Coagulant Therapy Lecture Notes PDF

Coagulant Therapy Samah M. Elaidy, MD, PhD, JMHPE Professor of Clinical Pharmacology Faculty of Medicine Suez Canal University  Learning Outcomes 1. Classify coagulant (hemostatic) agents including the local and systemic agents. 2. Explain the mechanism of action, routes of ad...

Coagulant Therapy Samah M. Elaidy, MD, PhD, JMHPE Professor of Clinical Pharmacology Faculty of Medicine Suez Canal University  Learning Outcomes 1. Classify coagulant (hemostatic) agents including the local and systemic agents. 2. Explain the mechanism of action, routes of administration, therapeutic uses, and adverse effects of the coagulant agents. 3. List different types of plasma concentrates used in the treatment of bleeding tendency. 4. Identify a management plan for the treatment of active bleeding. 5. Identify management plans for prophylaxis from bleeding in bleeding tendency patients. Introduction Hemostasis It is the physiological process of: Stopping bleeding (haemorrhage), and Preserving vascular integrity.  Blood Coagulation Cascades aPTT PT aPTT: Activated Partial Thromboplastin Time. PT (INR): Prothrombin Time (International Normalized Ratio) Normal Fibrinolytic System Activation Inhibition Coagulant Agents (Hemostatics, Anti-Fibrinolytics, Antiplasmin Drugs) They are substances that promote coagulation. Drugs block the conversion of plasminogen to plasmin and thus inhibit the fibrinolytic system. Causes of Bleeding  Coagulant Therapy Systemic Local Transfusional Non-transfusional Thrombin Vasoconstrictors Astringent Vit K Plasma Fractions Aminocaproic acid Fresh Frozen plasma tranexamic acid Whole blood Idarucizumab Protamine Sulfate Factor Xa Fibrinogen Desmopressin Adrenochrome monosemicarbazone Vitamin K Sources of vitamin K 1. In diet especially in green leafy vegetables: Vitamin K1 (phytonadione). 2. synthesized by bacteria living in human intestine Vitamin K2 (menaquinone). 3. Vitamin K3 is synthetic vitamin K that can be lipid soluble (menadione) or water soluble(menadione sodium bisulfate). Water soluble Vitamin K3 should not be used in practice (ineffective). Vitamin K: Mechanism of action Vit K acts as a cofactor at a late stage in the synthesis of prothrombin (factor II), and factors VII, IX and X by liver. Vitamin K: Pharmacokinetics Lipid soluble isoforms are Lipid-soluble absorbed from the intestinal Vitamins K1, and K2 tract in lymph which require bile salts for absorption. Vitamin K isoforms Lipid-soluble Vitamin K3 Onset of effect is delayed for 6 hours but the effect is complete Water-soluble by 24 hours. Vitamin K3 It is metabolized in liver and the Vitamin K1 can be given: metabolites are excreted in bile Orally. and urine. Parenteral: intravenous, intramuscular (IM), and subcutaneous (SC). However, SC and IM administrations are not preferred due to erratic or unpredictable absorption when given SC, and hematoma when given IM. Vitamin K: Indications Treating Warfarin (anticoagulant drug) overdose. Adjuvant in prevention and treatment of excessive bleeding episodes in hemophilia. Prevent the hemorrhagic disease of vitamin K deficiency in newborn babies. Treating Vitamin K deficiency resulting from: a. Obstructive jaundice and malabsorption. b. hospitalized patients in intensive care units because of poor diet. c. parenteral nutrition, recent surgery. d. multiple antibiotic therapy. e. Severe hepatic disease. Vitamin K: Side effects Well tolerated. Anaphylaxis may occur following rapid IV infusion of emulsified vitamin K that may lead to death. Aminocaproic acid and tranexamic acid Bleeding can be controlled by the administration of aminocaproic acid or tranexamic acid. Both agents are synthetic, orally active, excreted in the urine, and inhibit plasminogen activation. Tranexamic acid is 10 times more potent than aminocaproic acid. Uses: Adjuvant therapy in hemophilia, bleeding (postsurgical GIT, vaginal). Adverse effect: Intravascular thrombosis, muscle necrosis, seizures. Idarucizumab Idarucizumab is a monoclonal antibody fragment used to reverse bleeding caused by dabigatran (a direct thrombin inhibitor). Idarucizumab is administered intravenously and is rapidly eliminated. Idarucizumab is used in emergency situations, in the inpatient setting. Adverse effect: Most serious is Thrombosis. Others: Hypokalemia. Factor Xa Factor Xa is a recombinant modified human protein administered parenterally for the reversal of apixaban or rivaroxaban (Direct Factor Xa inhibitors) in the setting of life-threatening or uncontrolled bleeding. Adverse Effects: serious and life-threatening adverse events Arterial and venous thromboembolism, myocardial infarction, ischemic stroke, cardiac arrest, and sudden death. In order to reduce thromboembolic risk, apixaban or rivaroxaban should be resumed as soon as medically appropriate after treatment with Factor Xa. Protamine sulfate Protamine sulfate antagonizes the anticoagulant effects of heparin. Adverse effects Hypersensitivity as well as dyspnea, flushing, bradycardia, and hypotension when rapidly injected, nausea/vomiting, and anaphylaxis. Other systemic Coagulant drugs Fibrinogen The fibrinogen fraction of human plasma is employed to control bleeding in haemophilia, factor VIII deficiency and acute afibrinogenemic states. Desmopressin acetate It is an analogue of vasopressin (antidiuretic hormone). Increases factor VIII activity of patients with mild hemophilia A or Von Willebrand disease. It is administrated orally or intranasally. Adrenochrome monosemicarbazone Reduce capillary fragility, control oozing from raw surfaces and prevent microvessel bleeding.  