135 Fibrinolysis and Thrombolysis

Question 1

Plasminogen is synthesized primarily in the

Answer 1

Liver

The plasma half-life of plasminogen in adults is approximately 2 days

Question 2

Endogenous plasminogen activator

Answer 2

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

Question 3

Represent the major intravascular activator of Plg

Answer 3

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.

Question 4

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

Answer 4

Urokinase (u-PA)

Question 5

The action of plasmin is negatively modulated by a family of serine protease inhibitors, called

Answer 5

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.

Question 6

Examples of Plasmin Inhibitors

Answer 6

α2 -plasmin inhibitor (α2 -PI)
α2 -Macroglobulin
Nexin

Question 7

The most important and most rapidly acting physiologic inhibitor of both t-PA and u-PA

Answer 7

Plasminogen Activator Inhibitor-1

Of the two major PAIs, PAI-1 is the more ubiquitous

Question 8

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

Answer 8

Plasminogen Activator Inhibitor-2

Question 9

A nonserpin plasma carboxypeptidase that eliminates binding sites for plasminogen and t-PA on fibrin

Answer 9

Thrombin-activatable fibrinolysis inhibitor (TAFI)

Question 10

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.

Answer 10

Plg-R KT

Question 11

Acute promyelocytic leukemia overexpress __________ in proportion to their degree of hyperfibrinolytic coagulopathy ; __________ also appears to be upregulated by the PML-RARα oncoprotein

Answer 11

Annexin A2

S100A10

Question 12

TRUE OR FALSE

In the presence of fibrin, t-PA is a weak activator of plasminogen.

Answer 12

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.

Question 13

Pathophysiology of t-PA in fibrin degradation

Answer 13

• (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.

Question 14

Disorders/conditions in which plasminogen activation contributes to inflammation

Answer 14

• 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

Question 15

TRUE OR FALSE

Currently, little evidence that hypoplasminogenemia alone is a significant cause of deep venous thrombosis.

Answer 15

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.

Question 16

Congenital plasminogen deficiency is classified into 2 types

Type I:
Type II:

Answer 16

Type I: concentration of immunoreactive plasminogen is reduced in parallel with functional activity

Type II: immunoreactive protein is normal while functional activity is reduced

Question 17

Patients with type _ plasminogen deficiency are most likely to present with ligneous conjunctivitis

Answer 17

Type I plasminogen deficiency

This resolves completely upon infusion of Lys-Plg

Question 18

Conditions associated with acquired plasminogen deficiency

Answer 18

• 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.

Question 19

TRUE OR FALSE

Increased circulating PAI-1 appears to represent an independent risk factor for vascular reocclusion in young survivors of myocardial infarction.

Answer 19

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

Question 20

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.

Answer 20

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

Question 21

Present with a severe hemorrhagic disorder that was caused by impaired inactivation of plasmin and premature lysis of the hemostatic plug.

Answer 21

Congenital deficiency of α2-PI

Question 22

Conditions associated with acquired α2 -PI deficiency

Answer 22

• Severe liver disease: decreased synthesis
• Disseminated intravascular coagulation: consumption
• Nephrotic syndrome: attributable to urinary losses
• During thrombolytic therapy: excessive use of the inhibitor

Question 23

_____ levels are markedly reduced in liver cirrhosis, correlating with enhanced plasma fibrinolysis, and serving as an independent predictor of mortality.

Answer 23

TAFI

Question 24

Hyper or Hypo

Severe trauma is often characterized early on by a _____fibrinolytic state

Answer 24

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.

Question 25

# TRUE OR FALSE In the resting, nonstressed state, the plasmin-generating potential in the newborn is significantly greater than that of the adult.

Answer 25

FALSE In the resting, nonstressed state, the plasmin-generating potential in the newborn is significantly less than that of the adult. ## Footnote * 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.

Question 26

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

Answer 26

* Central venous line placement * Kawasaki disease * Henoch-Schönlein purpura

Question 27

# Hyper or Hypo Pregnancy is a ________fibrinolytic state.

Answer 27

Hypofibrinolytic state ## Footnote * 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.

Question 28

# TRUE OR FALSE In preeclampsia, the hemostatic and fibrinolytic imbalances seen in pregnancy are exaggerated.

Answer 28

TRUE In preeclampsia, the hemostatic and fibrinolytic imbalances seen in pregnancy are exaggerated.

Question 29

A marker of placental function that is reduced during preeclampsia Correlates with intrauterine growth retardation of the fetus

Answer 29

PAI-2 ## Footnote * **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.

