Ask the Clinical Instructor

Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Ask the Clinical Instructor
Author(s): 

Questions are answered by:
Todd Ginapp, EMT-P, RCIS, FSICP

Todd is the Cardiology Manager for Memorial Hermann Southeast in
Houston, Texas. He also teaches an online RCIS Review course for Spokane Community College, in Spokane, Washington, and regularly presents with RCIS Review Courses.

I get confused about the all anticoagulants used in the cath lab. I am not a nurse, and I can’t seem to “get” why they use which ones at certain times and why.
— Anonymous RCIS Review Online Learner

Yes, it can be confusing and intimidating. But, if you understand some of the basic principles behind these medication choices, it can be something that you won’t be intimidated by any longer. Even if you aren’t a nurse, or do not directly administer these medications, it can still help you understand what is going on with your patient before, during and after the procedure.

Each of these medications by themselves could fill a 2-3 hour class to fully discuss their actions and uses. To cover all of them in an article will require a very basic and brief overview to help you understand when and why each will be used. Also, there are many trials and studies in the literature concerning all of these medications, which your pharmaceutical clinical representative can certainly help you navigate so you can understand the data.

We will focus on the ‘real-world’ application of these medications during the course of a day in the cath lab. It is understood that the application of these standards can vary by physician or facility. Also, new and emerging studies and clinical trials can often change the indications for each medication. Only the ‘standard’ uses will be presented here.

Everyone who works in a cath lab can agree that CLOT IS BAD. During an acute myocardial infarction (AMI), we are concerned about clot that could be occluding/obstructing a coronary artery. During interventional cases, we worry about clot because of the catheters, wires, balloons and stents that are in the coronary arteries. If clotting was not inhibited, then clot would inevitably develop on this equipment. We also worry about clotting as a result of the body’s response to injury from plaque rupture or vessel damage. This vessel damage can present during an AMI (plaque rupture), or it can present as a natural response to the stretching of an artery with a balloon/stent during angioplasty.

To combat clot in these cases, we utilize a small group of medications, which we will sort into “heparins” and “anti-platelet agents.” First, it is important to understand a few basics of the clotting process. If you have ever looked at a detailed chart or read a chapter concerning clotting processes, it can be very overwhelming. Let’s break the whole process down into the targets that our medications will act upon.

The mechanisms that occur when you skin your knee aren’t much different than when a balloon is inflated within an artery or a plaque ruptures within the artery. At the point of damage, the injured area releases collagens and chemicals called ‘tissue factors’ into the bloodstream. This is the body’s way of sounding the emergency siren for help. During this time, the vessels at and around the injury site vasoconstrict in an attempt to reduce blood loss and localized swelling.

Platelets are always circulating in our blood, awaiting that emergency siren. Once it is received, the platelets “go into action,” i.e. become activated and respond to the site of injury. Once they find the site of injury, the platelets attach themselves to the injured area in an attempt to make a “patch.” The platelets send out little ‘fingers’ as an attempt to attract and catch more platelets (Figure 1a-c).

The same chemicals released during the body’s ‘emergency siren’ also trigger prothrombin, normally circulating in our body, to activate. When prothrombin is activated, it undergoes a chemical transformation that releases thrombin. The role of thrombin is to change fibrinogen to fibrin. Fibrin expands and connects with other fibrin strands to make a web. The web gets more and more dense until red blood cells can no longer pass through it. Once red blood cells stop, they stick to other red blood cells, and this continues until a clot is formed (Figure 1d). The generation of thrombus in the body also continues to send out activation signals for additional platelet arrival and activation, resulting in additional thrombus formation.

When we skin our knee, this mechanism is helpful so that we do not bleed to death. You could also note that in severe artery trauma (e.g. a hunter who cuts his femoral artery while field-dressing game), the forward flow of blood overrides any attempts of fibrin to make a web so that the hunter will continue to bleed. However, when we remove a sheath from the femoral artery, we compress the arteriotomy site, allowing the fibrin web to develop in order to control bleeding. Hence the old saying, “All bleeding stops eventually.”

Remember, this is the rudimentary explanation of clot formation. There are multiple chemical releases, reactions and changes working in the background to help these responses occur.

When we attempt to prevent clotting in the cath lab, we hope to stop the clotting process at some point in the chain. For the purpose of this article, we will sort our medications into those that affect THROMBIN and those that affect PLATELETS.

As we go through these medications, Chart 1 will be referenced. (This chart has existed for a long time, and as far as we know, the author/source is unknown. If you know where this chart originated, please do let us know so we can give appropriate credit.)

1. Medications Affecting Thrombin Heparins

Unfractionated heparin is one of the common medications used in the cath lab and has a proven track record. Its use can be documented back to 1916, before the United States Food and Drug Administration (FDA) existed. It was officially entered into clinical trials in 1935 and has been used extensively ever since.1

In lower doses, heparin helps to prevent the start of clotting by inhibiting in the conversion of prothrombin to thrombin. In high doses, such what as the boluses in the cath lab would achieve, heparin will almost completely neutralize the prothrombin-to-thrombin chain conversion, as well as having a degrading effect on existing thrombin. Since thrombin is eliminated, the conversion of fibrinogen to fibrin is also eliminated.

Low-molecular weight heparin (LMWH) (i.e. enoxaparin, Lovenox, Sanofi-Aventis) ultimately achieves a blocking of the conversion of prothrombin to thrombin. It does so through multiple chemical reactions, primarily on what is called “factor Xa.” Enoxaparin is administered subcutaneously (SQ) on the abdomen. These patients will come with a bruise on their abdomen at each injection site. Enoxaparin should not be administered the morning of a scheduled procedure.

