135 Fibrinolysis and Thrombolysis Flashcards
Plasminogen is synthesized primarily in the
Liver
The plasma half-life of plasminogen in adults is approximately 2 days
Endogenous plasminogen activator
Tissue-Type Plasminogen Activator (t-PA)
Urokinase (u-PA)
t-PA: synthesized in the endothelium and liver
u-PA: synthesized in the endothelium and kidney
Represent the major intravascular activator of Plg
Tissue-Type Plasminogen Activator (t-PA)
Alone, t-PA is actually a poor activator of plasminogen, but, in the presence of fibrin, the catalytic efficiency of t-PA–dependent plasmin generation (k cat /K m ) increases by at least 2 orders of magnitude.
Has much lower affinity for fibrin than t-PA, and is an effective plasminogen activator both in the presence and in the absence of fibrin
Urokinase (u-PA)
The action of plasmin is negatively modulated by a family of serine protease inhibitors, called
Serpins
Serpins form an irreversible complex with the active site serine of their target protease following proteolytic cleavage of the inhibitor by the target protease.
Within such a complex, both protease and inhibitor lose their activity.
Examples of Plasmin Inhibitors
α2 -plasmin inhibitor (α2 -PI)
α2 -Macroglobulin
Nexin
The most important and most rapidly acting physiologic inhibitor of both t-PA and u-PA
Plasminogen Activator Inhibitor-1
Of the two major PAIs, PAI-1 is the more ubiquitous
Inhibits both 2-chain t-PA and 2-chain u-PA with comparable efficiency but it is less effective toward singlechain t-PA and does not inhibit prourokinase
Plasminogen Activator Inhibitor-2
A nonserpin plasma carboxypeptidase that eliminates binding sites for plasminogen and t-PA on fibrin
Thrombin-activatable fibrinolysis inhibitor (TAFI)
A transmembrane receptor that binds plasminogen and colocalizes with u-PA and the urokinase-type plasminogen activator receptor (uPAR), and appears to be particularly important for regulation of plasminogen activation on macrophages.
Plg-R KT
Acute promyelocytic leukemia overexpress __________ in proportion to their degree of hyperfibrinolytic coagulopathy ; __________ also appears to be upregulated by the PML-RARα oncoprotein
Annexin A2
S100A10
TRUE OR FALSE
In the presence of fibrin, t-PA is a weak activator of plasminogen.
FALSE
In the absence of fibrin, t-PA is a weak activator of plasminogen.
However, in the presence of fibrin, the catalytic efficiency (k cat /K M ) of t-PA–dependent plasminogen activation is enhanced by approximately 500-fold.
Pathophysiology of t-PA in fibrin degradation
- (a) enhancing the catalytic efficiency of plasmin formation by t-PA
- (b) protecting plasmin from its physiologic inhibitor, α 2-PI
- (c) providing new binding sites for plasminogen and t-PA once its degradation has begun.
Disorders/conditions in which plasminogen activation contributes to inflammation
- Infections, such as Lyme disease, Staphylococcus aureus, and Cryptococcus neoformans
- Neurovascular damage in Alzheimer disease, demyelination in a model of multiple sclerosis (experimental allergic encephalitis), and inflammation after stroke
- Arthritis
- Myocardial infarction
TRUE OR FALSE
Currently, little evidence that hypoplasminogenemia alone is a significant cause of deep venous thrombosis.
TRUE
Currently, little evidence that hypoplasminogenemia alone is a significant cause of deep venous thrombosis.
Similarly, there are no reported cases of complete t-PA or u-PA deficiency in humans, and no mutations or polymorphisms in these genes have, as of this writing, been clinically linked to thrombophilia.
Isolated hypoplasminogenemia is not a risk factor for thrombosis.
Congenital plasminogen deficiency is classified into 2 types
Type I:
Type II:
Type I: concentration of immunoreactive plasminogen is reduced in parallel with functional activity
Type II: immunoreactive protein is normal while functional activity is reduced
Patients with type _ plasminogen deficiency are most likely to present with ligneous conjunctivitis
Type I plasminogen deficiency
This resolves completely upon infusion of Lys-Plg
Conditions associated with acquired plasminogen deficiency
- Liver disease
- Sepsis
- Argentine hemorrhagic fever
Results from decreased synthesis and/or increased catabolism, but associated thrombosis may be a result of abnormalities in other hemostatic factors in these very ill patients.
TRUE OR FALSE
Increased circulating PAI-1 appears to represent an independent risk factor for vascular reocclusion in young survivors of myocardial infarction.
TRUE
Increased circulating PAI-1 appears to represent an independent risk factor for vascular reocclusion in young survivors of myocardial infarction.
In addition, increased levels of PAI-1 are associated with deep vein thrombosis in patients undergoing hip replacement surgery and in individuals with insulin resistance
TRUE OR FALSE
While deficiencies of profibrinolytic proteins are not yet associated with thrombosis in humans, elevated levels of 2 antifibrinolytic proteins, PAI-1 and TAFI, are independent risk factors for venous thrombosis.
