Hemostasis I Flashcards
What are the active pro-coagulant enzymes?
Serine proteases
What are the following co-factors that favor coagulation, i.e. the accelerants
- ) Soluble
- ) Cell-bound
- ) V and VIII
2. ) Tissue factor
Another accelerant co-factor is
Von Willebrand Factor
What are three anti-coagulant factors?
Thrombomodulin, Protein C, and Protein S
What is step one of hemostasis?
Local Vasoconstriction
The local vasoconstriction is caused by the release of the powerful vasoconstrictor
Endothelin
Step 2 of primary hemostasis is formation of the
Platelet plug
Hemostasis depends on
Platelet function
Platelets originate from the
Hematopoetic stem cells
Thrombopoiesis is regulated by the
Megakaryocyte
The platelet massis regulated by
Thrombopoietin
We see decreased platelet and megakaryocyte mass with increased
TPO
DNA replicates without nuclear or cell division
Endomitosis
A megakaryocyte nucleus MUST be polypoid to produce
Platelets
Platelets are formed in the bone marrow from
Megakaryocytes
What is a normal platelet count
150K to 350K
Characterized by too few platelets
Thrombocytopenia
Characterized by too many platelets
Thrombocytosis
Platelet size correlates with reactivity i.e. larger platelets are typically younger and are
Prothrombotic
Normal endothelial monolayer is
Anti-thrombogenic
Important for platelet adhesion when the endothelial monolayer is injured
von Willebrand Factor
A large circulating multimer, synthesized in endothelial cells and megakaryocytes
von Willebrand Factor
von Willebrand factor is stored in
Weibel-Pallade bodies
Plays an important role in both primary and secondary hemostasis
von Willebrand Factor (vWF)
At the side of injury, vWF adheres to exposed
Collagen
Facilitates platelet tethering to subendothelial BM
vWF
With injury, vWF adheres to the vessel
Subendothelial matrix
With shear, vWF multimers uncoil, causing the adherence and activation of
Platelets
Activated platelets expose phosphatodyl serine and bind
-to facilitate clotting
FVIII
Bleeding ceases by platelet-fibrin plug, sealing vascular injury and is followed by
Thrombolysis and tissue repair
Deficiency of GpIIb-IIIa complex causes
Glanzmann thrombasthenia
Deficiency of GpIb causes
Bernard-Soulier syndrome
Deficiency of vWF causes
von Willebrand disease
Activatedby adhesion and soluble mediators
Platelets
Resting platelets are smooth and disc shaped, while activated platelets have an
Irregular shape
Platelet aggregation occurs through binding of two
GPIIb/IIIa’s
Primary hemostasis can be summarized as
Adhesion, Activation, and Aggregation
Adhesion is primarily through
vWF
Activation occurs primarily through
Collagen and ADP
Aggregation occurs primarily through
Fibrinogen, GPIIb/IIIa, and aIIbb3
What are three drugs that target platelet function improve outcome in patients with unstable angina
Aspirin, Thienopyridines, Glycoprotein IIb/IIIainhibitors
Blocks TXA2 production
Aspirin
Block ADP receptors (P2Y12)
Thienopyridines
Block platelet adhesion to fibrinogen/fibrin and vWF
Glycoprotein IIb/IIIainhibitors
Not normally active in circulation
Platelets
LOW platelet counts (<10 to 20K) result in
Petechiae
Reddish purple discolorations on the skin that do not blanche on applying pressure
Petechiae
Release trophic factors which maintain cell-cell contacts
Platelets
The initial platelet plug is not very
Strong
Thus, the platelet plug requires a strong
Sealant
An essential component of hemostasis is the formation of
Cross-linked fibrin
The process by which cross-linked fibrin is formed
Secondary hemostasis
The clotting cascade results in the formation of fibrinfrom
Fibrinogen
What are the three major classes of pro-coagultion players?
Serine proteases, cell-associated cofactors, and soluble cofactors
Serine proteases circulate as
Zymogens
An example of a cell-associated cofactor is
Tissue factor
Which three pro-coagulation players are NOT made in the liver?
Tissue factor, VIII, and vWF
Most coagulation factors are serine proteases that circulate as
Zymogens
When activated, coagulation factors are written with an
“a” i.e. X –> Xa
What are the two components of the Extrinsic hemostasis pathway?
Factor VII and tissue factor
What are the three components of the Intrinsic hemostasis pathway?
Factors IX, XI, and XII
What are the two components of the common hemostasis pathway?
Factor X and Factor II (prothrombin)
In the extrinsic pathway, vessel wall injury increases
Tissue factor expression
A transmembrane protein that is not normally accessible
Tissue Factor
Synthesized and expressed by endothelial cell AND monocytes
Transmembrane protein
Step 2 of the extrinsic pathway is tissue factor is bound by
Factor VII
Circulating Factor VII binds Tissue Factor (TF) and is activated, thus it becomes
Factor VIIa
Tissue Factor activates
Factor VII
Then Factor IX (9) is recruited to the complex and
Activated
Then, TF:FVIIa:FIXacomplex activates
Factor X
Then, FXaactivates Prothrombin (FII/2) to
Thrombin
Thrombin then cleaves fibrinogen to form
Fibrin
Step 4 is called
Amplification #1
During amplification #1, thrombin activated more
Factor IX and VIII
Anti-hemophilic factor activated by thrombin
Factor VIII
Factor VIII circulated in the plasma in a complex with
vWF
Links platelets to subendothelial BM
vWF
Binds to and stabilizes Factor VIII, extending half-life from 8 minutes to 8 hours
vWF
The most common inherited bleeding disorder
von Willebrand disease
Characterized by easy bruising, skin bleeding, and prolonged bleeding from mucosal surfaces
Von Willebrand Disease
A soluble co-factor with no enzymatic activity
Factor VIII
Factor VIIIa functions as an accelerant/catalyst for
Factor IXa
What is the clinical significance of the Factor VIII/IX complex?
Hemophilia A (VII) and Hemophilia B (IX)
Another soluble co-factor with no enzymatic activity that functions as an accelerant/catalyst for Factor Xa
Factor V
Factor IXa-VIIIacomplex generates LARGE amounts of activated
Factor X
Converts prothrombinto thrombin 300,000X faster than FREE factor Xa
Factor Xa-Va complex
What are the three pro-coagulant complexes that are essential to coagulation?
- ) Tissue Factor::Factor VIIa::IXa≈ Factor X
- ) Factor IXa::VIIIa≈ Factor X
- ) Factor Xa::Va ≈ Factor II (Prothrombin)
Which pro-coagulant factors are dependent on Vitamin K?
Prothrombin (II) and Factors VII, IX,
Which anticoagulants are dependent on Vitamin K?
Proteins, C, S, and Z
Dependent on Vitamin K
Serine proteases
Vitamin K dependent factors have glutamate rich
N-terminus
Carboxylation of the GLU residues is required for
Activation
Carboxylation is dependent on
Vitamin K
The basis for anticoagulant action of sodium citrate
Blocking Ca2+
VitK2 is synthesized by colonic flora which can be disturbed by antibiotics leading to relative
Vitamin K deficiency
What are the two important forms of Vitamin K
Phylloquinone(K1) and Menaquinones(K2)
A drug that targets Vitamin K,was initially developed as a rodenticide
Warfarin
Action of warfarin is to block VitK dependent
Reductases
How is the intrinsic pathway activated?
Contact activation
Contact activation is independent of
Tissue Factor
