1. Clinical Relevance of Clot Selectivity
Action of Clot-Selective Agents
Action of Non-Clot-Selective Agents
(TNK-tPA, staphylokinase, t-PA)
(r-PA, SK, n-PA, UK)
Lecture Notes
Fibrin selectivity refers to the increased enzymatic activity of a plasminogen activator in the presence of fibrin. The clinically relevant consequence of fibrin selectivity is termed clot selectivity.
Clot selectivity refers to the extent to which a drug activates clot-bound plasminogen to form plasmin. Because of their varying molecular structures, different thrombolytic agents exhibit different degrees of clot selectivity.
Drugs that are highly clot selective, such as t-PA and TNK-tPA focus their activity preferentially at the site of the clot and convert freely circulating plasminogen to plasmin only minimally. (Sobel, 1999) These drugs are very efficient and as the clot dissolves, new lysine binding sites are exposed, thereby facilitating continued lysis of the clot. TNK-tPA and staphylokinase, third generation agents, exhibit strong clot selectivity.
In contrast, drugs that are not clot selective, such as SK, urokinase, r-PA, and n-PA, act by creating a systemic lytic state to convert freely circulating plasminogen to plasmin. As a result, components of the coagulation cascade are activated rendering the blood hypercoagulable even in the presence of anticoagulation agents. (Sobel, 1999)
Clot-selective Clot Blood vessel
plasminogen activators
Non-clot-selective Clot Blood vessel
plasminogen activators

2. Percent Changes in Parameters
TIMI-10B: Clinical Evidence of Increased Fibrin Specificity with TNK-tPA
Fibrinogen
Plasminogen 30 40 40 30 40 30 30 30 30 50 40 50
TNK-tPA 50 40 40 50 50 50
Percent Changes in Parameters
(median)
TNK-tPA A
Lecture Notes
A fibrin-specific agent such as t-PA must generally assemble — along with its substrate, plasminogen—on the surface of a fibrin molecule so as to cleave plasminogen into plasmin. Plasmin enzymatically cleaves the fibrin strands, which bind the platelets and red blood cells together within the thrombus, leading to clot dissolution. t-PA is a significantly more potent activator of plasminogen, has a higher affinity for fibrin-bound plasminogen, and has a lower affinity for free circulating plasminogen. As t-PA dissolves the acute gelatinous clot, new sites on fibrin become available for alteplase binding. Fibrinolytics lacking fibrin specificity can be washed downstream from the clot site and induce lysis by promoting a systemic lytic state.
The Thrombolysis in Myocardial Infarction (TIMI)-10B trial evaluated TNK-tPA doses of 30, 40, and 50 mg for angiographic endpoints. The study also assessed the tendency of TNK-tPA to deplete the body’s systemic pools of circulating plasminogen and fibrinogen. These assays further supported the notion that TNK-tPA is more fibrin-specific than its predecessor, t-PA. (Cannon et al, 1998)
TNK-tPA doses of 30 to 50 mg reduced circulating levels of plasminogen by only 10% to 15% during the first 6 hours post-dose, compared with 50% for standard, front-loaded t-PA. A A A A
alteplase (t-PA) A
alteplase (t-PA) 1 1
Hours Post-Dose
Hours Post-Dose
Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:

3. 100 mg / dl is needed for normal hemostasis
Lower Fibrinogen Levels Are Associated with Bleeding
Wintrobs Clinical Hematology 9th Edition
100 mg / dl is needed for normal hemostasis
Fibrinogen mg/dl
Lecture Notes:
The importance of fibrinogen levels in the setting of thrombolysis is shown here. The fibrinogen levels in people who don’t bleed after receiving a thrombolytic agent are higher than in those patients who do sustain a bleeding event (125.5 mg/dl vs 54 mg/dl).
References:
1. Melerhenrich et al, Int J Cardiol 1998
Don’t Bleed
Bleed
Melerhenrich et al, Int J Cardiol 1998

4. Fibrinogen Depletion and Bleeding
Adapted from Smalling et al, Circ 1995;
TNK: Fibrinogen remains within 10-15% of baseline
TNK
Wintrobs Clinical Hematology 9th Edition
100 mg / dl is needed for normal hemostasis
Lecture Notes
The clinical advantages of enhanced fibrin specificity are shown here. A level of 100 mg / dl is felt to be necessary for normal hemostasis (Wintrobs Clinical Hematology Textbook, 9th edition). Based upon the data from TIMI 10A, it has been shown that TNK does not drop fibrinogen levels by more than 15%, and as shown by the green schematic, the fibrinogen levels in patients treated with TNK stay well above the level of 100 mg / dl required for hemostasis. tPA does drop fibrinogen levels near 100 for up to 12 hours, long after the drug is out of the body (half life of 3 to 4 minutes). As a less fibrin specific agent, rPA does drop fibrinogen levels below 100 mg / dl for up to 12 hours, again long after the drug is out of the body. Clinically, this may account for differences observed in bleeding rates and transfusion rates observed among different agents.
References:
1. Smalling et al, Circulation 1995;
2. Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:

5. ASSENT-2: Significantly Fewer Noncerebral Bleeding Events With TNK-tPA
P Value
Total bleeds (%)
26.4
29.0
0.0003
Major bleeds (%)
4.7
5.9
0.0002
Minor bleeds (%)
21.8
23.0
0.0553
Lecture Notes
As a result of improved fibrin specificity and weight adjusted dosing, the bleeding rates and transfusion rates were lower with TNK compared with tPA in the ASSENT-2 trial. TNK is therefore a safer agent than tPA.
References:
1. ASSENT II Investigators, Lancet 1999; 354:
Units transfused
Any
4.3
5.5
0.0002
1-2 units
2.6
3.2 -
>2 units
1.7
2.2 -
ASSENT-2 Investigators. Lancet. 1999;354: