3.1 Haemostasis & thrombosis Flashcards
Blood consists of blood cells (45%; with 99% _____________) and blood plasma (55%; with 90% water):
• Platelets represent a small proportion of blood cells and are fragments of _________________ (involved in primary haemostasis)
• Plasma clotting factors are divided into procoagulants (prothrombin, factors V, VII – XIII, fibrinogen) and anticoagulants (________________________)
erythrocytes;
megakaryocytes;
plasminogen, TFPI, protein C/S, antithrombin
Thrombosis is a pathophysiological process where blood coagulation occurs within an _____— blood vessel and blocks flow:
• Clot may become life-threatening if it dislodges from the vessel (embolises) and becomes trapped in another vessel
• May also form within an _____________; upon rupture, thrombus may be formed on the endothelium or embolise and become trapped in a smaller vessel (if trapped in coronary artery, patient suffers a myocardial infarction)
intact;
atherosclerotic plaque
White thrombi
- formed in _________
- high in _________
arteries;
platelets
Red thrombi
- formed in __________
- High in _____
veins; fibrin
Virchow’s triad describes the 3 main factors which increase the probability of thrombus formation (rate of flow, blood constituents, vessel wall integrity):
Rate of blood flow
- ______ flow
- No replenishment of _____ factors, balance is adjusted in the favour of coagulation
Consistency of blood
- Natural imbalance between procoagulation (↑) and anticoagulation (↓)
- e.g. factor V Leiden (abnormal binding of _____________) resulting in reduced breakdown and increased levels
blood vessel wall integrity
- Damaged _________ → blood is exposed to procoagulation factors
- E.g. prolonged increase in BP (pressure on endothelial cells), surgery (scraping of endothelial cells)
slow/ stagnating;
anticoagulation;
Protein C to factor V;
Endothelial cells
The cell-based theory of coagulation involves 3 steps (initiation, amplification, propagation):
Initiation
- small scale __________ production
- targeted by _____________ (initiation involves many factors of the coagulation cascade)
Amplification
- large scale thrombin production on ______ surface
- targeted by _________ (amplification involves platelets and some factors)
Propagation
- thrombin mediated generation of ______________
- targeted by __________ (where fibrin is generated)
thrombin;
anticoagulants;
platelet;
antiplatelets;
fibrin strands;
thrombolytics/ fibrinolytics
[Anti-coagulants]
During the initiation stage, tissue factor (TF)-bearing cells (primarily ___________) are present in the blood and also express ____________ (prothrombinase complex):
• Prothrombinase complex activates factor II (prothrombin) to create factor IIa (thrombin)
• The main anticoagulant in the blood antithrombin (AT-III) inactivates thrombin and prevents the process from moving into the _____________ phase (prevents thrombosis)
leukocytes;
factors Va and Xa ;
amplification
There are four main classes of anticoagulant
[Anticoagulants]
Direct thrombin (factor IIa) inhibitors (DTIs)
- Dabigatran: First orally available DTI; used for prophylaxis of VTEs during ______ and stroke in patients with ___________
- ______________: Parenteral anticoagulant; used primarily as an adjunct
Heparin and its derivatives – potentiates antithrombin activity
- UFH: Short half-life (1 hour) so must be given at regular intervals/by continuous infusion (largely replaced by LMWH; reserved for ____________ patients)
- LMWH (e.g. dalteparin): Possesses _____________ with weaker anti-IIa activity; used primarily for prophylaxis and treatment of DVT
Factor Xa inhibitors
- ____________: First orally available factor Xa inhibitor; used for prophylaxis of VTE during surgery, stroke in atrial fibrillation and prophylaxis and treatment of DVT
- _______________-: Parenteral factor Xa inhibitor; primarily used for prophylaxis and treatment of DVT in certain patients
Vitamin K antagonists – vitamin K is essential for factor II, VII, IX, X synthesis
- Warfarin: Commonly used oral anticoagulant, but possesses a long delay of onset (~5 days), narrow ____________ (dosage must be accurate), unpredictable pharmacokinetics (bioavailability among individuals varies), numerous drug interactions (affects ______________ metabolism)
surgery; atrial fibrillation ;
Bivalirudin;
renal failure;
anti-Xa activity;
Rivaroxaban; Fondaparinux;
therapeutic window;
CYP450 drug
[Antiplatelets]
During the amplification phase, thrombin activates platelets, which produce a number of other clotting factors:
• Activated platelets change shape from __________ to _______
• Thrombin also causes liberation of ___________from the endothelium, which activates even more factor II (prothrombin) to IIa (thrombin)
• Surface of the platelets contains _________________ which bind thrombin and cause increased intracellular Ca2+, resulting in the shape change and ______________ from dense granules into the bloodstream
ADP has both autocrine and paracrine effects affecting ________________ on platelets (leading to platelet aggregation) and liberation of ____________ from the cell membrane (allowing COX-1 to generate thromboxane A2 within the platelet):
• Thromboxane A2 also leads to the expression of _________________ on platelet surface (heavily involved in platelet aggregation → all platelets expressing it are likely to attach to each other)
circular; stellate;
vWF ;
protease-activated receptors (PARs) ;
exocytosis of ADP;
P2Y12 subtype ADP receptors;
arachidonic acid;
GpIIb/IIIa integrin receptor
[Antiplatelets]
P2Y12 receptor antagonists
- _______________: Used mainly for atherothrombotic disorders
COX-1 inhibitors: Aspirin
- Irreversibly inhibits COX-1 (preferred over ___________ which reversibly inhibits it):
• 75mg tablets are generally used to treat atherothrombotic disorders or secondary prevention of cardiovascular disease
• 500mg tablets are used to treat headaches
• High doses not more effective at treating CVD, but have more side effects
GpIIb/IIIa receptor antagonists
- _____________: Binds specifically to GpIIb/IIIa integrin receptor (limited use and only by specialists)
Clopidogrel and Prasugel;
ibuprofen;
Abciximab
[Thrombolytics]
During the propagation phase, large scale production of thrombin causes the conversion of fibrinogen (present in lumen) to fibrin strands, which trap blood cells in a mesh-like net to form the thrombus:
• Anticoagulants and antiplatelets are not effective in _________________ because they only prevent further clot formation (thrombolytics must be used)
• Thrombolytics convert __________________ (natural protease which degrades fibrin strands and breaks down the clot → clot-busting treatment)
o Most effective when administered as soon as possible after thrombus formation → indicated for ________________________
removing pre-formed clots;
plasminogen to plasmin;
myocardial infarction and other thromboembolic disorders (e.g. DVT)
[Thrombolytics]
- Alteplase: __________________ used to activate plasminogen to plasmin and promote clot dissolution
- ____________: Bacterial-derived tPA which is cheap and effective
Tissue type plasminogen activator (tPA) ;
Streptokinase
use what to treat DVT?
anticoagulants
use what to treat PE?
Anticoagulants, thrombolytics
Use what to treat strokes?
Antiplatelets, thrombolytics