TRUE
While deficiencies of profibrinolytic proteins are not yet associated with thrombosis in humans, elevated levels of 2 antifibrinolytic proteins, PAI-1 and TAFI, are independent risk factors for venous thrombosis.
One should bear in mind that PAI-1 is itself an acute-phase reactant, and may not induce a prothrombotic tendency in every case
Present with a severe hemorrhagic disorder that was caused by impaired inactivation of plasmin and premature lysis of the hemostatic plug.
Congenital deficiency of α2-PI
Conditions associated with acquired α2 -PI deficiency
- Severe liver disease: decreased synthesis
- Disseminated intravascular coagulation: consumption
- Nephrotic syndrome: attributable to urinary losses
- During thrombolytic therapy: excessive use of the inhibitor
_____ levels are markedly reduced in liver cirrhosis, correlating with enhanced plasma fibrinolysis, and serving as an independent predictor of mortality.
TAFI
Hyper or Hypo
Severe trauma is often characterized early on by a _____fibrinolytic state
Hyperfibrinolytic state
- Characterized by massive release of t-PA leading to depletion of PAI-1, subsequent hemorrhage, and early mortality
- This phase may be followed by a fibrinolytic “shutdown” phase, caused by abnormal polymerization of fibrin, and leading to thrombotic complications and organ dysfunction.
TRUE OR FALSE
In the resting, nonstressed state, the plasmin-generating potential in the newborn is significantly greater than that of the adult.
FALSE
In the resting, nonstressed state, the plasmin-generating potential in the newborn is significantly less than that of the adult.
- Plasma concentrations of plasminogen in the neonate are approximately 50% to 75% of those observed in adults.
- Neonatal plasminogen is heavily glycosylated, less-readily activated by t-PA, and only weakly bound to the endothelial cell surface.
- Reduced fibrinolytic activity may contribute to the thrombogenic state commonly observed in the newborn, but this predilection may be reversed under conditions of physiologic stress.
Throughout childhood, global plasma fibrinolytic activity and plasmin generation are decreased in comparison to adults, and this relative deficiency may contribute to the high frequency of thrombosis associated with
- Central venous line placement
- Kawasaki disease
- Henoch-Schönlein purpura
Hyper or Hypo
Pregnancy is a ________fibrinolytic state.
Hypofibrinolytic state
- Plasminogen and fibrinogen levels in plasma increase by 50% to 60% in the third trimester
- Between the 20th week of pregnancy and term, PAI-1 levels increase to 3 times their normal level, while PAI-2 levels rise to 25 times their normal level in early pregnancy.
- Less-dramatic increases in both u-PA and t-PA levels are also observed.
- Within 1 hour of delivery, however, concentrations of both PAI-1 and PAI-2 begin to decrease, and return to normal within 3–5 days.
TRUE OR FALSE
In preeclampsia, the hemostatic and fibrinolytic imbalances seen in pregnancy are exaggerated.
TRUE
In preeclampsia, the hemostatic and fibrinolytic imbalances seen in pregnancy are exaggerated.
A marker of placental function that is reduced during preeclampsia
Correlates with intrauterine growth retardation of the fetus
PAI-2
- Elevated TAFI levels may be a cause of fibrin deposition and occlusion of placental vessels in preeclampsia.
- Deficiency of endometrial annexin A2: decidualization resistance implicated in the pathogenesis of severe preeclampsia.
The goal of thrombolytic therapy
Rapid restoration of flow to an occluded vessel achieved by accelerating fibrinolytic proteolysis of the thrombus
The basic principle of all fibrinolytic therapy
Administration of sufficient plasminogen activator to achieve a high local concentration at the site of the thrombus
Thereby accelerating conversion of plasminogen to plasmin, and increasing the rate of fibrin dissolution.
Critical in determining the intensity of action at the site of a thrombus
Degree of “fibrin specificity”
TRUE OR FALSE
The plasma half-life of most agents is long.
FALSE
The plasma half-life of most agents is short.
TRUE OR FALSE
Systemic therapy via peripheral vein is simpler and does not require specialized facilities, but results in greater systemic complications.
TRUE
Systemic therapy via peripheral vein is simpler and does not require specialized facilities, but results in greater systemic complications.
Type of fibrinolysis delivery can provide a high local concentration with a smaller total dose, thereby increasing the local effect and limiting systemic exposure
Regional delivery
with a catheter placed close to the proximal end of the thrombus
TRUE OR FALSE
Fibrinolytic therapy is often administered in combination with an anticoagulant and atiplatelet.
TRUE
Fibrinolytic therapy is often administered in combination with an anticoagulant and atiplatelet.