Coagulant Therapy Systemic Local Transfusional Non-transfusional Thrombin Vasoconstrictors Astringent Vit K Plasma Fractions Aminocaproic acid Fresh Frozen plasma tranexamic acid Whole blood Idarucizumab Protamine Sulfate Factor Xa Fibrinogen Desmopressin Adrenochrome monosemicarbazone  Plasma Fractions Whole Blood Plasma Fractions Types: Concentrated plasma fractions Recombinant protein preparations of coagulation factors Are available for the treatment of coagulation factors deficiencies. Fresh frozen plasma or whole blood is used for factor deficiencies for which no recombinant form of the protein is available Preparations of coagulation factors can be: Highly purified, or Intermediate purity lyophilized (freeze- dry) factors, or, Recombinant preparations.  Plasma Fractions for hemophilia Factor VIII deficiency (hemophilia A) and factor IX deficiency (hemophilia B) can be prevented and treated by lyophilized human plasma concentrates or recombinant factors VIII or IX, respectively. Longer acting factor VIII and IX preparations Eloctate is a factor VIII-Fc domain conjugate that prolongs the factor VIII half-life and administrated twice a week for the prophylaxis and treatment of hemophilia A. Idelvion is a factor IX-albumin conjugate with a half-life of 100 hours (native factor IX has a half-life of 16 hours) administrated once a week for the prophylaxis and treatment of hemophilia B.  Plasma fractions for treatment of bleeding associated with von Willebrand disease Intermediate purity factor VIII concentrates contain significant amounts of von Willebrand factor. Humate-P is a factor VIII concentrate that is used for the treatment of bleeding associated with von Willebrand disease. Vonicog alfa is a recombinant Von Willebrand factor. Plasma fractions: Side Effects Development of immune reactions against these concentrates → eg: hemophilia a or B with inhibitors. Recombinant factor VIIa is approved for treatment of inherited or acquired hemophilia A or B with inhibitors. Factor VIIa initiates activation of the clotting pathway by activating factor IX and factor X in association with tissue factor.  Coagulant Therapy Systemic Local Transfusional Non-transfusional Thrombin Vasoconstrictors Astringent Vit K Plasma Fractions Aminocaproic acid Fresh Frozen plasma tranexamic acid Whole blood Idarucizumab Protamine Sulfate Factor Xa Fibrinogen Desmopressin Adrenochrome monosemicarbazone LOCAL HAEMOSTATICS (STYPTICS) Are substances used to stop bleeding from a local site. To help stop local bleeding eg: small injury the following is used: 1. Manual pressure. 2. Cotton-gauze pressure pack. 3. Suturing. LOCAL HAEMOSTATICS (STYPTICS) 1. Thrombin obtained from bovine plasma may be applied to the bleeding surface in hemophiliacs. 2. Vasoconstrictors like 0.1% Adrenaline solution may be used to stop from bleeding tooth socket or nose in case of epistaxis. 3. Astringents such as tannic acid or metallic salts are occasionally applied for bleeding gums, bleeding piles,  Learning Outcomes 1. Classify coagulant (hemostatic) agents including the local and systemic agents. 2. Explain the mechanism of action, routes of administration, therapeutic uses, and adverse effects of the coagulant agents. 3. List different types of plasma concentrates used in the treatment of bleeding tendency. 4. Identify a management plan for the treatment of active bleeding. 5. Identify management plans for prophylaxis from bleeding in bleeding tendency patients.  Formative Assessment Which of the following drugs is the antidot for apixaban, a direct Factor Xa inhibitor? (A) Aminocaproic acid. (B) Alteplase. (C) Factor Xa. (D) Protamine sulphate. Answer: C (E) Vitamin K1.  Formative Assessment What is the antidot of heparin? Protamine sulphate. What is the antidot of dabigatran? Idarucizumab. What is the antidot of warfarin? Vitamin K1 (phytonadione).  Formative Assessment List TWO adverse effects for protamine sulphate. Hypersensitivity and anaphylaxis. Dyspnea. Flushing. Bradycardia, and hypotension when rapidly injected. Nausea/vomiting.  Formative Assessment List TWO monitoring parameters for aminocaproic acid. Complete blood picture (CBC). Muscle enzymes. Blood pressure. Learning Moments This Photo by Unknown Author is licensed under CC BY-NC Samah M. Elaidy, MD, PhD, JMHPE Professor of Clinical Pharmacology Faculty of Medicine Suez Canal University, Egypt E-mail: [email protected] ORCID ID: orcid.org/0000-0002-8464-4051