Enoxaparin is gaining popularity in the acute coronary syndrome field, and there are also some new indications for its use as IV bolus in emergencies (see Table 1). There have been concerns about activated clotting time (ACT) monitoring of enoxaparin in patients receiving the medication SQ. With intravenous (IV) administration, “the ACT is equally sensitive to IV enoxaparin and dalteparin. These data support an ACT-guided strategy for intravenously administered LMWH during percutaneous coronary intervention (PCI). Additional studies with larger patient populations may be indicated to determine the ideal target ACT for LMWH in PCI.”2

Risks of heparins include undesired high levels of anticoagulation (can be reversed by protamine sulfate), increased bleeding events and heparin-induced thrombocytopenia (HIT) (an article for another time), of which enoxaparin offers less risk. Therapeutic levels of heparin administration are recommended around 250-299 seconds (based upon ACT results) during a PCI, or 200-250 seconds if used with a glycoprotein (GP) IIb/IIIa medication.

Bivalirudin’s (Angiomax, The Medicines Company) main role is as a replacement for heparin. It is a direct thrombin inhibitor that binds to thrombin to prevent it from activating the thrombin receptor that eventually activates fibrinogen to create fibrin (Figure 1c). Because of its very short half-life (25 minutes), bivalirudin initially stops the thrombin from forming a thrombus, and then allows a rapid return of this function after the procedure, when sheaths are to be removed and hemostatic ability is needed.3

Simply put, bivalirudin temporarily inhibits the aggregation of platelets, but not their activation. Bivalirudin can also be used as a replacement for heparin in cases of HIT and can be administered with GP IIb/IIIa inhibitors during PCI in those cases. It is important to know that heparin prevents the formation of clot by reacting with thrombin. However, heparin does not work against clot-bound thrombin. We mentioned that existing thrombus recruits additional platelets to develop more clot. Bivalirudin not only works on the thrombin site at the platelet level in the circulation, but also on the thrombin that is bound to an existing clot. The “call for reinforcements” is stopped.

A great advantage of bivalirudin over heparin in our daily work is its half life. What this means is that once the procedure is over, bivalirudin can be turned off. Sheaths can be removed 2 hours after the drip is turned off. This DOES NOT apply to patients with severe renal function or on dialysis. It can occur without the need for ACT tests. Standard ACT tests have a poor correlation to bivalirudin levels, leading to uncertainty regarding adequate anticoagulation in PCI patients.4 The accurate monitoring of bivalirudin levels needs further investigation and development. This also applies to post-procedure results. Studies have shown that sheath removal after 2 hours is safe and effective.5,6

2. Medications that Affect Platelets

The use of aspirin (acetylsalicylic acid, ASA) in cardiovascular disease has been well documented. You have probably seen all the television ads for the use of ASA during a heart attack. ASA interrupts the clotting process by blocking a chemical called thromboxane A2 (TXA2) (Figure 1). TXA2 release results in the initial vasoconstriction at the injury site, as well as mediating platelet aggregation. The result of this is a “slippery” platelet. Because the platelets are slippery they do not clump together (aggregate). Because they do not clump together, red blood cells do not stick to them. This can result in blood cells being “slippery” as well. If things do not stick together, the clotting occurrence is reduced.

ASA has an onset of action of 15-30 minutes, even at low doses of 81 mgs. When a patient is at a therapeutic level of ASA, the effects can last for 4-7 days.7

Glycoprotein IIb/IIIa inhibitors [abciximab (ReoPro, Eli Lilly), eptifibatide (Integrilin, Millennium Pharmaceuticals), tirofiban (Aggrastat, Merck & Co., Inc.), etc.] work on the receptor sites that allow fibrinogen to ‘connect’ platelets together. Once these sites are blocked, platelets cannot connect together to create a clot (Figure 1b).

References: 

1. Linhardt RJ. Heparin: an important drug enters its seventh decade. Chem Indust 1991;2:45-50.

2. Cavusoglu E, Lakhani M, Marmur JD. The activated clotting time (ACT) can be used to monitor enoxaparin and dalteparin after intravenous administration. J Invas Cardiol 2005;17(8):416-421.

3. Angiomax prescribing information, The Medicines Company, Parsippany, NJ.

4. Carroll RC, Chavez JJ, Simmons JW, et al. Measurement of patients' bivalirudin plasma levels by a thrombelastograph ecarin clotting time assay: a comparison to a standard activated clotting time. Anesth Analg 2006 May;102(5):1316-1319.

5. Mehta S, Yebara SM, Ibrahim M, et al. Cedars Medical Center’s experience: early ambulation post PCI with the use of direct thrombin inhibitor, bivalirudin. Cath Lab Digest 2004;12:24-27.

6. Minutello RM, Wong SC, Chou ET, et al. Angiomax Facilitates Early Sheath Removal After Coronary Angioplasty: The AFRICA Study. Am J Cardiol 2003; 6 Suppl 1;146L.

7. Libby P, Bonow RO, Mann DL, Zipes DP. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 8th Edition. Philadelphia: Elsevier Science; 2007, 1-2183.

8. ReoPro full prescribing information, Eli Lilly and Company, Indianapolis, Indiana.

9. Field J, Hazinski MF, Gilmore D, eds. Handbook of Emergency Cardiovascular Care: for Healthcare Providers (AHA Handbook of Emergency Cardiovascular Care). Dallas, Texas: American Heart Association; 2008.


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