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A 62-year-old man comes to the emergency department because of leg pain for the past 3 hours. Past medical history is significant for chronic atrial fibrillation, hypertension, and diabetes mellitus. Physical examination of the right lower extremity shows positive Homan sign and a palpable cord in the mid-calf. Doppler ultrasound shows the presence of a deep venous thrombosis. Platelet count show no abnormalities. The patient is admitted and low molecular weight heparin is initiated. 2 days later, laboratory tests show:
Leukocyte count: 9,000/mm³
Hemoglobin: 13.7 g/dL
Platelet count: 110,000/mm³
Prothrombin time: 13s
Partial thromboplastin time: 35s
Which of the following is the most likely cause of the abnormal laboratory finding(s)?
Contributors:Ursula Florjanczyk, MScBMC, Robyn Hughes, MScBMC, Tanner Marshall, MS, Sam Gillespie, BSc, Jake Ryan, Samantha McBundy, MFA, CMI, Sean Watts, MD
Anticoagulant medications are used to prevent blood clots from forming. These medications work by interfering with the normal function of plasma proteins called coagulation factors, which take part in secondary hemostasis-- where hemo refers to blood, and stasis meaning to halt or stop. In this video we’re going to focus on heparin, which works by indirectly inhibiting two clotting factors called thrombin and factor Xa by binding to and enhancing the activity of an anticoagulant protein called antithrombin III.
Now, before we discuss heparin in detail, we need to talk about the coagulation cascade, which is where heparin exerts its effect. The coagulation cascade starts via two pathways --the extrinsic and intrinsic pathways. The intrinsic pathway starts when circulating factor XII comes into contact with the surface of activated platelets or collagen. Activated factor XII, then activates factor XI, which activates factor IX which activates factor X. Factor Xa starts the common pathway where it activates factor II, or thrombin, which activates factor I that builds the fibrin mesh. When factor II gets activated it also activates 4 other factors: V, VIII, IX, and XIII. Factor V gets activated and acts as a cofactor for X, factor VIII acts as a cofactor for factor IX, and factor XIII helps factor I, or fibrin, form crosslinks. In the extrinsic pathway, exposed tissue factor activates factor VII, which activates factor X and starts the common pathway.
Now, the most important point of clot regulation is when a coagulation factor called thrombin is produced. Thrombin, or activated factor II, is a very important clotting factor, because it has multiple pro-coagulative functions. Think of thrombin as the accelerator on a car--the pedal that takes secondary hemostasis from 20 miles per hour to 100 miles per hour! First, thrombin binds to receptors on platelets and causes them to activate. Activated platelets change their shape to form tentacle-like arms that allow them to stick to other platelets. Second, thrombin activates two cofactors; factor V used in the common pathway, and factor VIII used in the intrinsic pathway. Third, thrombin proteolytically cleaves fibrinogen or factor I, into fibrin or factor Ia which binds with other fibrin proteins to form a fibrin mesh. And finally, thrombin proteolytically cleaves stabilizing factor or factor XIII into factor XIIIa.
Factor XIIIa combines with a calcium ion cofactor to form cross links between the fibrin chains, further reinforcing the fibrin mesh. Since thrombin is so crucial to coagulation, it makes sense that it serves as the main target of antithrombin III, which is one of the body’s anticoagulation proteins. Now, antithrombin III, sometimes just called antithrombin is a protein made by the liver and released into the blood, where it binds both thrombin and factor Xa in the common pathway. The thrombin in the blood can bind to antithrombin and become unavailable. Antithrombin also binds to active factor X, which is a pivotal coagulation protein that converts prothrombin into thrombin. Antithrombin also inhibits factors VII, IX, XI and XII--although with much less affinity.
Heparin is a carbohydrate molecule with a pentasaccharide chain followed by a tail made of glycosaminoglycans. Heparin can be unfractionated or fractionated. Unfractionated heparin refers to heparin derived physiologically--usually from pig intestine--and is a mixture of high molecular weight heparins, (or HMWH), and low molecular weight heparins (or LMWH). HMWH has a longer glycosaminoglycan tail, while LMWH have a much shorter tail. Fractionated heparin is created when unfractionated heparin undergo a process where the HMWH get depolymerized, meaning part of their tail gets chopped off, so it only consists of LMWH. The length of the tail is crucial for the function of these 2 types of heparin. Both high and low molecular weight heparins can bind to antithrombin III via the pentapeptide region, to increase its activity in inhibiting factor Xa. However, in order to increase antithrombin III’s activity against thrombin, the thrombin needs to bind to the long tail of the heparin, meaning only high HMWH has an effect on thrombin. Compared to unfractionated heparin, LMWH like Enoxaparin and Dalteparin have better bioavailability and have a two to four times longer half-life. Additionally, low molecular weight heparin does not require laboratory monitoring because it does not affect thrombin. Another medication that shares these features is Fondaparinux which is a synthetic molecule similar to LMWH but only contains the pentasaccharide chain.
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