Hematologic Lesson 1 Flashcards
Maintaining fluidity of the blood, repairing vascular injury, and
limiting blood loss
HEMOSTASIS
Breakdown of the hemostatic mechanism
could result to either ______ or _______
Excessive bleeding
or Thrombosis.
What are the common causes of dysregulated
hemostasis?
- Hereditary
- Acquired defects in the clotting
mechanism - Secondary effects of infection/cancer
What are the steps in Hemostasis?
- Vasoconstriction
- Primary hemostatic plug
- Secondary hemostasis
- Counter regulation
It is the site of injury due to local nueral response and release of endothelin from the endothelium
VASOCONSTRICTION
This is due to the platelet adhesion, activation, degranulation (ADP,TXA2) and recruitment of other platelets
PRIMARY HEMOSTATIC PLUG
It is the activation of coagulation cascade by tissue factor and phospholipid via extrinsic pathway
SECONDARY HEMOSTASIS
It is the fibrin formation (clot)
SECONDARY HEMOSTASIS
The tissue plasminogen activator (t-PA promotes fibrinolysis)
COUNTER REGULATION
It is the antithrombotic cascade (ATIII and others)
COUNTER REGULATION
It is involved in the formation of thrombi that serves a plug to the injured blood vessel, thus arrest bleeding and prevent blood loss
PRIMARY HEMOSTASIS
What are the stages of Primary Hemostasis?
- Platelet adhesion
- Platelet Activation
- Platelet Aggregation
Injury to the cell membrane exposes
collagen and von Willbrand factor
Platelet Adhesion
The platelet membrane receptors,
glycoprotein (GP) Ia receptor binds to
collagen (C) and GP Ib receptor binds to
von Willebrand factor (vWF) causes the
platelet to adhere into the wall
Platelet Adhesion
This event is followed by subsequent
activation of the platelets
Platelet Adhesion
Upon adhesion of the platelet to the
injured wall, activation follows along with
the synthesis and secretion of
vasoconstrictors and platelet-recruiting
and activating molecules
Platelet Activation
The degranulating platelet releases adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin (5-HT) which are aggregating
substances
Platelet Activation
It is synthesized
from arachidonic acid within platelets
and is a platelet activator and potent
vasoconstrictor.
Thromboxane A2 (TXA2)
A powerful inducer of platelet aggregation
Adenosine diphosphate (ADP)
It stimulates
aggregation and vasoconstriction
Serotin (5-HT)
Activation of platelets results in a
conformational change in what?
GP IIb/IIIa receptor
Fibrinogen cross-links to adjacent
platelets, resulting in aggregation and
formation of a platelet plug
Platelet Aggregation
It cross-links to adjacent
platelets, resulting in aggregation and
formation of a platelet plug
Fibrinogen
The coagulation system
cascade is activated, resulting in thrombin
generation and a fibrin clot, which
stabilizes the platelet plug
Platelet Aggregation
The unstable primary platelet plug (thrombus) is stabilized through a cascade of events that converts fibrinogen into
fibrin (stable) clot
Blood Coagulation Cascade
The exposure of TF
on damaged endothelium or to blood that hasextravasated into tissue binds TF
to factor VIIa
Initiation of Clotting
Clotting factor IXa together with VIIIa activates what?
X into Xa
Factor Xa along with factor Va catalyze what?
The conversion of prothrombin (factor II) to thrombin (factor IIa)
Thrombinm (Factor IIa) converts the _______
Soluble fibrinogen (Factor I)
Soluble fibrinogen (Factor I) converts into an __________
Insoluble fibrin (Factor Ia)
It further activates upstream clotting
factors
THROMBIN
What are the primary factors resulting in amplification of thrombin generation.
Primary factors V, VIII, and XI
What are the clotting factors that inhibited by heparin?
Clotting factors;
1. IXa
2. Xa
3. IIa
What are the clotting factors that is inhibited by warfarin?
Factors;
1. VII
2. IX
3. X
4. II
It is attenuate blood
clotting by proteolysis of cofactors Va and
VIIIa
- Protein C
- Protein S
Drugs that inhibit blood
coagulation.
Anticoagulants
These are substances that act on the
secondary hemostatic stage or the blood
coagulation cascade
Anticoagulants
What are the classes of anticoagulants
- Endogenous anticoagulant
- Indirect thrombin inhibitors
- Warfarin and Coumarin Anticoagulants
- Oral direcct factor Xa Inhibitors
- Direct thrombin inhibitors
It is the Protein C and Protein S, Antithrombin III (ATIII)
Endogenous Anticoagulant
Unfractionated heparin (UFH) also known as what?
High Molecular Weight (HMW) heparin
Unfractionated heparin (UFH), also known as high-molecular-weight (HMW) heparin, low molecular-weight (LMW) heparin, and
the synthetic pentasaccharide fondaparinux
Indirect thrombin inhibitors
From what class is these drugs belong? Rivaroxaban, Apixaban, and Edoxaban
Oral direct factor Xa inhibitors
From what class these drugs belong? Hirudin (leech protein), Bivalirudin, Argatroban, Lepirudin
Direct thrombin inhibitors
What causes proteolysis?
Protein C and Protein S
It inactivates clotting factors IIa, IXa, Xa, XIa, and XIIa
Antithrombin (AT)
Heparin binds to ________ and enhance its inactivation of factor _____ Xa
Antithrombin; Xa
Acts like a catalyst that speeds up the interaction between AT and thrombin
Heparin
Heparin’s activity as anticoagulant is dependent on what?
