Editor’s Note: Be sure to check out Jim’s article “Platelets and coagulation basics for EMS” as a primer for his discussion on coagulation and anticoagulation drugs.
Maintaining our internal oxygen transportation system is essential to life and the red blood cells are the carriers. Excessive red blood cell loss can produce organ system damage or death.
It’s as simple as this: kill enough cells, kill the organ; kill enough organs or the right organ, kill the organism. Fortunately, we have an internal leak management system comprised of circulating platelets and coagulation factors that can provide a seal.
The initial event in clot formation is the development of a platelet plug. As the plug develops it stimulates the coagulation cascade to spin a fibrin web thorough out the gathered (aggregated) platelets to trap red blood cells (RBCs).1 As these RBCs settle into the gaps, they form a tight seal against further blood loss. While this finely orchestrated process is beneficial most of the time, it can occur unwanted and induce conditions such as stroke, coronary artery obstruction or pulmonary embolus.
Clotting cascade
The clotting cascade can proceed down one of two paths, the extrinsic pathway or the intrinsic pathway (Figure 1). The extrinsic pathway is initiated by a tissue factor that is released from damaged cells. The intrinsic pathway is initiated through contact with the injured or altered inner surface of blood vessels.1
Most of these coagulation pathway factors are made in the liver, so it is not surprising that the patient with severe liver failure can have bleeding problems due to an inadequate supply of these factors. We can therapeutically decrease the supply or effectiveness of coagulation factors to prevent or treat abnormal clot formation in certain conditions. Although the bleeding risks naturally increases with anti-clot medication, it is administered in a controlled manner and the therapeutic effect outweighs the risk for most patients. It is important to understand how anticoagulant medications work and how to monitor patients who use them.
Anticoagulants
The “miracle blood lubricant”2 heparin was discovered in 1916 but was very expensive to extract and was produced only in small quantities. It was not until the 1930s that heparin was available in adequate amounts to perform the clinical trials that proved its usefulness.3 Heparin produces anticoagulation by supercharging the action of antithrombin III up to 1000 times. Antithrombin III blocks many of the components of the clotting process.4 For our discussion, the most important factors that antithrombin III inhibits are thrombin and Factor X (Figure 2).
Heparin comes in two flavors, unfractionated and fractionated. Unfractionated heparin contains both long chains and short chains of heparin molecules, each with a different action. When the long chains combine with antithrombin III they increase thrombin inactivation, and when the short chains combine with antithrombin III they increase inactivation of Factor X. Fractionated heparin contains only the short chains thus primarily inactivates Factor X5 (Figure 2).
Heparin cannot be administered orally because the heparin chains are not absorbed, thus we give heparin by subcutaneous (SC) injection or intravenously (IV). There has been work on developing a carrier molecule to bind with heparin to facilitate absorption in the gastrointestinal tract,6 but I am not aware of a commercially available product at this time. We don’t give heparin intramuscularly because of the higher number of blood vessels in muscle versus SC tissue and the potential for bleeding in the muscle.
Unfractionated heparin
Unfractionated heparin may be administered SC or IV to prevent or treat abnormal clot formation. Unfractionated heparin is a potent anticoagulant and, when administered intravenously, it has to be monitored by a blood test to prevent excessive anticoagulation. The PTT or Partial Thromboplastin Time measures the time in seconds it takes your blood to clot using the intrinsic pathway (Figure 2). The normal values for the test are determined by testing a lot of ‘normal’ people and determining average values to define the normal range.7 Besides testing the effects of heparin on clotting, the PTT can detect intrinsic pathway clotting factor defects caused by ailments like hemophilia or liver disease (Figure 2).
Fractionated heparin
Fractionated heparin or low molecular weight heparin such as enoxaparin (Lovenox) contains only the short chains of heparin molecules which, as noted above, combine with antithrombin III to block mostly Factor X. The result is a therapeutic level of anticoagulation with a much-decreased potential for bleeding from excessive anticoagulation. Generally, low molecular weight heparin generally does not require laboratory monitoring. And it does not require intravenous administration as it is effective with once or twice daily SC injections using a dose based on the patient’s weight and the condition under treatment.
