NMR in Studies of Thrombolysis

Lysis of occlusive thrombi initially proceeds via penetrating channels that recanalize the occluded vessel, but does not result in a complete dissolution of the clot. When the first reperfusion channel pierces the clot, blood starts flowing through the channel and further blood clot lysis proceeds from the borders of the channel into the direction of the remaining clot. It has not been known whether tangential flow of blood plasma along the clot causes exchange of the serum inside the clot by diffusion alone or also by convective exchange when the tangential flow is turbulent. Our aim was to test by high resolution magnetic resonance imaging on an in vitro model system how non-occlusive whole blood clots were dissolved by tangential flow of plasma, that contained either fibrin-specific tissue plasminogen activator (t-PA), or fibrin nonspecific streptokinase.

Concentrations of t-PA at 2 ag/ml and streptokinase at 250 IU/ml were chosen to represent the average therapeutic concentrations during thrombolytic treatment of myocardial infarction. Cylindrical clots with a diameter of 3 mm and length of 3 cm were formed in glass tubes and pierced lengthwise by a needle with a diameter of 0.7 mm. The nonocclusive clots were connected to a perfusion system. The velocity of plasma flowing through the preformed channel in the clot was initially 426 +- 13 cm/s and fell to 86 +- 3 cm/s (n = 5) after a complete clot dissolution. Magnetic resonance imaging of transverse clot sections was used for measuring the transport of plasma, containing the contrast agent Gd-DTPA, from the flow channel into the clot. Simultaneously, the clot dissolution was measured. In each experiment, 20 consecutive T1 weighted magnetic resonance images (TE/TR = 12.5/400 ms) at the field of view 2 cm and the slice thickness 2 mm were acquired in 2 min intervals.



Movie showing clot cross-section during lysis. MRI images were acquired at 2 min intervals.

Penetration of contrast agent-containing plasma into clots did not depend on the choice of a thrombolytic agent. At 6 min GdDTPA containing areas were found at a distance 1.78 +- 0.49 mm (n = 4) from the border of the channel in clots dissolved with streptokinase, and at a distance of 2.22 +- 0.25 mm (n = 4) in clots dissolved with t-PA (p = 0.11). However, the dissolution of blood clots was significantly faster when t-PA was used in comparison with streptokinase. After 12 min of clot lysis the cross section of clots, exposed to t-PA was reduced to 0.49 +- 0.25 (n = 4) of their initial size, whereas clots exposed to streptokinase were reduced to only 0.79 +- 0.16 (n = 4) of their initial size (p = 0.029). The differences in clot size remained significant through 40 min. The concentration of plasminogen did not change substantially in plasma containing t-PA, but was reduced to about one third of its initial value when streptokinase was used.



Graph depicts dynamics of clot lysis by two different agents: t-PA and streptokinase.

Rapid, turbulent flow of plasma through a channel in the clot caused rapid exchange of the serum inside the clot with outer plasma. The rate of plasma-serum exchange was much more rapid than transport caused by diffusion alone. Using fibrin-specific t-PA that did not deplete the plasma of its plasminogen favorably affected the rate of blood clot lysis in comparison with non fibrin-specific streptokinase that depleted the plasma of two thirds of its plasminogen content.

References:

  1. SERŠA, Igor, ŠTRUKELJ, Mitja, BLINC, Aleš. Influence of tangential plasma flow on fibrinolysis of non-occlusive thrombi : study by MR microscopy. V: Proceedings of the International Society for Magnetic Resonance in Medicine, 9th Scientific Meeting and Exhibition [and] European Society for Magnetic Resonance in Medicine and Biology, 18th Annual Meeting and Exhibition: 21 - 27 April 2001 Glasgow, Scotland. Berkeley: International Society for Magnetic Resonance in Medicine, 2001, vol. 2, p. 875. [PDF]
  2. KOZAK, Matija, BLINC, Aleš, SERŠA, Igor, MIKAC, Urša, ŠURLAN, Miloš. Magnetic resonance imaging of arterial thrombi and its possible correlation to fibrinolytic treatment. Cell. Mol. Biol. Lett., 2002, vol. 7, p. 82-86. [PDF]
  3. TRATAR, Gregor, BLINC, Aleš, ŠTRUKELJ, Mitja, MIKAC, Urša, SERŠA, Igor. Turbulent axially directed flow of plasma containing rt-PA promotes thrombolysis on non-occlusive whole blood clots in vitro. Thromb. Haemost., 2004, vol. 91, p. 487-496. [PDF]
  4. SERŠA, Igor, TRATAR, Gregor, BLINC, Aleš. Blood clot dissolution dynamics simulation during thrombolytic therapy. Journal of chemical information and modeling (formerly Journal of chemical information and computer sciences), 2005, vol. 45, p. 1686-1690. [PDF]
  5. KOZAK, Matija, MIKAC, Urša, BLINC, Aleš, SERŠA, Igor. Lysability of arterial thrombi assessed with MRT. VASA, 2005, vol. 34, p. 262-265. [PDF]
  6. SERŠA, Igor, TRATAR, Gregor, MIKAC, Urška, BLINC, Aleš. A mathematical model for the dissolution of non-occlusive blood clots in fast tangential blood flow. Biorheology (Oxf.), 2007, vol. 44, p. 1-16. [PDF]
  7. TRATAR, Gregor, BLINC, Aleš, PODBREGAR, Matej, KRALJ, Eduard, BALAŽIC, Jože, ŠABOVIČ, Mišo, SERŠA, Igor. Characterization of pulmonary emboli ex vivo by magnetic resonance imaging and ultrasound. Thromb. res., 2007, vol. 120, p. 763-771. [PDF]
  8. SERŠA, Igor, VIDMAR, Jernej, GROBELNIK, Barbara, MIKAC, Urška, TRATAR, Gregor, BLINC, Aleš. Modelling the effect of laminar axially directed blood flow on the dissolution of non-occlusive blood clots. Phys. Med. Biol., 2007, vol. 52, p. 2969-2985. [PDF]
  9. GROBELNIK, Barbara, VIDMAR, Jernej, TRATAR, Gregor, BLINC, Aleą, SERŠA, Igor. Flow-induced permeation of non-occlusive blood clots: an MRI study and modelling. Eur. Biophys. J., 2008, vol. 37, p. 1229-1233. [PDF]
  10. VIDMAR, Jernej, SERŠA, Igor, KRALJ, Eduard, TRATAR, Gregor, BLINC, Aleš. Discrimination between red blood cell and platelet components of blood clots by MR microscopy. Eur. Biophys. J., 2008, vol. 37, p. 1235-1240. [PDF]
  11. VIDMAR, Jernej, BLINC, Aleš, SERŠA, Igor. A comparison of the ADC and T2 mapping in an assessment of blood-clot lysability. NMR Biomed., 2010, issue 1, vol. 23, p. 34-40. [PDF]
  12. BAJD, Franci, VIDMAR, Jernej, BLINC, Aleš, SERŠA, Igor. Microscopic clot fragment evidence of biochemo-mechanical degradation effects in thrombolysis. Thromb. res., 2010, vol. 126, p. 137-143. [PDF]
  13. VIDMAR, Jernej, BLINC, Aleš, KRALJ, Eduard, BALAŽIC, Jože, BAJD, Franci, SERŠA, Igor. An MRI study of the differences in the rate of thrombolysis between red blood cell-rich and platelet-rich components of venous thrombi ex vivo. J. magn. reson. imaging, 2011, vol. 34, issue 5, p. 1184-1191. [PDF]
  14. BAJD, Franci, VIDMAR, Jernej, FABJAN, Andrej, BLINC, Aleš, KRALJ, Eduard, BIZJAK, Nina, SERŠA, Igor. Impact of altered venous hemodynamic conditions on the formation of platelet layers in thromboemboli. Thromb. res. [Print ed.], 2012, vol. 129, issue. 2, p. 158-163. [PDF]
  15. BAJD, Franci, VIDMAR, Jernej, BLINC, Aleš, SERŠA, Igor. Analysis of blood clot degradation fragment sizes in relation to plasma flow velocity. Gen. physiol. biophys., 2012, vol. 31, no. 3, p. 237-245. [PDF]
  16. BAJD, Franci, SERŠA, Igor. A concept of thrombolysis as a corrosion-erosion process verified by optical microscopy. Microcirc. (N.Y. N.Y. 1994), 2012, vol. 19, no. 7, p. 632-641. [PDF]
  17. BIZJAK, Nina, BAJD, Franci, VIDMAR, Jernej, BLINC, Aleš, MARDER, Victor J., NOVOKHATNY, Valery, SERŠA, Igor. Comparison of local thrombolytic efficacy of plasmin and rt-PA in an in-vitro flow system : a pilot study. Blood coagulation & fibrinolysis, ISSN 0957-5235, 2013, vol. 24, no. 7, p. 711-714. [PDF]
  18. BAJD, Franci, SERŠA, Igor. Mathematical modeling of blood clot fragmentation during flow-mediated thrombolysis. Biophysical journal, ISSN 0006-3495, 2013, vol. 104, no. 5, p. 1181-1190. [PDF]
  19. BIZJAK, Nina, BAJD, Franci, VIDMAR, Jerneja, BLINC, Aleš, POHAR PERME, Maja, MARDER, Victor J., NOVOKHATNY, Valery, SERŠA, Igor. Direct microscopic monitoring of initial and dynamic clot lysis using plasmin or rt-PA in an in vitro flow system. Thrombosis research, 2014, vol. 133, issue 5, p. 908-913. [PDF]
  20. VIDMAR, Jernej, KRALJ, Eduard, BAJD, Franci, SERŠA, Igor. Multiparametric MRI in characterizing venous thrombi and pulmonary thromboemboli acquired from patients with pulmonary embolism. J. magn. reson. imaging, 2015, vol. 42, issue 2, p. 354-361. [PDF]
  21. VIDMAR, Jernej, SERŠA, Igor, KRALJ, Eduard, POPOVIĆ, Peter. Unsuccessful percutaneous mechanical thrombectomy in fibrin-rich high-risk pulmonary thromboembolism. Thrombosis journal, 2015, vol. 13, p. 30-1-30-6. [PDF]
  22. VIDMAR, Jernej, BAJD, Franci, MILOŠEVIĆ, Zoran, KOCIJANČIČ, Igor, JEROMEL, Miran, SERŠA, Igor. Retrieved cerebral thrombi studied by T2 and ADC mapping: preliminary resutls. Radiol. Oncol., 2019, vol. 53, p. 427-433. [PDF]
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