pathology

Deep Venous Thromboembolism Proximal DVTs have a higher risk of PE than distal DVTs. Proximal DVTs are those that affect the popliteal or femoral veins. Treatment of DVT Oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban) are a better choice than the traditional warfarin heparin combination. The factor Xa inhibitors work quickly, do not require monitoring of INR, and avoid the adverse effects and restrictions associated with warfarin use. Patients who are not candidates for factor Xa inhibitors include those with poor renal function and those with malignancy associated thrombosis. Warfarin and heparin are the traditional anticoagulants used to treat DVTs. Unfractioned heparin or low molecular weight heparin (enoxaparin) must be given first as it acts quickly and works to combat the initial pro-coagulant effect of warfarin (due to the fact that warfarin first reduces protein C & S production before affecting other vitamin K-dependent factors). With this combinati...

Thrombolysis Plasminogen is converted to plasmin, and this step can be enhanced using thrombolytics/ fibrinolytics (e.g. streptokinase, tPA, and urokinase). Plasmin then acts to promote fibrinogen degradation as well as degradation of the fibrin clot into fibrin split products. The formation of plasmin from plasminogen is inhibited by antithrombolytics/ antifibrinolytics (e.g. aminocaproic acid, tranexamic acid). Thrombolytics Tissue plasminogen activator (tPA) derivatives including reteplase, alteplase and tenecteplase are fibrin-specific and act only on fibrin that is part of a recently formed clot. Because they do not act systemically, these are drugs are associated with a smaller risk of bleeding. Streptokinase and urokinase are non-fibrin specific thrombolytics that act more systemically. Contraindications to Thrombolytic Use

Aspirin Aspirin works by irreversibly acetylating platelet cyclooxygenase 1 (COX-1) resulting in decreased production of thromboxane A2. Aspirin also irreversibly acetylates COX-2 when given at high doses which results in an anti-inflammatory effect. P2Y12 Inhibitors Examples include clopidogrel , prasugrel and ticagrelor as well as ticlodipine . They work by binding to the P2Y12 component of ADP  receptors on platelets resulting in inhibition of platelet aggregation. Phosphodiesterase inhibitors Dipyridamole and Cilostazol also cause inhibition of platelet aggregation and they work by inhibiting phosphodiesterase activity which leads to elevated cAMP. Glycoprotein IIb/IIIa inhibitors Examples include abciximab , eptifibatide , and t irofiban . These work by inhibiting binding of platelet glycoprotein IIb/IIIa with fibrinogen and fibronectin. Quizlet Flash Cards

Mechanism Unfractioned heparin (UFH) has a pentasacharide sequence that binds to antithrombin to form a complex. The UFH-antithrombin complex is better at inactivating factor Xa then antithrombin alone. This is because once bound to UFH, antithrombin undergoes a conformational change. The UFH-antithrombin complex can also inactivate thrombin by binding to it. Low moleculer weight heparin (LMWH) also has a pentasaccharide sequence that binds to antithrombin to form a complex. The LMWH-antithrombin complex also inactivates factor Xa, however, it doesn't work on thrombin. This is because the pentasaccharide sequence on LMWH is too short to both complex with antithrombin and bind thrombin. LMWHs typically end in "parin", examples include enoxaparin and dalteparin . Adverse effect:  Heparin-Induced Thrombocytopenia (HIT) Heparin is a common cause of thrombocytopenia. LMWH (e.g. enoxaparin) is less likely than unfractioned heparin to cause HIT.   There are two m...

Coagulation Cascade To understand the coagulation disorders, an understanding of the coagulation cascade is necessary. The coagulation cascade consists of an extrinsic and intrinsic pathway both of which end in a common pathway. The extrinsic pathway begins when damaged tissue releases thromboplastin. Thromboplastin activates factor VII and the activated factor VII then activates factors IX and X. The intrinsic pathway begins when exposure to subendothelial collagen or exposure to high molecular weight kininogen (HMWK) activates factor XII which is also known as Hageman factor. The activated factor XII then activates factor XI which goes on to activate factor X. Activated factor IX needs to be in a complex with activated factor VIII, platelet factor 3 (PF3) and calcium. Calcium is needed to bind the activated coagulation factor. The common pathway begins with activated factor X which can be arrived at by either the intrinsic or extrinsic pathways. Activated factor X forms a comp...

Mechanism Warfarin is a commonly used anticoagulant that works by inhibiting synthesis of vitamin K dependent clotting factors (II, VII, IX, and X) and proteins C and S by the liver. Specifically, warfarin inhibits the enzyme vitamin K reductase resulting in inhibition of vitamin-K dependent gamma-carboxylation of glutamic acid residues on clotting factors II, VII, IX and X. Warfarin takes a few days to start working and it first affects protein C and S production. Because proteins C and S have anticoagulant properties, warfarin, initially results in a temporary increase in the risk of thrombus formation. Therefore, before starting warfarin patients are generally given another anticoagulant such as heparin. Metabolism Warfarin is metabolized by cytochrome P450, a microsomal enzyme in the liver. Reversing the effects of Warfarin Fresh frozen plasma (FFP) restores vitamin-K dependent clotting factors, making it the quickest way to normalize prothrombin time (PT). Vitami...