The human body is smart enough that if it makes a clot, it can remove the clot once it has served its purpose. Thrombolysis (clot breakdown) involves breaking up the clot’s fibrin meshwork causing the clot to fall apart. The clot fragments or fibrin degradation products (FDP) then float downstream to be eaten by large vacuum-cleaner-like-cells called macrophages.
Interestingly, as a clot develops it incorporates plasminogen into the clot in preparation for the time when the clot is no longer needed. The plasminogen in the clot can then be converted to plasmin by Tissue Plasminogen Activator (TPA). Plasmin is the agent that will break down the fibrin web to disassemble the clot. The maturing clot itself stimulates the release of TPA from surrounding cells to generate plasmin and begin fibrin breakdown as the usefulness of the clot decreases.1 (Fig 1)
Manufactured TPA
We can use this same clot busting action for treating unwanted blood clots obstructing arteries in the heart, brain, lungs or extremities via commercially produced TPAs such as tenecteplase, alteplase, and reteplase. The more accurate name for these drugs are fibrinolytics because they lyse or break fibrin, but thrombolytics is also an accurate term because it describes the final desired outcome of getting rid of the clot.
Small doses of TPA can also be used to dissolve clots that form in central venous catheters. These long catheters are used when long term intravenous access is necessary. They may be inserted into the central veins such as the subclavian, internal jugular or femoral vein or through a peripheral vein via a peripherally inserted central catheter (PICC). Either way, the tip of the catheter is positioned in the superior vena cava and on occasion becomes obstructed by clot formation inside the lumen.
There are two types of clot-busting drugs, indirect fibrinolytics and direct fibrinolytics.
Indirect fibrinolytics
Commercial TPAs are produced by genetic engineering using DNA to produce a TPA that can be given intravenously or intra-arterially to dissolve clots. Deoxyribonucleic Acid or DNA carries the genetic blueprint used to build living creatures like you and me.2 We all started out as one cell that divided billions of times with each cell carrying a copy of the DNA blueprint to construct and then maintain life.
The genetic engineering process is called recombinant DNA technology. The process involves taking the desired piece of DNA from one type of cell and inserting it into another cell where it is incorporated or recombines with the DNA present in the receiving cell. As the cells with the rDNA, shorthand for recombined or recombinant DNA, begins to grow on a culture medium they produce whatever that DNA segment produced in the original cell.
A specific example is the production of alteplase. To make alteplase, the TPA DNA segment is extracted from human melanoma cells and then genetically inserted into Chinese hamster ovary cells (no kidding!).3 The TPA DNA recombines with the DNA in the ovarian cells producing rTPA DNA. As the cells grow in a culture medium, the rTPA DNA begins to manufacture the rTPA. Just my opinion, but that’s amazing (and weird), but it works. The purchase price for the rTPAs is significant, but the good news is that the pharmaceutical companies reinvest part of that cost into research and development for all kinds of new medications.
Bottom line, when I have my ST segment elevation myocardial infarction (STEMI) from a clot completely blocking one or more of my coronary arteries or experience a thrombotic stroke, I will be happy to pay the price for rTPA administration.
Direct fibrinolytics
There are fibrin busting agents that directly target the fibrin in the clot. These agents do not use TPA to activate the plasmin contained in the clot. These include plasmin, substances made from plasmin and certain snake venom enzymes. Their potential advantage may be fewer hemorrhagic complications. Although some have undergone clinical trials, none have yet been approved for clinical use.4
Anticoagulation post-TPA
It is important to keep in mind that clot busting drugs do not prevent a clot from reforming. So after the bust, the patient will require anticoagulation with heparin to help prevent new clot formation.
Conclusion
There is increasing evidence that prehospital fibrinolysis is an effective component of a comprehensive approach to STEMI care.5 And when indicated, the sooner intravenous fibrinolytics are administered, the better they work. If your system currently does not provide field fibrinolytics, you can still help shorten the time interval from facility arrival to rTPA administration, known as the door to needle time. A fibrinolytic risk screen must be performed prior to fibrinolytic administration in any location. You can do this in the field at the same time you do your TIMI risk score for your chest pain patient. Hand over that information along with the patient to the receiving facility. Those facilities that value EMS as a part of their health care team will recognize the benefit and appreciate your effort.
References
1. B, Furie BC. Mechanisms of Thrombus Formation. New Engl J Med 2008:359:938-949.
2. The Basics of Recombinant DNA. Retrieved from http://www.rpi.edu/dept/chem-eng/Biotech-Environ/Projects00/rdna/rdna.html
3. Activase (Alteplase). Retrieved from http://www.gene.com/gene/products/information/cardiovascular/activase/insert.jsp
4. Marder VJ, Novokhatny V. Direct Fibrinolytic Agents: Biochemical Attributes, Preclinical Foundation and Clinical Potential. J. Thromb Haemost 2010; 8:433-44.
5. Huynh T, MD, Birkhead J, Huber K, O’Loughlin J, Stenestrand U, Weston C, Jernberg T, Schull M, Welsh RC, Denktas AE, Travers A, Sookram S, Theroux P, Tu JV, Timmis A, Smalling R, Danchin N. The Pre-Hospital Fibrinolysis Experience in Europe and North America and Implications for Wider Dissemination. J Am Coll Cardiol Intv, 2011; 4:877-883.
