Pharmacotherapy of Coagulation Disorders PDF

Pharmacotherapy of Coagulation Disorders Shane Valerie G. Bautista, RPh Faculty Instructor, College of Pharmacy Our Lady of Fatima University S.Y. 2024 - 2025 Clinical Pharmacy and Pharmacotherapeutics 1 | PHCP 311 LEARNING OBJECTIVES Recall basic conce...

Pharmacotherapy of Coagulation Disorders Shane Valerie G. Bautista, RPh Faculty Instructor, College of Pharmacy Our Lady of Fatima University S.Y. 2024 - 2025 Clinical Pharmacy and Pharmacotherapeutics 1 | PHCP 311 LEARNING OBJECTIVES Recall basic concepts of hemostasis Explaining the pathophysiology of coagulation disorders Identifying factors that may induce or potentiate the diseases Describing the clinical presentation of the disorder, including diagnostic and laboratory tests Evaluating the therapeutic outcomes Hemostasis & Thrombosis Preventing Blood Loss 1. Vascular spasm 2. Platelet plug formation 3. Blood clotting Hemostasis 1. Vascular spasm - an immediate but temporary constriction of a blood vessel resulting from a contraction of smooth muscle within the wall of the vessel - to restrict blood flow out of the vessel Thrombosis 2. Platelet plug formation - an accumulation of platelets that can seal up a small break in a blood vessel Thrombosis 2. Platelet Plug Formation a. Platelet adhesion occurs when von Willebrand factor connects exposed collagen to platelets. b. The platelet release reaction r e s u l t s in t h e r e l e a s e o f A D P , thromboxanes, and other chemicals that activate other platelets. c. P l a t e l e t a g g r e g a t i o n o c c u r s when fibrinogen receptors on activated platelets bind to fibrinogen, connecting the platelets to one another. A platelet plug is formed by the accumulating mass of platelets. Thrombosis 3. Blood clotting  Coagulation/Blood clotting – formation of blood clot  Blood clot – a network of threadlike protein fibers called fibrin, that traps blood cells, platelets, and fluid  formation of a blood clot depends on a number of proteins – clotting factors  manufactured in the liver  require vitamin K for synthesis Thrombosis Extrinsic Pathway  Begins with chemicals outside the blood  Damaged tissues release Thromboplastin/Tissue factor (TF) or factor III  TF (+) Ca 2 + = factor VII complex  Factor VII complex – activates factor X  Factor X – start of common pathway Thrombosis Intrinsic Pathway  Begins with chemicals inside the blood  Damaged tissues expose collagen  Collagen + plasma factor XII = activation of factor XII & stimulation of factor XI  Factor XI – activates factor IX  Activated factor IX + factor VIII, plt phospholipids, Ca2+ = activate factor X  Factor X – beginning of common pathway Thrombosis Common Pathway  activated factor X + factor V, platelet phospholipids, Ca2+ = prothrombinase  Prothrombinase – Prothrombin (sol. Plasma protein) Thrombin (ins. enzyme)  Thrombin – Fibrinogen (sol plasma protein) Fibrin (ins. protein)  Fibrin – forms fibrous network of clot Control of Clot Formation  The blood contains several anticoagulants, which prevent clotting factors from forming clots.  Antithrombin Inactivate thrombin f ibrinogen is not  Heparin converted to fibrin Clot formation Clot Retraction and Fibrinolysis Clot retraction  Platelets form small extensions that attach to fibrin through surface receptors.  Contraction of the extensions pulls on the fibrin and is responsible for clot retraction.  Serum - plasma without the clotting factors, is squeezed out of the clot during clot retraction.  Retraction of the clot pulls the edges of the damaged blood vessel together, helping stop the flow of blood, reducing the probability of infection, and enhancing healing.  The damaged vessel is repaired by the movement of fibroblasts into the damaged area and the formation of new connective tissue. Epithelial cells around the wound divide and fill in the torn area. Fibrinolysis Fibrinolysis is a process by F which clots are dissolved. 1. T h r o m b i n a n d t i s s u e p l a s m i n o g e n activator(t- PA) convert i n a c t i v e plasminogen into plasmin. 2. Plasmin breaks down the fibrin in a blood clot, r e s u l t i n g i n clot fibrinolysis.  