Question 30

The goal of thrombolytic therapy

Answer 30

Rapid restoration of flow to an occluded vessel achieved by accelerating fibrinolytic proteolysis of the thrombus

Question 31

The basic principle of all fibrinolytic therapy

Answer 31

Administration of sufficient plasminogen activator to achieve a high local concentration at the site of the thrombus ## Footnote Thereby accelerating conversion of plasminogen to plasmin, and increasing the rate of fibrin dissolution.

Question 32

Critical in determining the intensity of action at the site of a thrombus

Answer 32

Degree of “fibrin specificity”

Question 33

# TRUE OR FALSE The plasma half-life of most agents is long.

Answer 33

FALSE The plasma half-life of most agents is short.

Question 34

# TRUE OR FALSE Systemic therapy via peripheral vein is simpler and does not require specialized facilities, but results in greater systemic complications.

Answer 34

TRUE **Systemic therapy** via peripheral vein is simpler and **does not require specialized facilities**, but results in **greater systemic complications.**

Question 35

Type of fibrinolysis delivery can provide a **high local concentration** with a **smaller total dose**, thereby **increasing the local effect and limiting systemic exposure**

Answer 35

Regional delivery ## Footnote with a catheter placed close to the proximal end of the thrombus

Question 36

# TRUE OR FALSE Fibrinolytic therapy is often administered in combination with an anticoagulant and atiplatelet.

Answer 36

TRUE Fibrinolytic therapy is often administered in combination with an anticoagulant and atiplatelet. ## Footnote Anticoagulant: block fibrin formation Antiplatelet: to limit continued platelet deposition

Question 37

Plasminogen activators given as bolus

Answer 37

Anistreplase Reteplase (double bolus) Tenecteplase

Question 38

Recombinant plasminogen activators

Answer 38

Urokinase Alteplase (t-PA) Reteplase Saruplase (scu-PA) Staphylokinase Tenecteplase ## Footnote Streptokinase: Streptococcus (Y) Anistreplase: Streptococcus + plasma product

Question 39

Antigenic plasminogen activators

Answer 39

Streptokinase Staphylokinase

Question 40

Plasminogen activators (longest half life)

Answer 40

Anistreplase- 70 mins

Question 41

Plasminogen activators (shortest half life)

Answer 41

Saruplase (scu-PA)- 5 mins Alteplase (t-PA)- 5 mins

Question 42

# TRUE OR FALSE The potential benefits of fibrinolysis for arterial disease are less clear and more likely to be associated with bleeding problems.

Answer 42

FALSE The potential benefits of fibrinolysis for **venous disease**are **less clear and more likely to be associated with bleeding** problems. ## Footnote * 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.

Question 43

Conditions most likely to respond and benefit from thrombolysis

Answer 43

* Acute myocardial infarction * Stroke * Peripheral arterial obstruction * Deep vein thrombosis * Pulmonary embolism

Question 44

Timing of thrombolytic therapy in Acute myocardial infarction

Answer 44

Within 12 hours of onset ## Footnote Consider percutaneous intervention

Question 45

Timing of thrombolytic therapy in Stroke

Answer 45

4.5 hours of symptom onset

Question 46

Major contraindications

Answer 46

* Risk of intracranial bleeding * Recent head trauma or central nervous system surgery * History of stroke or subarachnoid bleed * Intracranial metastatic disease

Question 47

Risk of major bleeding

Answer 47

* Active gastrointestinal or genitourinary bleeding * Major surgery or trauma within 7 days * Dissecting aneurysm

Question 48

Relative contraindications

Answer 48

* 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

Question 49

# TRUE OR FALSE Thrombolysis has had a smaller impact for stroke than it has for myocardial infarction

Answer 49

TRUE Thrombolysis has had a smaller impact for stroke than it has for myocardial infarction ## Footnote * 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

Question 50

The only FDA-approved therapy for acute stroke is

Answer 50

**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** ## Footnote * 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.**

Question 51

The most serious complication of thrombolysis is

Answer 51

Intracranial hemorrhage (1%)

Question 52

Treatment of bleeding associated with thrombolysis

Answer 52

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 ## Footnote *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.

Question 53

Agents that inhibit fibrinolysis by competitively blocking binding of plasminogen to lysine residues on fibrin.

Answer 53

ε-aminocaproic acid and tranexamic acid ## Footnote * 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.

Question 54

Only ε-aminocaproic acid is approved for use in the United States, with the exception that tranexamic acid can be used for treatment of _________.

Answer 54

Menorrhagia

Question 55

Dosing of ε-Aminocaproic acid

Answer 55

* 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

Question 56

Dosing of tranexamic acid

Answer 56

* 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

Question 57

A naturally occurring, broad-spectrum proteinase inhibitor derived from bovine lung

Answer 57

Aprotinin ## Footnote * 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