drugs used in hemorrhagic disease Flashcards
what is hemostasis?
- hemostasis (blood stop): sequence of responses that results in wound repair
- balanced homeostasis: helps maintain circulatroy homeostasis:
- prevent prolonged hemorrhage (bleeding)
- prevent spontaneous thrombosis (clotting)
what are the stages of homeostasis?
if we have a cut and we have bleeding then…
1. vascular spasm causes vasoconstriction
2. breach of the blood vessels exposed collagen fibers causes platelets to stick, forming a plug
3. coagulation: fibrin is formed, trapping the platelets and some RBCs, forming a clot
4. clot dissolves once tissue damage is repaired
describe the first stage of homeostasis
- vasospasm (vasoconstriction)
- damaged endothelial cells (b/w blood and bv) release endothelin that signals to surrounding smooth muscle to contract
- if the smooth muscle is damaged, this will intrinsically contract as well
- immediate; restricts blood flow
describe the second stage of homeostasis
- platelet response: formation of platelet plug
- platelet adhesion: von Wilebrand’s factor (VWF) is now exposed and binds to platelets
- “stuck” platelets (platelet plug) now secrete ADP, thromboxane A (TXA2), and serotonin to:
* recruit other platelets to the site
* further promote vasoconstriction
* initiate the coagulation cascade
describe the third stage of homeostasis
- coagulation cascade
- the platelet plus is strengthened by an insoluble mesh of protein called fibrin, which together with the platelet plug form a blood clot
- fibrin is converted from fibrinogen through a series of enzymatic activation of blood factors
- conversion may occur through:
* intrinsic pathway (damaged vessel wall) - disease
* extrinsic pathway (extravascular damage) - coagulation to your arm
intrinsic vs extrinsic pathway
describe the third stage of homeostasis the intrinsic pathway
- coagulation cascade
intrinsic pathway:
- most blood coagulation factors (proteins) are produced in the liver, and are inactive within circulation
- damage to the endotheial cells reveals collagen, which activates Factor XII
- Factor XII activates Factor XI
- Factor XIa activates Factor IX
- Factor IXa, with VIIIa, activates Factor X
describe the third stage of homeostasis the extrinsic pathway
- coagulation cascade
extrinsic pathway:
- damaged extravascular cells release tissue factor (TF) into the bloodstream
- TF activates Factor VII (7)
- TF-Factor VIIa activates Factor X (10)
- expedited pathway that leads to the activation of the factor needed to produce fibrin
describe the third stage of homeostasis the common pathway
- coagulation cascade
common pathway:
- Factor X is needed to convert prothrombin (floats around the blood and is inactive) into thrombin
- prothrombin is a Vitamin K-dependent glycoprotein
- thrombin converts fibrinogen to fibrin (main protein in capuring platelets and making a blood clot)
describe the fourth stage of homeostasis
- clot dissolution (fibrinolysis)
- once tissue has repaired Factor XIIa (12) and/or tissue plasminogen activator (tPA) convert plasminogen to plasmin in the bloodstream
- plasmin breaks down (lyses) fibrin proteins (fibrin degradation products; FDPs)
- clot (thrombus) is dissolved and blood can flow normally within this repaired blood vessel
what are the 3 excessive bleeding disorders
- platelet deficiencies
acquired: thrombocytopenias (low platelet count; drug-induced, infection)
genetic: von willebrand’s disease (mutation in VWF gene) - coagulation deficiencies
acquired: vitamin K deficiency (multiple factors)
genetic: hemophilia A (factor VIII), hemophilia B (factor IX) - fibrinolytic hyperactivity
acquired: liver cirrhosis (↑ t-PA)
inherited: plasmin inhibitor deficiency
what are they 5 ways (drugs) to treat hemorrhagic disease?