COAGULATION CASCADE - refers to the series of steps that occur during the formation of a blood clot after injury by activating a cascade of proteins called clotting factors. There are three pathways:  intrinsic  extrinsic  common  COAGULATION DISORDERS - are disorders which affect the coagulation cascade and can either cause ex c e ssi v e o r inadequate clotting. - usually involve a deficiency in at least one clotting factor, and the most common disorders include:  Hemophilia  Von Willebrand Disease  Vitamin K Deficiency  HEMOPHILIA - an inherited bleeding disorder in which the blood does not clot properly. This can lead to spontaneous bleeding as well as bleeding following injuries or surgery. - caused by a mutation or change, in one of the genes, that provides instructions for making the clotting factor proteins needed to form a blood clot.  THREE TYPES OF HEMOPHILIA Hemophilia A Hemophilia B Hemophilia C deficiency in deficiency in deficiency in Factor VIII Factor IX Factor XI  CLINICAL PRESENTATION Common signs of hemophilia include: Bleeding into the joints Bleeding into the skin or muscle and soft tissue causing a build- up of blood in the area Bleeding of the mouth and gums, and bleeding that is hard to stop after losing a tooth. Bleeding after circumcision Bleeding after having shots, such as vaccinations. Bleeding in the head of an infant after a difficult delivery. Blood in the urine or stool Frequent and hard-to-stop nosebleeds.  DIAGNOSIS 1. SCREENING TESTS - show if the blood is clotting properly 2. CLOTTING FACTOR TESTS - shows the type of hemophilia and the severity. v SCREENING TESTS  Complete Blood Count (CBC)  Activated Partial Thromboplastin Time (APTT) Test  Prothrombin Time (PT) Test  Fibrinogen Test  DIAGNOSIS v CLOTTING FACTOR TESTS  TREATMENT The two main types of clotting factor concentrates available are: Plasma-derived Factor Concentrates Recombinant Factor Concentrates Drug products available: Desmopressin Acetate (DDAVP® or Stimate®) Aminocaproic Acid (Amicar®) Cryoprecipitate Emicizumab  TREATMENT Aminocaproic Acid Desmopressin Acetate (Amicar®) (DDAVP® or Stimate®) - prevents blood clots from - similar to a hormone that breaking down, resulting in a occurs naturally in the body. firmer clot, and is often used The medications release factor for bleeding in the mouth or VIII from where it is stored in after a tooth has been the body tissues. removed because it blocks a - synthetic form of vasopressin substance found in the saliva (spit) that breaks down clots.  TREATMENT Emicizumab Cryoprecipitate - works by replacing the - a substance that comes from function of factor VIII, rather thawing fresh frozen plasma. It than replacing the missing is rich in factor VIII, and was clotting factor VIII directly. c o m m o nly us e d t o c o n t r o l It can be used to either serious bleeding in the past. prevent or reduce the frequency of bleeding episodes in people with hemophilia A. Clotting Factor II deficiency Prothrombin -> thrombin ☐ Deficiency: hypoprothrombinemia/ dysprothrombinemia ☐ Inherited, autoimmune, drug induced, very rare ☐ S/S: hypoprothrombinemia, mucosal bleeding, soft tissue bleeding, hemarthrosis, muscle hematoma, intracranial bleeding, pulmonary hemorrhage, melaena, hematochezia ☐ Autoimmune: Lupus anticoagulant hypoprothrombinemia ☐ Drug: antibiotic induced hypoprothrombinemia ☐ Beta lactam antibiotics due to decreased normal flora-> dec. vitamin K ☐ Cefazolin: thiol content interacts with vitamin K ☐ DX: PT/INR, Assay Factor II, PTT, factor VI, IX and X ☐ TX: control bleeding, ☐ SLE: give Azathioprine, immunoglobulin, fresh frozen plasma ☐ Warfarin overdose: give Vitamin K, hemostatic agents ( aminocaproic acid: 6- aminohexanoic acid that inhibits fibrinolysis that inhibits TPA substance) Clotting Factor V deficiency  Rare disorder known as Owren’s disease or parahemophilia  - less than 200 cases world wide  Dx: Prolonged: @PTT, PT, thrombin time  Stypven time (Russel viper venom time)  Factor V antigen assay  TX: fresh frozen plasma, blood products Clotting Factor VII deficiency  Rare genetic disorder, due to autosomal recessive manner  Normal @PTT but prolonged PT  Dx: Factor VII deficiency plasma  S/s: bleeding, hemarthrosis, joint swelling, mild fever, joint limitation, bruising with or without trauma, hematoma  Lab test: APTT, PT and platelet  Tx: FVII/ FVIIa replacement, fresh frozen plasma, antifibrinolytics ( Aminocaproic acid) Clotting Factor X deficiency