thrombolysis firbiolytic drugs Flashcards
(15 cards)
1- 4th step in haemostasis : firbinlytic/thrombolytic cascade :
Purpose: to limit – to immediate site of injury
And to — components of clot after tissue repair
2- intact endothelium regulates coagulation:
- Secrete— (to dissolve existing fibrin-rich clot)
-express – & — on their surface (to prevent the formation of new fibrin-rich clot)
produce inhibitory reagents — & — that prevent platelet activation (to prevent the formation of new platelet-rich clot)
clot formation
remove
tissue plasminogen activator tPA
expresses heparin and thrombodulin
NO and PGI2
Fibrinogen is a — polypeptide MW=340kD
synthesised in –
Comprised of — polypeptides: 2 X — (Pink), 2 X – (green), 2 X – (orange)
It is a — plasma protein present at approx 3mg/ml in normal plasma (represents ~7% of all plasma proteins)
It is a — for —
Thrombin, (an enzyme) cleaves short — terminal peptides to release — charged — , —
large
love
6
alpha
beta
gamma
soluble
substrate
thrombin
carboy-terminal peptides
-ve charged
Fibrinopeptide A and Fibrinopeptide B (FPA/B)
— cleaves fribinogen to fibrin
Thrombin is a — that — specific bonds on the – and – chains of fibrinogen to yield —
This removes intensely—-charged peptides from Fibrinogen. The product is called –
The removed peptides are called Fibrinopeptides A & (FPA & FPB)
Fibrin monomers are innately —
They polymerize – in a regular — array, forming an— fibrin clot
- Spontaneous assembly of fibrin into 3-D polymers, These polymers are then stabilized by the action of Factor XIIIa,
a transglutaminase
thrombin factor lla
protease
hydrolyses
alpha and beta
fibrin monomer
-ve
soluble ( but they become insoluble when polymerized into a stable fibrin )
spotnaously
regular staggered array
insoluble fibrin clot
fibrinolytic cascade and its regulation:
thrombin is generated in — endothelial cells to make FXIII —> FXIIIa which then the thrombin will convert fribongen to — –> — > then —
1- Plasminogen is bound within the —-rich clot as it forms. This clot-bound Plasminogen is more sensitive to activation by—
2- Plasminogen Activator
Inhibitor (PAI-1)
3- . a2-Anti-Plasmin
damaged
monomer fibrin
polymer fibrin
fibrin degradation product
fibrin rich
tPA
control of the fibrinolytic cascade:
Plasminogen (PLG) is an — plasma protein (a—).
— is its activated form.
PLG binds to both — and — and becomes incorporated in clots as they form
tissue Plasminogen Activator (tPA) is synthesised and released by — endothelial cells & promotes — formation from plasminogen.
It is more effective on —-bound PLG than on free-floating plasma PLG
Note:— plasmin is ‘clot-bound’
Any inappropriate tPA in plasma is immediately inactivated by —
Any inappropriate plasmin in the plasma is inactivated by —
α2-antiplasmin (AP) only inactivates— plasmin in plasma, not —plasmin
inactive
pro enzyme
plasmin
firbongen and firkin
intact
plasmin
clot bound
active
Plasminogen-Activator-Inhibitor (PAI-1)
α2-antiplasmin (AP)
free
clot bound
Fibrinolysis is a highly regulated process, whose function is to limit a clot to the vicinity of —
Everytime a clot occurs, the fibrinolytic cascade is activated to— it
Dissolution starts from the — where the endothelial layer on the blood vessel is —.
Fibrinolysis degrades cross-linked — Polymers to yield — products
One particularly long-lasting fibrin degradation product is —
damage
dissolves
margins
intact
fribin
fribin-degradation products
d dimer
4 main coagulation tests:
Assess — Pathway (Tissue Factor pathway):
Prothrombin Time or PT test / INR
Assess — Pathway:
Activated partial thromboplastin time (aPTT) test
Assess clotting – (Final common pathway):
Thrombin Thrombin Time (TT)
D-Dimer test
Other standard tests in coagulation suite:
— quantification
These tests can help identify the basis for bleeding or thrombotic disorders clinically
- D-Dimer is a specific degradation fragment of cross-linked – .
It is produced naturally as part of the wound healing process by — of – .
It has a — half-life in plasma.
Measurement of plasma D-Dimer levels is useful to aid in the diagnosis of — :
Venous Thrombosis
pulmonary thromboembolism (PTE)
disseminated intravascular coagulation (DIC)
extenrsic
intesnic
rate
firbonogen
fibrin
plasmid degradation of thrombus
long
systemic thrombosis
qualitative d dimer test:
A positive D-Dimer test showing — levels of D-dimer, indicates the occurrence of recent — event.
A negative D-dimer result excludes thrombo-embolic events such as deep vein thrombosis and pulmonary embolism with a very high probability.
However, a positive D-Dimer test doesn’t differentiate between appropriate thrombosis (wound healing following surgery or injury) or inappropriate (pathological thrombi)
Thus, a positive D-Dimer test is not definitive evidence for the presence of a thombotic clot.
A definitive diagnosis must be accompanied by an image/scan: MRI scanning, angiography, CAT scans etc
Most of these scans are expensive, and demand highly sophisticated medical equipment, ‘a high degree of suspicion’ is necessary to justify their use;
- d dimer test PLUS wells test :
A normal D-dimer concentration excludes thrombo-embolic events such as deep vein thrombosis and pulmonary embolism with a very high probability.
A Wells score*, together with a normal D-dimer, safely excludes – in outpatients
In summary, the Wells score helps assess your — of — , guiding further— steps
Score of 3 or higher: High risk of DVT.
Score of 1 or 2: Moderate risk of DVT.
