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When tissue injury occurs, platelets gather around the injured site to form the primary hemostatic plug. This step in turn activates other platelets and releases additional cellular and humoral components of hemostasis. Furthermore, exposed tissue factors promote thrombin generation during the coagulation phase of hemostasis to stabilize the weak platelet hemostatic plug. This process leads to a cascade of protease activation that foster the formation of a fibrin clot localized to the injury (Figure 180-1). Further fibrin clot formation is limited due to a series of inhibitors balancing out the coagulation. Normal hemostasis is a balance between procoagulant and anticoagulant mechanism. When there is an imbalance, a hypercoagulable state can lead to unwanted arterial of venous thrombosis. This can give rise to devastating injury and leave the patient disabled with an increase in mortality.

Figure 180-1

Coagulation cascade and associated laboratory tests.

(Reproduced with permission from Longo DL, Harrison TR, Harrison’s Principles of Internal Medicine, 18th ed. New York: McGraw-Hill; 2012.)

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Unfractionated heparin (UFH) is a sulfated polysaccharide that binds to its cofactor, antithrombin III or simple antithrombin (AT), to accelerate the rate of anticoagulant activity. The enhanced antithrombin activity inhibits clotting cascade proteins—in particular, thrombin and Factor Xa. Unfractionated heparin has a unique pentasaccharide sequence that is found on one-third of the chains of commercial heparins that is highly specific for AT. Subsequently, this “AT-Heparin” complex promotes a conformational change to enhance the rate of inhibition to thrombin and Factor Xa. UFH requires at least an addition of 18 saccharides downstream to tightly bring the two proteins together to enzymatically form a stable covalent “Heparin-AT-Thrombin” complex. This binding promotes a suicidal effect to thrombin but the heparin molecule is able to dissociate unchanged. In contrast, inhibition of Factor Xa requires that heparin bind to AT to enhance anticoagulant activity without a suicidal effect. Generally, UFH affects the intrinsic pathway, but at higher level it may stimulate the release of tissue factor plasma inhibitor (TFPI) and limit the formation of the prothrombinase complex with FXa via the extrinsic pathway. Heparin can directly affect platelet itself and subsequently disrupt aggregation.


Hemorrhage is one complication that can occur with intravenous heparin therapy. The risk is greatest with concomitant administration, with other drugs affecting hemostasis such as antiplatelet or fibrinolytic therapy. On the other hand, it is rarely seen with prophylactic use for DVT. Approximately up to 30% of patients who suffer from anticoagulant-induced hemorrhage may have preexisting lesion that goes undetected. The incidence of major life-threatening bleeding is about 5%. In such a case, protamine sulfate can be given to neutralize heparin. Protamine sulfate, a polypeptide isolated from salmon sperm, binds with high affinity to heparin. This inactive complex is eventually removed from circulation by the kidney, thus removing any heparin activity.


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