Stuart prower factor, vitamin K dependent serine protease ☐ Aquired: ☐ Congenitally through mutation/ deletion ☐ Liver disease: vit. K reduction ☐ Prophylthiouracil or Vit. K antagonists ☐ Diseases/ drugs that can cause: ☐ Mycoplasma pneumoniae, lupus anticoagulant prothrombinemia, sodium valproate use in epilepsy, leprosy, sever burn in children, topical thrombin administration Patient history: ☐ Sever umbilical cord stump bleeding, Prolonged bleeding upon circumcision, Recurring epistaxis, Hematoma, Hematuria, Post partum bleeding, hemarthrosis Lab test: ☐ Prolonged PT, @PTT and RVVT ☐ Bleeding time is within the reference range Tx: Plasma derivative factor X, vitamin K, Factor X ( coagadex) and factor IX Clotting Factor 12 Deficiency Hageman factor deficiency q Begins asymptomatically and usually only discovered during preoperative blood test q 1 in 1 million q Genetic disorder: gene mutation of F12 gene at the long arm chromosome q Common in Asian q Complications: increased risk for DVT, increased risk and repeated miscarriage  VITAMIN K DEFICIENCY - may occur when a sufficient amount of vitamin K is not absorbed from foods or when not enough foods with vitamin K are consumed. Vitamin K is a cofactor required to make factors II, VII, IX, and X functional. Therefore, vitamin K deficiency affects all three pathways.  VON WILLEBRAND DISEASE - is the most common bleeding disorder and is characterized by a deficiency in Von Willebrand factor due to an autosomal dominant genetic mutation. The Von Willebrand factor is mostly involved in primary hemostasis where it helps platelets stick together. The factor also plays a role in secondary hemostasis by helping stabilize factor VIII. VWF disease Inherited gene mutation: VWF gene in the short arm of chromosome 12 ☐ Autosomal Dominant: ( one gene is mutated, while the other gene is normal) ☐ Type 1 and some type 2 ☐ Autosomal Recessive ( both parents have mutated gene) ☐ Some type 2 and type 3 Pseudo Willebrand disease: gene mutation at the GPIb, autosomal dominant) ☐ S/S: prolonged bleeding, epistaxis, excessive bleeding after surgery, trauma, dental procedures, Lab tests: CBC( for VWF type 2B), coagulation test, VWF antigen test, ristocetin co-factor test, factor VIII clotting test, Molecular gene therapy Treatments: ☐ Desmopressin: for type 1 and 2 ☐ Contraindicated for type 2B: dec. platelet ☐ Replacement therapy for VWF type 2M, 3 and 2B ☐ Aminocaproic acid/ tranexamic acid NOTE: C/I: aspirin, NSAIDs and Blood thinners  TYPES OF VWD Type 2  Type 2A - VWF is not the right size and doesn’t help Type 1 the platelets attach together in order to form a clot. This is the most  Type 2B - VWF attaches to platelets at the wrong time common and mildest form of VWD, (when there is no injury). The body removes the platelets in wh i c h a p e r s o n attached to VWF, causing a reduced amount of both has lower-than- platelets and VWF in the blood when needed to form a normal levels of VWF. clot.  Type 2M - VWF does not attach to the platelets as it Type 3 should, which decreases the platelets’ ability to form a This is the most severe clot when an injury occurs. form of VWD, in which  Type 2N - VWF attaches to the platelets normally. a person has very little However, the VWF does not attach to another protein, or no VWF and low levels of factor VIII. Factor VIII (8), which is also needed for blood to clot. This is the rarest type This causes the body to remove the Factor VIII (8) of VWD. protein.  CLINICAL PRESENTATION Major signs of VWD Frequent or Hard-to-Stop Nosebleeds Easy Bruising Heavy Menstrual Bleeding Longer than Normal Bleeding After Injury, Surgery, Childbirth, or Dental Work  DIAGNOSIS The blood tests that a doctor can order to diagnose VWD (or another platelet disorder) include: Factor VIII clotting activity―To measure the amount of factor VIII in the blood Von Willebrand factor antigen―To measure the amount of VWF in the blood Ristocetin cofactor or other VWF activity―To measure how well the VWF works Von Willebrand factor multimers―To measure the makeup or structure of the VWF Platelet aggregation tests―To measure how well the platelets are working  TREATMENT Desmopressin Acetate Injection Desmopressin Acetate Nasal Spray Factor Replacement Therapy Antifibrinolytic Drugs Birth Control Pills ANTICOAGULANTS