IE 2: Hematopoietic Growth and Coagulation Factors

Hematopoiesis is a process that allows what?

• Allows immature precursor cells in the bone marrow to proliferate, differentiate, mature, and become functional blood cells

What do the functional blood cells do?

• Transport oxygen and carbon dioxide

• Contribute to host immunity

• Facilitate blood clotting

Hematopoietic growth factors (HGFs) are specific circulating factors that do what?

• Mediate growth and survival of early blood cells

Most HGFs are what?

• Glycoproteins (glycosylated single-chain polypeptides)

What is the production of recombinant HGF proteins like?

• Identifying and isolating a particular HGF gene

• Inserting the HGF DNA into a plasmid

• Expressing the recombinant growth factor protein in a biologic system

What are the Hematopoietic growth factors?

• Erythropoietin

• Granulocyte colony stimulating factor

• Granulocyte macrophage colony stimulating factor

• Stem cell factor

• Thrombopoietin

What is the target cells of Erythropoietin and its actions?

• Erythroid progenitors

• Increase RBC count

What is the target cells of Granulocyte-colony-stimulating factor and its actions?

• Granulocyte progenitors and mature neutrophils

• Increase neutrophil counts

What is the target cells of Granulocyte-macrophage colony-stimulating factor and its actions?

• Granulocyte-macrophage progenitors and eosinophil progenitors

• Increase neutrophil, eosinophil, and monocyte counts

What is the target cells of Stem cell factor and its actions?

• Granulocyte-erythroid progenitors, lymphoid progenitors, and natural killer cells

• Increase pluripotent stem cells and progenitor cells

What is the target cells of Thrombopoietin and its actions?

• Stem cells, megakaryocytic, erythroid progenitors

• Increase platelet counts

Where is erythropoietin secreted by? What does it stimulate?

• Secreted by the kidneys in response to hypoxia

• Stimulates RBC production and stimulates erythocytic progenitors

Cloning EPO gene facilitated development of what?

• Recombinant erythropoietins and analogs (erythropoiesis-stimulating agents)

Most EPO in the human body is produced in what cells?

• Renal cortex peritubular cells

The partial pressure of oxygen does what to EPO? What else stimulates EPO production?

• The partial pressure of oxygen directly regulates EPO production

• Low hemoglobin levels stimulate EPO production

What is the normal range of EPO? When can it be increased? When can it be decreased?

• 5-36 IU/L

  • EPO increases in pregnancy

  • May be increased by phlebotomy, anabolic steroids, androgens, TSH, ACTH, angiotensin, epinephrine, daunorubicin, fenoterol, growth hormone levels, and other drugs

  • Decreased following acetazolamide, amphotericin B, cisplatin, enalapril, furosemide, and theophylline

  • May be decreased by transfusions and estrogens

What are the Erythropoietin Stimulating Agents (ESA)?

• Epoeitin Alpha

• Darbepoietin Alpha

• Methoxy Polyethylene glycol epoetin beta

For the Erythropoiesis stimulating agents, what is Epoetin Alpha?

• Epogen, Procrit, Retacrit

For the Erythropoiesis stimulating agents, what is Darbepoetin alpha? What is known about the half life?

• Aranesp

• Longer serum half life compared to Epoetin Alpha

For the Erythropoiesis stimulating agents, what is Methoxy Polyethylene Glycol Epoetin Beta? What is known about the half life

• Mircera

• Longer serum half life compared to epoetin alpha

  • LONGEST HALF LIFE

What are the Erythropoiesis Stimulating Agents (ESA) clearance pathways? What plays a MINOR role in ESA elimination?

• Capacity limited clearance pathway utilizing EPO receptor mediated endocytosis by erythroid progenitor cells

• An EPOR-independent linear clearance reflecting other mechanisms

• RENAL excretion and HEPATIC metabolism of ESA play minor roles in elimination

What is the MOA, boxed warning, and comments on Epoetin Alpha?

• MOA: induce erythropoiesis by stimulating division of erythroid progenitor cells; induce release of reticulocytes from bone marrow to blood stream

• Boxed Warning:

  • CV events: ESA increase death risk, MI, stroke, venous thromboembolism, thrombosis

  • CKD, Cancer, DVT prophylaxis

• Comments: SQ preferred except in CKD; do not shake

What is the MOA, boxed warning, and comments on Darbepoeitin Alpha?

• MOA: induce erythropoiesis by stimulating division of erythroid progenitor cells; induce release of reticulocytes from bone marrow to blood stream

• Boxed Warning:

  • CV events: ESA increase death risk, MI, stroke, venous thromboembolism, thrombosis

  • CKD, Cancer

• Comments: IV route rec in hemodialysis pts, Do not shake

What is the MOA, boxed warning, and comments on Methoxypolyethylene glycol epoetin beta?