- plasma fractions
- vitamin K
- desmopressin
- protamine sulfate
- aminocaproic acid (Amicar)
describe plasma fractions to treat hemorrhagic disease
fractionation of plasma (taken from the whole blood of healthy patients) to provide concentrated coagulation factors to patients who have:
- Hemophilia A (Factor VII deficiency: classic hemophilia)
- Hemophilia B (Factor IX deficiency; christmas disease)
- Von Willebrand’s disease (VWF deficiency)
- spontaneous deficiency of coagulation factors (5-10% of normal levels)
recombinant coagulation factors now available: eliminate need for plasma donation, reduce risk of infection
describe vitamin k to treat hemorrhagic disease
- vitamin k is essential for blood clotting; it’s required to produce prothrombin and is a cofactor for the biological activity of factors II, VII, IX and X
- low vitamin k levels are often found in:
- newborns: low levels at birth
- patients taking anticoagulants (warfarin - vitamin K antagonist)
- individuals with vitamin absorption disorders
- liver disease
- exist in two forms: vitamin K1 (phytonadione) found in food, vitamin K2 found in intestinal bacteria
- not used in the treatment of hemophilia
- treatment: IV or oral, depending on individual patient’s needs and health status
- IV route: give slowly (over 30 mins; risk of anaphylaxis); takes 2-4 hours to take effect (no known risk of anaphylaxis)
- considered very safe; no upper limit reported
- fat soluble vitamin: requires bile salts for absorption
describe desmopressin to treat hemorrhagic disease
- desmopression - anti-diuretic used to treat diabetes insipidus (replaces low ADH)
- desmopressin acetate (DDAVP) also used to treate mild hemophilia or von Willebrand’s disease by transiently increasing Factor VIII activity
- DDAVP activates signaling cascade in kidney cells that also induces exocytosis of VWF and Factor VIII from their storage sites
- available parenterally or a nasal spray if high doses are needed
describe protamine sulfate to treat hemorrhagic disease
- protamine sulfate (antagonist to heparin): used to treat heparin overdoses (heparin is a blood thinner)
- recombinant protein; binds to heparin, neutralizing its anti coagulant effects
- administered IV in situations of heparin overdose or to reverse heparin effects after coronary artery bypass surgery
- allergic reactions can be severe and include anaphylaxis
describe aminocaproic (amicar) to treat hemorrhagic disease
- aminocaproic (Amicar): fibrinolytic inhibitor
- during clot (thrombus) dissolution, plasmin binds to fibrin, resulting in lysis
- amicar is a synthetic drug that is similar to lysine → binds and blocks lysine binding site on plasmin → no lysis
- used in the treatment of fibrinolytic hyperactivity (such as after treatment with thrombi-busting drugs) or as adjunct therapy for hemophiliacs
what are most of the drugs in this class used to treat?
- most drugs in this class are used to treat patients with genetic deficiencies in coagulation OR to reverse anti-coagulant therapy or overdose
what is classic and aplastic anemia and their causes
classic anemia: characterized by a deficiency in red blood cells (RBCs) or hemoglobin leading to reduced oxygen transport to tissues
causes:
- iron deficiency
- vitamin deficiency
- RBC disorders
- chronic disease
aplastic anemia: bone marrow failure; deficiency of myeloid progenitors that give rise to RBCs and other immune cells
causes:
- cancer or cancer treatment
- sensitivity to chloramphenicol
what is the aim of anemia therapy?
- Provide components needed for RBC and hemoglobin function
- Stimulate bone marrow formation of RBCs
what is iron therapy for anemia?
Essential Nutrients
Iron Therapy: Treatment or prevention of anemia associated with iron deficiency
- Chronic blood loss in adults (mainly women)
- Prevention of newborn iron deficiencies
- Chronic renal failure
- Inadequate iron absorption from GI tract
Oral therapy as ferrous salts usually adequate
Parenteral administration as iron dextran used in certain cases
what is vitamin therapy for anemia?
Essential Nutrients
Vitamin Therapy: Treatment or prevention of vitamin-deficiency anemia
Folic acid and Vitamin B12: Essential for DNA synthesis and required for RBC production
Oral: Available alone or in multi-vitamin form Injectable form also available for severe deficiencies
what are the three growth factors with anemia?
- rHuEPO (Epogen®, Procrit®)
- rHuG-CSF; Filgastrim (Neupogen®)
- Oprelvekin; IL-11 (Neumega)
growth factor rHuEPO (Epogen®, Procrit®) for anemia
rHuEPO (Epogen®, Procrit®): Recombinant erythropoietin (EPO) → stimulates proliferation and differentiation of RBCs
Use cases:
* Chronic anemia due to reduced EPO production in chronic renal failure
* AIDS, cancer*, surgeries
Increases RBC count over 2-6 weeks; iron supplementation is advised alongside EPO therapy
*EPO can promote tumor progression
growth factor rHuG-CSF; Filgastrim (Neupogen®) for anemia
rHuG-CSF; Filgastrim (Neupogen®): Recombinant granulocyte colony-stimulating factor (G-CSF) → stimulates proliferation and differentiation of myeloid progenitor cells
* Activates neutrophils, increasing their lifespan in circulation
* Mobilizes hematopoietic stem cells from the bone marrow to enter circulation
- indicated for aplastic anemia and chemotherapy-induced neutropenia
growth factor Oprelvekin; IL-11 (Neumega) for anemia
Growth Factors
Oprelvekin; IL-11 (Neumega)
- Stimulates myeloid and lymphoid progenitor
cells and megakaryocytes to produce platelets
- Treatment for aplastic anemia as well as
severe thrombocytopenia (low platelet count) in patients treated with myelosuppressant chemotherapy drugs