Antithrombin III
Heparin’s activity as anticoagulant is dependent on what?
Antithrombin III
It inhibits clotting factors thrombin (IIa), IXa, and Xa, by forming
equimolar stable complexes with them
Antithrombin
In the absence of heparin, these reactions are ______; but in the presence of heparin,
these reactions are accelerated by _______
Slow; 1000-fold
The accelerating effect of heparin is due
to the unique _________ that has high binding affinity to
antithrombin
Pentasaccharide sequence
It is work by
interfering the synthesis of Vitamin K-dependent clotting factors (II, VII, IX, X)
Coumarin anticoagulants
It is directly inhibit factor Xa, thus preventing
the cascade to proceed
- Rivaroxaban
- Apixaban
- Edoxaban
It exert their anticoagulant effect by directly binding to the active site of thrombin,
thereby inhibiting thrombin’s downstream
effects
Direct thrombin inhibitors (DTIs)
_______ and ______ bind at the catalytic or active site of thrombin as well as at a substrate recognition site.
Hirudin; bivalirudin
_____ and ______(small molecules) bind only at the thrombin active site
Argatroban; melagatran
What are he indications of Heparin?
- Prevent post-op. deep vein thrombosis
- Pulmonary embolism
What are the undesirable effects of heparin?
- Bleeding
- Hemorrhage
- Thrombocytopenia
- Hematoma
What are the reversal of action in heparin?
- For excessive anticoagulaion-discontinuation of the drug
- If bleeding occurs- IV administation of specific antagonist, Protamine sulfate
What is the below normal values/level?
Increases risk of thrombosis
What is the above normal values/level?
Serious bleeding risk increases
What is the toxicity and miscellaneous effects of heparin?
Bleeding
What are the toxicity and miscellaneous effects of heparin?
Should be used with caution in hypersensitive patients
What are the toxicity and miscellaneous effects of heparin?
Increased hair loss and reversible alopecia
What are the toxicity and miscellaneous effects of heparin?
Osteoporosis - long-term therapy
What are the toxicity and miscellaneous effects of heparin?
accelerates the clearing of postprandial lipemia by causing the
release of lipoprotein lipase from tissues
What are the toxicity and miscellaneous effects of heparin?
Long-term use is associated with
mineralocorticoid deficiency
A systemic hypercoagulable state that occurs in 1–4% of individuals treated with
UFH
Heparin-Induced Thrombocytopenia (HIT)
Could lead to increase risk of thrombosis
(e.g.,venous thrombosis) and skin
necrosis in individuals treated with
warfarin
Heparin-Induced Thrombocytopenia (HIT)
Patients who develop HIT are treated by what?
- Discontinuance of heparin
- Administration of the direct thrombin inhibitor. Argatroban
What are the contraindications of Heparin?
- HIT
- Hypersensitivity to the drug
- Active bleeding
- Hemophilia
- Significant thrombocytopenia
What are the contraindications of Heparin?
- Purpura
- Severe hypertension 3. Intracranial hemorrhage
- Infective endocarditis
- Active tuberculosis
What are the contraindications of Heparin?
- Ulcerative lesions of the gastrointestinal
tract - Threatened abortion
- Visceral carcinoma
- Advanced hepatic or renal disease
What are the two containdications that will not likely lead to bleeding?
- HIT
- Hypersensitivity
Should be avoided in patients who have
- Brain surgery
- Spinal cord surgery
- Eye surgery
- undergoing lumbar puncture
- Regional anesthetic block
Should be used in patients whoa are
- Pregnant
What are the indications under warfarin (Coumadin)?
- Deep venous thrombosis
- Ischemic heart disease
- RHD
- Pulmonary embolism
What are the undesirable effects of warfarin?
- Bleeding
- Hemorrhage
- Necrosis
- GI upset
What is the contraindication of warfarin?
Do not administer to pregnant women since it can cause a hemorrahgic disorder in the fetus (teratogenic)
What are the reversal of action in warfarin for excessive anticoagulant effect and bleeding?
- Stopping the drug
- Oral or Parenteral vitamin K1 (phytonadione)
- Fresh-frozen plasma
- Prothrombin complex concentrates
- Recombinant factors VIIa (rFVIIa)
What is the term in therapeutic range for oral anticoagulant therapy?
International normalize ratio (INR)
INR is the ______
Prothrombin time ratio
ISI exponent refers to what?
International Sensitivity Index
It is a narrow therapeutic index drug
It is a narrow therapeutic index drug
Warfarin
INR Below 2.0
Increases risk of thrombosis
INR above 4.0 1
Serious bleeding risk increases
What are the Pharmacokinetic effects of warfarin?
- Enzyme induction
- Enzyme inhibition
- Reduced plasma protein binding
What are the Pharmacodynamic effects of warfarin?
- Synergism
- Competitive antagonism
- Altered physiologic control loop for vitamin K
Given as fixed doses and do not require
monitoring
ORAL DIRECT FACTOR Xa INHIBITORS
Have a rapid onset of action and shorter
half-lives than warfarin
ORAL DIRECT FACTOR Xa INHIBITORS
Drugs that prevent
platelet aggregation, thus are also
referred to as antiplatelets.
Antithrombotics
What are the classes under antiplatelet drugs?
- GP IIb/IIIa receptor antagonist
- ADP receptor antagonist
- TXA2 (COX) inhibitor
- PDE/adenosine uptake inhibitor