Score of 0 or less: Low risk of DVT.
elevated
thrombotic
VTE
risk of DVT
diagnostic
ati-firbinolytic drugs:
This refers to a group of drugs / that inhibit the action of — and promote — in clinical — situations such as dental extraction, post-partum haemorrhage
Include
1- Epsilon Aminocaproic acid
Binds — to — ; blocking the binding of — to — and the subsequent conversion to — , resulting in inhibition of — ( — ).
2- Tranexemic acid
Forms a — complex that – plasmiogen from fibrin resulting in inhibition of — ; it also inhibits the — activity of plasmin
plasmin
coagulation
haemorraghic
competitively
plasminogen
plasminogen to fibrin
plasmin
fibrin degradation ( fibrolysis )
reversible
displaces
firbolysis
proteolytic
Fibrinolytic / Thrombolytic drugs are agents that mimic endogenous tissue —
They rapidly — thrombi by — the formation of — from its precursor zymogen, — .
They are used at concentrations that greatly exceed — concentrations of tPA
These drugs create a generalized — state when administered intravenously.
Drugs in this class do not discriminate between protective haemostatic thrombi, and pathogenic thrombi or thromboemboli. –so they must be used with extreme caution
tissue plasminogen activator tPA
lyse
catalysing
plasmin
plasminogen
physiological
lytic state
thrombolytic therapy:
- Used for acute treatment of :
myocardial infarction (heart attack)
ischaemic stroke*
deep vein thrombosis (DVT)
Massive pulmonary embolism
Acute limb ischaemia
-to clear a — artery and avoid – damage to the perfused tissue (e.g., heart, brain, leg)
-A less frequent use is to clear blocked — that are used in—term medical therapy
*Note: thrombolytic therapy in strokes is controversial due to the difficulty in differentiating between — and – and the — involved
blocked
permanent damage
blocked catheters
long term
hemorrhagic ad thrombotic stroke
time involved
fibrinolytic/thrombolytic drugs:
Pharmaceutic versions of tPA were generated to — an existing fibrin-containing clot in patients.
*t-PA (formulated as a recombinant human proteins):
alteplase (rtPA)
reteplase (longer half-life)
tenecteplase
*streptokinase (purified from —bacteria)
Mimic of— , Note: Streptokinase is not available in USA or Canada
-Administered in very – doses
-Aim is to — an existing— in a blood vessel
-Are most effective if administered — after it has been determined they are clinically appropriate.
-Administered —
-The advantage of administration is highest within the first —, but may extend up to —- after the start of symptoms.
are often given in combination with intravenous heparin, or LMW heparin, and Aspirin in treatment of acute coronary syndromes
lyse
streptococcal
endogenous tPA
very high
lyse
thrombus
immedielty
intravenously
ninety min
6 hours
Effectiveness of Thrombolytic agents such as tPA or streptokinase:
Thrombolytic agents such as tPA or streptokinase decrease the incidence of death following – by approximately 25% (Panel A)
Has additive effect with – (Panel C)
Has additive effect with – (not shown)
side effects of thrombolytic therapy:
1- — :(Note: can be ± limited with anti-fibrinolytic drugs Aminocaproic acid / Tranexemic acid)
2- — is a rare but serious complication of thrombolytic therapy.
-If a patient has had thrombolysis before, an — response against the thrombolytic drug may have developed (especially after streptokinase).
If the symptoms are mild, the infusion is stopped and the patient is commenced on an antihistamine before infusion is recommenced. Anaphylaxis generally requires immediate cessation of thrombolysis.
3-Contra-indicated where major surgery or injury has occurred* in the previous weeks.
Also contraindicated where patient is currently being treated with anticoagulant drugs, has a known bleeding diathesis, during pregnancy, or if patient has history of hemorrhagic / diabetic retinopathies or active peptic ulcer.
*Thrombolytic drugs cannot distinguish between a pathological clots (eg causing a heart attack / MI) and a functional clot (eg a clot that has formed to close a wound)
stemi
aspirin
heparin
bleeding
hemorrhagic stroke ( also in statin for anti lipid)
allergic response
Streptokinase vs Recombinant tPA as a Thrombolytic Drug:
Thrombolytic therapy is given — as soon as possible after the onset of a heart attack to ‘—’ clots in the arteries of the heart wall.
This reduces the amount of damage to the heart muscle
1- Streptokinase is a — product that acts as a —
It is —
However, because of its bacterial origins, the body will likely build up an – response to it.
— against Streptokinase will inhibit its thrombolytic action
Therefore, Streptokinase should not be used again after – days from the first administration, as it may not be as effective and can also cause an — reaction.
2- Recombinant tPA is — to normal plasma tPA recombinant tPA is relatively —
there are no problems associated with its administration
-For this reason, streptokinase is usually given only for a person’s first heart attack. Further thrombotic events are treated with tPA
intravenously
dissolve
bacterial
plasminogen activator
cheap
immunity
antibodies
4 days
allergic
identical
expensive
Thrombolytic therapy vs PCI?:
In the late1980 to ~2010, intravenous thrombolytic therapy for acute myocardial infarction was found to significantly reduce mortality.
Percutaneous coronary intervention (PCI) now favours the use — and placement of a — over thrombolytic therapy.
However, thrombolysis is still very important where PCI is not readily available- such as non-specialist coronary care centres.
Thrombolysis is often administered by trained first responders in ambulances.
summary:
The intact endothelium plays a critical role in regulating —
The thrombolytic pathway is a carefully regulated pathway involving tPA
Numerous drugs can impact on the thrombolytic pathway (recombinant versions of tPA and Streptokinase)
These drugs are used in the acute treatment of thrombotic disorders.
PCI technologies / angioplasty with stenting is preferred in specialist centres
catherisation
placement od stent
haemostasis
