Physiology of Hemostasis Flashcards
What is the Coagulation System?
Highly complex, regulated interaction of cells and plasma proteins
What does the coagulation system provide?
Immediate activation when hemostasis is required and confines its activity to the site of blood loss
End result of the Coagulation System?
Complex of cross linked fibrin molecules and platelets that terminate a hemorrhage
Components of the Coagulation System
Platelets
Endothelial Cells
Tissue-Factor Bearing Cells
Coagulation Factors
Antithrombotic Factors
What are platelets?
-Fragments of megakaryocytes
-Creation is stimulated by cytokines and thrombopoietin (TPO)
-Important source of phospholipids which are required for the function of the coagulation system proteins
What do platelets intracellularly contain?
Dense granules and alpha granules
What is platelet activation called?
Degranulation
What are endothelial cells?
Cells that line blood vessels
What are tissue-factor bearing cells?
Principle initiator of BLOOD COAGULATION
What do activated forms of factors have at the end?
“a”
What are protein C and S?
natural anticoagulants that are also vitamin K dependent
Which factors are dependent on gammacarboxylase?
II, VII, IX, X (2,7,9,10)
Antithrombin inactivates…
Serine proteases IIa, IXa, XIa, Xlla (2,9,11,12)
Primary Hemostasis
Vasoconstriction
Platelet: Adhesion, Activation, Aggregation
Which line of hemostatic defense is primary hemostasis?
First
How does primary hemostasis work?
Begins within seconds of vessel injury and is mediated by circulating platelets.
Involves vasoconstriction, platelet adhesion and activation.
Collagen and thrombin activate platelets –> increase in intracellular Calcium –> secretion of platelet granules
The role of platelets: Adhesion
Adhere to collagen in the vascular subendothelium.
Exposed collagen releases von willebrand factor
The role of platelets: Activation
Granules release ADP, calcium, and thromboxane A2 to activate further platelets
-GP llb/llla receptors are exposed on the platelet
The role of platelets: Aggregation
Changes shape from discord –> spherical with extensions and then a flat shape to cover the injury
Secondary Hemostasis
Formation of fibrin via initiation, amplification, and propagation
Where does initiation occur?
the SURFACE of INJURED CELLS
What is released first in initation?
Tissue factor (TF) by the injured cells
Which factors does TF activate? (initiation)
Factor VII (7)
Which factors does Factor VII activate? (initation)
Factors IX and X (9 and 10)
What does the activation of factors IX and X catalyze? (initiation)
The conversion of factor II to IIa (activates it)
What is factor II?
Thrombin
What does factor IIa do? (initiation)
cleaves fibrinogen to fibrin
What is fibrin?
Small insoluble proteins that polymerize to form the complex fibrin
The amount of fibrin generated during initiation is…
Insufficient to stabilize the platelet plug
Where does amplification occur?
the SURFACE of PLATELETS
Thrombin is generated in initiation activates…
platelets and coagulation factors V, VIII, and XI (found on platelet surface) (5, 8, 11)
Factor VIII is activated by… (amplification)
releasing it from Von Willebrand Factor
Factor XIa catalyzes… (amplification)
activation of IX and IXa
What is propagation?
Activated platelets recruit other circulating platelets to the site of injury
What are the two main complexes formed in propagation?
Tenase and Prothrombinase
What is tenase?
factors VIIIa and IXa with phospholipids and calcium (8,9)
What does tenase activate?
factor X on the platelet surface
What is prothrombinase?
factors Xa and Va with phospholipids and calcium (5,10)
What does the prothrombinase complex catalyze?
The cleavage of factor II to IIa
The cleavage of factor II to IIa is…
prothrombin –> thrombin
Thrombin activates _____ fibrin to stabilize platelet plug
enough
Thrombin activates factor XIIIa which…
solidifies the fibrin polymer
What is fibrinolysis?
Process of breaking down fibrin into degradation products
Plasmin is a serum protease that cleaves fibrin, which leads to…
the breakdown of clot and creation of fibrin degradation products
Thrombin catalyzes formation of…
plasmin from its inactive precursor plasminogen which functions as its own negative feedback loop
Coagulation Cascade: Platelets initiate here
Vascular Injury
Coagulation Cascade: This pathway amplifies and propagates the cascade
Surface Activation
Coagulation Cascade: Which has to do with amplification (thrombin activates V, VIII, and XI on platelet surface?
Thrombin
Why does a clot form to begin with?
Virchow’s Triad!
