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    • Basic and Clinical Science Course - Excerpt
  • 2020–2021 BCSC Basic and Clinical Science Course™

    Go to Academy Store Learn more and Purchase.

    1 Update on General Medicine

    Chapter 8: Hematologic Disorders

    Disorders of Hemostasis

    Secondary Hypercoagulable States

    Malignancy may stimulate thrombosis directly by elaborating procoagulant substances that initiate chronic DIC. This appears to be most prominent in patients with pancreatic cancer, adenocarcinoma of the gastrointestinal tract or lung, or ovarian cancer. Myeloproliferative disorders (see the earlier section “Thrombocytosis and essential thrombocythemia”) are major causes of thrombosis and paradoxical bleeding, as is paroxysmal nocturnal hemoglobinuria, a related stem cell disorder.

    Antiphospholipid syndrome is characterized by both venous and arterial thrombosis, including recurrent spontaneous abortions, deep venous thrombosis, and thrombotic events involving the cerebrovascular arteries. Evaluation of patients with this syndrome includes tests for anticardiolipin antibodies and lupus anticoagulants. See the section Antiphospholipid Syndrome in Chapter 9 for additional discussion.

    Hypercoagulability associated with pregnancy involves a progressive state of DIC throughout the course of pregnancy, activated in the uteroplacental circulation. Oral contraceptives induce similar changes. The postoperative state and trauma are significant causes of venous thrombosis.

    Ophthalmic considerations Ophthalmic complications of antiphospholipid syndrome include retinal vein and artery occlusion, retinal vasculitis, choroidal infarction, and nonarteritic anterior ischemic optic neuropathy.

    Therapeutic anticoagulation

    Many clinical situations require intentional disruption of the hemostatic process. The effect of aspirin on platelet function has already been discussed.

    Unfractionated heparin (UFH) is a mucopolysaccharide that binds antithrombin III, potentiating its effects and inhibiting the formation of thrombin. It is given intravenously or subcutaneously, and therapy is assessed by measuring the aPTT. Aspirin should not be given to patients receiving heparin because the resultant platelet dysfunction may provoke bleeding. Low-molecular-weight (LMW) heparins are another type of parenteral anticoagulant. LMW heparins have a number of advantages over UFH, including greater bioavailability when given by subcutaneous injection and greater duration of anticoagulant effect, permitting once- or twice-daily administration. The dose is highly correlated with body weight, allowing administration of a fixed dose, and laboratory monitoring is not necessary. In addition, the risk of heparin-induced thrombocytopenia is lower. Direct parenteral thrombin inhibitors, such as lepirudin, argatroban, and bivalirudin, are utilized during percutaneous coronary intervention and for the treatment of heparin-induced thrombocytopenia.

    There are 2 groups of direct oral anticoagulants: factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban, and betrixaban) and direct thrombin inhibitors (eg, dabigatran). These are fixed-dose oral agents that, unlike vitamin K antagonists, do not require routine laboratory monitoring or dose adjustments. Another advantage is that they reach their peak efficacy in 1–4 hours after ingestion; therefore, a period of bridging therapy is not required when switching from the initial treatment (eg, heparin) to these agents. Furthermore, unlike heparin and vitamin K antagonists, these drugs bind to circulating as well as clot-bound thrombin or factor Xa. Until recently, the major disadvantage of these drugs was that no antidotes were readily available in case of bleeding events. However, idarucizumab, a dabigatran-specific Fab fragment, is now available and has been shown in vitro to reverse the effect of dabigatran within 15 minutes. More recently andexanet alfa, a recombinant factor Xa decoy molecule, has been approved for reversal of rivaroxaban and apixaban. Ciraparantag, which can potentially inhibit the anticoagulant effect of factor Xa inhibitors, is under investigation but is not yet FDA-approved. Fondaparinux, which binds to antithrombin, is a synthetic anticoagulant that is very similar to UFH and LMW heparin. It exclusively catalyzes antithrombin inhibition of factor Xa. Because it is eliminated in the kidney, it should be used cautiously in patients with renal disease. See Chapter 5, Table 5-1, in this volume for a list of direct oral antithrombotic agents.

    The orally administered warfarin derivatives, of which warfarin sodium is the most widely used, inhibit the production of normal vitamin K–dependent coagulation factors (II, VII, IX, and X). Therapeutic effect is assessed by measuring the patient’s INR. One critical issue is the long list of commonly used drugs that interact with warfarin. These interactions may cause an unintended increase or decrease in the INR, depending on the drug.

    Heparin and the warfarin derivatives are used to prevent the formation of new thrombi and the propagation of existing thrombi, but neither affects the original clot. Thrombolytic agents such as streptokinase, urokinase, and tissue plasminogen activator (tPA) are sometimes indicated to lyse existing thrombi, as in the very early stages of myocardial infarction and in the early treatment of thrombotic stroke. See Chapter 5, Table 5-2, in this volume for a list of intravenous and subcutaneous antithrombotic agents.

    • Goldman L, Schafer AI. eds. Goldman-Cecil Medicine. 25th ed. Philadelphia: Elsevier/Saunders; 2015. Section XIV, Hematologic Diseases.

    • Milling TJ Jr, Kaatz S. Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Med. 2016;129(11S):S80–S88.

    • Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377(5):431–441.

    Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.

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    2022-2023 Basic and Clinical Science Course, Complete Print Set
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    2022-2023 Basic and Clinical Science Course, Section 01: Update on General Medicine
    2022-2023 Basic and Clinical Science Course, Section 02: Fundamentals and Principles of Ophthalmology
    2022-2023 Basic and Clinical Science Course, Section 03: Clinical Optics and Vision Rehabilitation
    2022-2023 Basic and Clinical Science Course, Section 04: Ophthalmic Pathology and Intraocular Tumors
    2022-2023 Basic and Clinical Science Course, Section 05: Neuro-Ophthalmology
    2022-2023 Basic and Clinical Science Course, Section 06: Pediatric Ophthalmology and Strabismus
    2022-2023 Basic and Clinical Science Course, Section 07: Oculofacial Plastic and Orbital Surgery
    2022-2023 Basic and Clinical Science Course, Section 08: External Disease and Cornea
    2022-2023 Basic and Clinical Science Course, Section 09: Uveitis and Ocular Inflammation
    2022-2023 Basic and Clinical Science Course, Section 10: Glaucoma
    2022-2023 Basic and Clinical Science Course, Section 11: Lens and Cataract
    2022-2023 Basic and Clinical Science Course, Section 12: Retina and Vitreous
    2022-2023 Basic and Clinical Science Course, Section 13: Refractive Surgery
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