikrein, high molecular weight
kininogen)
 Contact factor deficiency is not associated with clinical bleeding
o Isolated aPTT prolongation rarely occurs with multiple factor deficiencies such
as DIC or liver failure
o Lupus anticoagulant (nonspecific inhibitor)
o Medications: unfractionated heparin (note: aPTT is commonly used to monitor
unfractionated heparin therapy), direct thrombin inhibitors
 Causes of prolonged PT and aPTT
o Deficiency of or inhibitor to common pathway factors
o Dilutional coagulopathy
o DIC
o Nonspecific inhibitor: lupus anticoagulant with hypoprothrombinemia
o Afibrinogenemia, hypofibrinogenemia or dysfibrinogenemia
o Severe liver disease
o Vitamin K deficiency (severe)
 o Medications: supratherapeutic warfarin, superwarfarins, supratherapeutic
unfractionated heparin, direct Xa inhibitors (high levels), direct thrombin
inhibitors (high levels)

3. All about hemophilia

CO
1. Describe  and understand mechanism normal hemostasis
2. Describe and understand mechanism thrombosis and fibrinolysis.
3. Understand pathophysiology and can be diagnose Hemophilia A and B
4. Knows what is Hemophilia and the genetic aspect of Hemophilia.
5. Can be give first treatment hemophilia therapy before referring the patient to
specialist
6. Understand prevention complications of Hemophilia.
7. Understand strategies of prevention for surgery in Bleeding Disorders.
8. Diagnostic Approach to bleeding  disorders, vascular disorder and
platelets disorder