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WILLIAM'S HEMATOLOGY > 135 Fibrinolysis and Thrombolysis > Flashcards

135 Fibrinolysis and Thrombolysis Flashcards

1
Q

Plasminogen is synthesized primarily in the

A

Liver

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

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2
Q

Endogenous plasminogen activator

A

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

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3
Q

Represent the major intravascular activator of Plg

A

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.

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4
Q

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

A

Urokinase (u-PA)

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5
Q

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

A

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.

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6
Q

Examples of Plasmin Inhibitors

A

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

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7
Q

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

A

Plasminogen Activator Inhibitor-1

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

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8
Q

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

A

Plasminogen Activator Inhibitor-2

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9
Q

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

A

Thrombin-activatable fibrinolysis inhibitor (TAFI)

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10
Q

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.

A

Plg-R KT

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11
Q

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

A

Annexin A2

S100A10

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12
Q

TRUE OR FALSE

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

A

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.

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13
Q

Pathophysiology of t-PA in fibrin degradation

A
  • (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.
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14
Q

Disorders/conditions in which plasminogen activation contributes to inflammation

A
  • 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
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15
Q

TRUE OR FALSE

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

A

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.

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16
Q

Congenital plasminogen deficiency is classified into 2 types

Type I:
Type II:

A

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

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

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17
Q

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

A

Type I plasminogen deficiency

This resolves completely upon infusion of Lys-Plg

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18
Q

Conditions associated with acquired plasminogen deficiency

A
  • 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.

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19
Q

TRUE OR FALSE

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

A

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

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20
Q

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.

A

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

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21
Q

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

A

Congenital deficiency of α2-PI

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22
Q

Conditions associated with acquired α2 -PI deficiency

A
  • Severe liver disease: decreased synthesis
  • Disseminated intravascular coagulation: consumption
  • Nephrotic syndrome: attributable to urinary losses
  • During thrombolytic therapy: excessive use of the inhibitor
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23
Q

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

A

TAFI

24
Q

Hyper or Hypo

Severe trauma is often characterized early on by a _____fibrinolytic state

A

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.
25
Q

TRUE OR FALSE

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

A

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.
26
Q

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

A
  • Central venous line placement
  • Kawasaki disease
  • Henoch-Schönlein purpura
27
Q

Hyper or Hypo

Pregnancy is a ________fibrinolytic state.

A

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.
28
Q

TRUE OR FALSE

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

A

TRUE

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

29
Q

A marker of placental function that is reduced during preeclampsia

Correlates with intrauterine growth retardation of the fetus

A

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.
30
Q

The goal of thrombolytic therapy

A

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

31
Q

The basic principle of all fibrinolytic therapy

A

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.

32
Q

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

A

Degree of “fibrin specificity”

33
Q

TRUE OR FALSE

The plasma half-life of most agents is long.

A

FALSE

The plasma half-life of most agents is short.

34
Q

TRUE OR FALSE

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

A

TRUE

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

35
Q

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

A

Regional delivery

with a catheter placed close to the proximal end of the thrombus

36
Q

TRUE OR FALSE

Fibrinolytic therapy is often administered in combination with an anticoagulant and atiplatelet.

A

TRUE

Fibrinolytic therapy is often administered in combination with an anticoagulant and atiplatelet.

Anticoagulant: block fibrin formation
Antiplatelet: to limit continued platelet deposition

37
Q

Plasminogen activators given as bolus

A

Anistreplase
Reteplase (double bolus)
Tenecteplase

38
Q

Recombinant plasminogen activators

A

Urokinase
Alteplase (t-PA)
Reteplase
Saruplase (scu-PA)
Staphylokinase
Tenecteplase

Streptokinase: Streptococcus (Y)
Anistreplase: Streptococcus + plasma product

39
Q

Antigenic plasminogen activators

A

Streptokinase
Staphylokinase

40
Q

Plasminogen activators (longest half life)

A

Anistreplase- 70 mins

41
Q

Plasminogen activators (shortest half life)

A

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

42
Q

TRUE OR FALSE

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

A

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.
43
Q

Conditions most likely to respond and benefit from thrombolysis

A
  • Acute myocardial infarction
  • Stroke
  • Peripheral arterial obstruction
  • Deep vein thrombosis
  • Pulmonary embolism
44
Q

Timing of thrombolytic therapy in Acute myocardial infarction

A

Within 12 hours of onset

Consider percutaneous intervention

45
Q

Timing of thrombolytic therapy in Stroke

A

4.5 hours of symptom onset

46
Q

Major contraindications

A
  • Risk of intracranial bleeding
  • Recent head trauma or central nervous system surgery
  • History of stroke or subarachnoid bleed
  • Intracranial metastatic disease
47
Q

Risk of major bleeding

A
  • Active gastrointestinal or genitourinary bleeding
  • Major surgery or trauma within 7 days
  • Dissecting aneurysm
48
Q

Relative contraindications

A
  • 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
49
Q

TRUE OR FALSE

Thrombolysis has had a smaller impact for stroke than it has for myocardial infarction

A

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
50
Q

The only FDA-approved therapy for acute stroke is

A

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.
51
Q

The most serious complication of thrombolysis is

A

Intracranial hemorrhage (1%)

52
Q

Treatment of bleeding associated with thrombolysis

A

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.

53
Q

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

A

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.
54
Q

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

A

Menorrhagia

55
Q

Dosing of ε-Aminocaproic acid

A
  • 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
56
Q

Dosing of tranexamic acid

A
  • 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
57
Q

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

A

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

WILLIAM'S HEMATOLOGY (109 decks)

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