Anticoagulant: block fibrin formation
Antiplatelet: to limit continued platelet deposition
Plasminogen activators given as bolus
Anistreplase
Reteplase (double bolus)
Tenecteplase
Recombinant plasminogen activators
Urokinase
Alteplase (t-PA)
Reteplase
Saruplase (scu-PA)
Staphylokinase
Tenecteplase
Streptokinase: Streptococcus (Y)
Anistreplase: Streptococcus + plasma product
Antigenic plasminogen activators
Streptokinase
Staphylokinase
Plasminogen activators (longest half life)
Anistreplase- 70 mins
Plasminogen activators (shortest half life)
Saruplase (scu-PA)- 5 mins
Alteplase (t-PA)- 5 mins
TRUE OR FALSE
The potential benefits of fibrinolysis for arterial disease are less clear and more likely to be associated with bleeding problems.
FALSE
The potential benefits of fibrinolysis for venous diseaseare less clear and more likely to be associated with bleeding problems.
- For patients with acute myocardial infarction or stroke there is a higher tolerance of bleeding complications, because lytic therapy can be lifesaving and limit disability.
- Timing of treatment is also critical, with greater benefit achieved with earlier administration.
Conditions most likely to respond and benefit from thrombolysis
- Acute myocardial infarction
- Stroke
- Peripheral arterial obstruction
- Deep vein thrombosis
- Pulmonary embolism
Timing of thrombolytic therapy in Acute myocardial infarction
Within 12 hours of onset
Consider percutaneous intervention
Timing of thrombolytic therapy in Stroke
4.5 hours of symptom onset
Major contraindications
- Risk of intracranial bleeding
- Recent head trauma or central nervous system surgery
- History of stroke or subarachnoid bleed
- Intracranial metastatic disease
Risk of major bleeding
- Active gastrointestinal or genitourinary bleeding
- Major surgery or trauma within 7 days
- Dissecting aneurysm
Relative contraindications
- Remote history of gastrointestinal bleeding
- Remote history of genitourinary bleeding
- Remote history of peptic ulcer
- Other lesion with potential for bleeding
- Recent minor surgery or trauma
- Severe, uncontrolled hypertension
- Coexisting hemostatic abnormalities
- Pregnancy
TRUE OR FALSE
Thrombolysis has had a smaller impact for stroke than it has for myocardial infarction
TRUE
Thrombolysis has had a smaller impact for stroke than it has for myocardial infarction
- The arterial anatomy of the brain is more complex
- The time from onset of ischemia to irreversible necrosis is shorter
- The risk and consequences of bleeding are greater
- There is more variability in the thrombo(embolic) occluding lesion
- The occlusive lesion causing ischemic stroke may be a large in situ thrombus, small platelet–fibrin embolus, or large embolus of varying age and composition originating from the left atrium
The only FDA-approved therapy for acute stroke is
Intravenous alteplase (recombinant t-PA) given within 3 hours of symptom onset
Dose: 0.9 mg/kg (maximum: 90 mg) of t-PA administered intravenously with 10% as an initial bolus and the remainder infused over 60 minutes
- Randomized studies with rt-PA have shown that intravenous thrombolytic therapy can be safely extended to 4.5 hours after symptom onset in selected patients
- Streptokinase is associated with an unacceptably high rate of intracranial hemorrhage.
The most serious complication of thrombolysis is
Intracranial hemorrhage (1%)
Treatment of bleeding associated with thrombolysis
Local measures as well as correction of the systemic hypocoagulable state
- Antifibrinolytic agent, such as ε-aminocaproic or tranexamic acid*
- Cryoprecipitate 5–10 U and 2 U freshfrozen
plasma - Platelet concentrates
- Correct other hemostatic defects: stop anticoagulant and antiplatelet agents; consider protamine to reverse heparin
*Will be effective only if the fibrinolytic agent remains in the blood
Platelet concentrates: fibrinolytic therapy results in platelet dysfunction from proteolysis of surface proteins.
Agents that inhibit fibrinolysis by competitively blocking binding of plasminogen to lysine residues on fibrin.
ε-aminocaproic acid and tranexamic acid
- Pharmacologically, tranexamic acid is approximately 10-fold more potent than ε-aminocaproic acid because of its higher binding affinity.
- Both drugs have a short half-life of 2–4 hours and must, therefore, be administered frequently.
Only ε-aminocaproic acid is approved for use in the United States, with the exception that tranexamic acid can be used for treatment of _________.
Menorrhagia
Dosing of ε-Aminocaproic acid
- Loading dose of approximately 100 mg/kg over 30–60 minutes followed by a continuous infusion of up to 1 g/h, or the dose can be divided for intermittent administration
- Oral: same loading, 24 g/day in divided doses given every 1–6 hours
Dosing of tranexamic acid
- 100 mg/kg over 30–60 minutes followed by a continuous infusion of up to 1 g/h, or the dose can be divided for intermittent administration
- Oral: 25 mg/kg given three or four times daily
A naturally occurring, broad-spectrum proteinase inhibitor derived from bovine lung
Aprotinin
- Its use became associated with an increased risk of postoperative renal dysfunction, cardiac and cerebral events, and increased short-term and long-term mortality in patients who received aprotinin compared to patients who received εaminocaproic acid, tranexamic acid, or placebo