• MOA: induce erythropoiesis by interaction with erythropoietin receptor on progenitor cells in bone marrow

• Boxed Warning:

  • CV events: ESA increase death risk, MI, stroke, venous thromboembolism, thrombosis

  • CKD, Cancer

• Comments: Do not administer SQ in pediatric; do not shake

What are the Myeloid Hematopoietic Growth Factors?

• Filgrastim

• Pegfilgrastim

• Eflapegrastim

• Sargramostim

What is the MOA of Filgrastim and the comment?

• MOA: stimulate production, maturation, activation of neutrophils to increase migration and cytotoxicity

• Comment: SHORT acting recombinant methionyl human G-CS

What is the MOA of Pegfilgrastim and the comment?

• MOA: stimulate production, maturation, activation of neutrophils to increase migration and cytotoxicity

• Comment: Most adverse effect is bone pain

What is the MOA of Eflapegrastim and the comment?

• MOA: bind to granulocyte colony-stimulating factor receptors on myeloid progenitor cells and neutrophils, triggering cell differentiation, proliferation, migration, and survival

• Comments: long acting recombinant human granulocyte growth factor conjugated with IgG

What is the MOA of Sargramostim and the comment?

• MOA: stimulate proliferation, differentiation, and functional activity of neutrophils, eosinophils, monocytes, macrophages

• Comments: in line membrane filter should not be used for IV admin; DO NOT SHAKE to avoid foam

What are the Thrombopoietic Growth Factors?

• Romiplostim

• Eltrombopag

• Avatrombopag

• Lusutrombopag

What is the MOA of Romiplostim and comment?

• MOA: TPO PEPTIdE mimetic that increase platelet count in ITP by binding to and activating human TPO receptor

• Comments: SQ only, flipflop PK

What is the MOA of Eltrombopag and the comment?

• MOA: TPO NON peptide agonist which increases platelet counts by binding to and activating human TPO receptor

• Comment: ORAL admin; boxed warning of hepatotoxicity

What is the MOA of Avatrombopag and the comment?

• MOA: small molecule thrombopoietin receptor agonist that stimulate growth of megakaryocytic from bone marrow progenitor cells resulting in more platelet production

• Comments: Oral admin, give with food

What is the MOA of Lusutrombopag and the comment?

• MOA: small molecule thrombopoietin receptor agonist that stimulate growth of megakaryocytic from bone marrow progenitor cells resulting in more platelet production

• Comments: Oral admin, give with or without food

Hemostasis involves what? What forms the thrombus?

• The interaction of the coagulation cascade with activated blood platelets and the vessel wall

• Activated platelets and cross linked fibrin form thrombus

Disruption of the balance between coagulation (thrombus formation and fibrinolysis (thrombus dissolution) causes what?

• Causes bleeding or thrombosis

Bleeding disorders occur because of what?

• Defect of deficiency in one of the constituents of the coagulation cascade

What are the two forms of thrombotic disorders?

• Venous thrombosis: due to excessive coagulation and can lead to pulmonary embolism

• Arterial thrombosis: associated with atherosclerosis, stroke, and acute coronary syndrome

What is Hemophilia B? Hemophilia A?

• B: A defect in the gene encoding factor IX

• A: Factor VIII deficiency

Genes encoding factor VIII and factor IX are located where?

• On the X chromosome

What is the most common bleeding disorder?

• Von Willebrand’s disease (a deficiency or dysfunction of Von Willebrand factor)

What is Recombinant Factor VIII? What are the product types? Indication and ROA?

• 3d structure of B domain-deleted factor VIII with Fc fragment of IgG1 fused to the C-terminus of the C2 domain

• Product types: Full length F VIII, B-domain deleted F VIII

• Indication: hemophilia A and IV admin

What is Recombinant Factor IX and the Product types?

• 3D structure of factor IX with human albumin

• Product type: wild type F IX, Engineered F IX

Management of thrombosis is more complex compared to what?

• Compared to bleeding management

Partial deficiencies of what are risk factors that predispose for venous thrombosis?

• Antithrombin or Protein C

Lysis of what is an immediate target of ischemia, MI, or stroke? Using what?

• Lysis of occluding thrombosis using plasminogen activators

What are the plasminogen activators? Which has longest half life?

• Alteplase (Activase)

• Reteplase (Retevase)

• Tenecteplase (TNKase)

  • Longest half life