Hypercoagulable state, Vascular injury, circulatory stasis
Risk factors for clotting: Hypercoagulable State…
Malignancy, Pregnancy, Inflammatory state, Factor V Leiden, Protein C/S deficiency, Oral contraceptives
Risk factors for clotting: Circulatory Stasis…
Hospitalizations, surgery, obesity, long distance travel
Risk factors for clotting: Vascular Injury…
Orthopedic Surgery, trauma, venous catheters, smoking
Risk factors for clotting: Multiple Components…
History of VTE, Age (older = increase risk)
Other risk factors: Metabolic syndrome…
especially in presence of abdominal obesity
Other risk factors: inflammatory disorders…
Crohn’s disease, ulcerative colitis, rheumatoid arthritis, infections
What is VTE?
Venous Thromboembolism
clot occurring in the VENOUS circulation
What are the two types of VTE?
Deep Vein Thrombosis (DVT)
Pulmonary Embolism (PE)
Deep Vein Thrombosis (DVT)
Usually occurs in a lower extremity
Due to blockage (thrombosis= clot in diseases vessel)
Rarely fatal
Pulmonary Embolism (PE)
Occurs in the lung
Usually due to dislodged blockage (embolism= mobile clot)
Can be fatal (usually the more serious VTE)
Embolus
traveling clot (usually more serious)
Thrombus
located in the spot where it started to form
Signs and Symptoms of DVT?
Unilateral leg pain, redness, swelling, and/or warmth
Positive Horman’s sign (dorsiflexes foot)
Elevated D-dimer (byproduct of thrombin generation)
What % of DVTs are proximal?
70-80%
Location of proximal DVTs?
Knee and above! Closer to the heart
What % of DVTs are distal?
20-30%
Location of distal DVTs?
Isolated in veins under the knee! Further from the heart
Why do we care about proximal vs distal DVT?
Distal DVT is unlikely to lead to PE
What is Pulmonary Embolism (PE)?
Most commonly thromboembolism (>95%) but can be made of other material
What test is used for DVT?
Duplex ultrasound with doppler flow
Usually diagnosed through this, it allows the radiologist to see blood flow, relatively quick and easy
In PE, the lungs possess…
Excess functional capacity and redundant vascular supply allowing them to filter a significant amount of emboli within minimal impact on lung function or hemodynamics
Large thrombi or an accumulation of smaller ones can cause…
Substantial impairment of cardiac and respiratory function/death
Where does PE never usually originate from?
The pulmonary circulation
Signs and Symptoms of PE?
The Classic Triad (dyspnea, pleuritic chest pain, hemoptysis)
Dyspnea most common
Cough, tachypnea, tachycardia, elevated D-dimer
Where are symptoms of DVT usually identified?
Legs
Creation of ‘dead space’ ventilation is…
When there is oxygen in the area but there is no perfusion (no blood flow)
Limits the ability to eliminate carbon dioxide
How does the body usually overcompensate for ‘dead space’ ventilation?
It increases minute ventilation which blows off extra carbon dioxide, which can lead to respiratory alkalosis
(little to no impact on oxygenation- oxygen saturation is normal or moderately reduced)
Testing for PE…
Multiple options
Ventilation/perfusion scan
CT pulmonary angiography
Severity of PE is dependent on…
Clot burden, neurohormonal reflexes, pre-existing cardiopulmonary disease
Without cardiopulmonary disease: can accommodate….
an occlusion up to about 1/3 of their pulmonary circulation
Adapts to diverted blood flow through the recruitment and dilation of compliant pulmonary arterial vessels
Without cardiopulmonary disease: hemodynamic compromise occurs when…
larger emboli occur or vasoconstricting mediators are elaborated
In patients with cardiopulmonary disease: the size of the emboli,,,
does not correlate with the level of hemodynamic compromise
Normal adaptive mechanisms are ineffective
PE Severity Classification: Low Risk
PE not meeting other criteria
PE Severity Classification: Intermediate Risk
Right ventricular strain:
On ECHO, (+) troponin, (+) BNP
PE Severity Classification: High Risk
Systolic BP < 90 mmHg or decrease of 40 mmHg from baseline
PE Severity Classification: High Risk…what does it require?
Vasopressors, Pulseless
Provoked VTE
Caused by a known event
Some known events for Provoked VTE?
Long-distance travel, surgery, hospitalization, other elements of Virchow’s Triad!
Unprovoked VTE
No identifiable factor causing VTE