Warfarin
Check the label on your favorite rat poison, and likely you will find it contains warfarin. Coumadin (a.k.a. warfarin) blocks the liver’s ability to use vitamin K to make some of those clotting factors required in the coagulation cascade and thus produces anticoagulation, or ‘thinning’ of the blood. Warfarin can be taken orally and offers an alternative to heparin injections for long term anticoagulation required by such conditions as DVTs, atrial fibrillation, coronary heart disease, stroke and mechanical heart valves.
The PT or Prothrombin Time measures the time in seconds it takes your blood to clot using the clotting factors from the extrinsic pathway. The normal values for the PT test are determined in the same way as for the PTT.7 Besides measuring the effects of warfarin on coagulation, the PT will detect extrinsic pathway clotting factor defects caused by conditions like vitamin K deficiency and liver disease (Figure 2).
The International Normalized Ratio or INR is the ratio of the patient’s PT with the average PT of a large population: patient’s PT ÷ population average PT. The normal range for the INR is 1.0-1.5, just numbers without measurement units like milligrams or international units because it is a ratio and any measurement units cancel out, i.e. 100mg ÷ 10mg = 10. We can then follow the INR in patients who need to transition from heparin to long term anticoagulation with warfarin for conditions such as a DVT, or to prevent clot formation in the atria of a patient with atrial fibrillation. Therapeutic INR for DVTs and atrial fibrillation is 2.0-3.0 and for mechanical heart valves 2.5-3.5. If the INR increases above the therapeutic level it can be corrected by adjusting the warfarin dose until the INR level is back in the therapeutic range. If the patient is bruising or bleeding, the warfarin anticoagulation effect can be decreased rapidly with administration of vitamin K. On the other side, if the patient’s INR is below the desired therapeutic range it may be due to a diet change that includes excessive vitamin K intake or medication non-compliance. (Figure 2)
New players
Anticoagulation research has not stagnated since the early 1900s. New anticoagulant medications have been developed, some successful, some not. Without going into detail about these drugs, you may begin to see your patients taking new anti-clot medications like idrabiotaparinux, semuloparin, rivaroxaban and dabigatran.8 Keeping up with our patient’s ever-changing medicine chest is a constant challenge.
Prehospital and interfacility transport considerations
After reviewing the information above, it is obvious that, during transport of a patient who has received or is receiving any of the anti-clot medications, the key monitoring focus is on bleeding. Actively look and relook for external clues of bleeding like bruising or leaks from previous venous blood draws or arterial blood gas punctures or peripheral and central line insertion sites. Monitor the patient for nosebleeds or hematuria (bloody urine), or hematemesis (bloody vomit) or hemoptysis (bloody sputum), or bright red blood per rectum (BRBPR). There are times when external bleeding signals an internal source and times when internal bleeding is concealed. During transport, the onset of tachycardia or decreasing blood pressure may signal hemorrhage hidden in the abdomen, pelvis or retroperitoneal space. A change in mental status may be an evolving brain hemorrhage. Be vigilant.
And the treatment? Stop any anti-platelet or anti-coagulation medication, apply pressure on visible and compressible bleeding sites. Begin volume replacement to maintain an adequate systolic perfusion pressure of 90-100 mmHg. Don’t make the blood pressure ‘normal’ as the increased pressure may increase bleeding. And contact medical control for further guidance.
Summary
Now you know how to clot, how to anti-clot, how to administer and monitor anti-clot medication, and you have a plan to manage bleeding complications should they arise during your time with the patient.
References:
1. Furie B, Furie BC. Mechanisms of Thrombus Formation. New Engl J Med 2008:359:938-949.
2. Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928-1937. Retrieved from http://www.healthheritageresearch.com/Heparin-Conntact9608.html.
3. Jorpes E. The Chemistry of Heparin. Biochem J 1935:29(8);1817-1830.
4. Butenas S, Mann KG. Blood Coagulation. Biochemistry (Moscow) 2002; 67:3-12.
5. Hirsch J, Warkentin TE, Shauhnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE. Heparing and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. CHEST 2001; 119:64s-94s.
6. Arbit E, Goldgerg M, Gomez-Orellana I, Majuru S. Oral heparin: status review. Thrombosis Journal 2006; 4:1-7. Retrieved from http://www.thrombosisjournal.com/content/4/1/6
7. Lab Tests Online. Retrieved from http://www.labtestsonline.org/.
8. Harenberg J, Marx S, Wehling M, Krejczy, M. New Anticoagulants – Promising and Failed Developments (Accepted Article). Br J Pharmacol 2011 Jul 8.
