Hematology and Oncology Flashcards
Erythrocyte
Carries O2 to tissues and CO2 to lungs. Anucleate and biconcave, with large surface area-to-volume ratio for rapid gas exchange. There lifespan is 120 days. Source of energy is glucose (90% used in glycolysis, 10% used in HMP shunt). Membrane contains Cl-/HCO3- antiporter, which allows RBCs to export HCO3- and transport CO2 from the periphery to the lungs for elimination. Eryth=red; cyte=cell.
Erythrocytosis
polycythemia; an increase hematocrit
Anisocytosis
varying sizes of RBCs
Poikilocytosis
varying shapes of RBCs.
Reticulocyte
an immature RBC; reflects erythroid proliferation.
Thrombocyte
Platelet. Involved in primary hemostasis. Small cytoplasmic fragment derived from megakaryocytes. Life span of 8-10 days. When activated by endothelial injury, aggregates with other platelets and interacts with fibrinogen to form platelets and interacts with fibrinogen to form platelet plug. Contains dense granules (ADP and Ca) and alpha granules (vWF and fibrinogen). Approximately 1/3 of platelet pool is stored in the spleen. Thrombocytopenia or a decrease in platelet function results in petechiae. vWF receptor binds GpIb. Fibrinogen receptor binds GpIIb/IIIa.
Leukocyte
Divided into granulocytes (neutrophil, eosinophil, basophil) and mononuclear cells (monocytes, lymphocytes). Responsible for defense against infections. Normally 4,000-10,000 cells/mm3.
WBC differential
Neutrophils: 54-62%. Lymphocytes: 25-33%. Monocytes: 3-7%. Eosinophils: 1-3%. Basophils: 0-0.75%.
Neutrophil
Acute inflammatory response cell. Increased in bacterial infections. Phagocytic. Multilobed nucleus. Specific granules contain SLP, collagenase, lysozyme, and lactoferrin. Azurophilic granules (lysosomes) contain proteinases, acid phosphatase, myeloperoxidase, and beta-glucuronidase. Hypersegmented polys (5 or more lobes) are seen in vitamin B12/ folate deficiency. An increase in band cells (immature neutrophils) reflect states of increased myeloid proliferation (bacterial infections, CML). Important neutrophil chemotactic agents: C5a, IL-8, LTB4, Kallikerin, platelet-activating factor.
Monocyte
Differentiates into macrophages in tissues. Large, kidney shaped nucleus. Extensive frosted glass cytoplasm. Mono=one (nucleus); cyte=cell.
Macrophage
Phagocytoses bacteria, cellular debris, and senescent RBCs. Long life is tissues. Macrophages differentiate from circulating blood monocytes. Activated by gamma-interferon. Can function as antigen-presenting cell vis MHC II. Important component of granuloma formation (eg TB, sarcoidosis). Lipid A from bacterial LPS binds CD14 on macrophages to initiate septic shock.
Eosinophil
Defends against helminthic injections (major basic protein). Bilobate nucleus. Pack with large eosinophilic granules of uniform size. Highly phagocytic for antigen-antibody complexes. Produces histaminase and major basic protein (MBP, a helminthotoxin).
Causes of eosinophilia
Neoplasia, Asthma, Allergic processes, Chronic adrenal insufficiency, Parasites (invasive) NAACP.
Basophil
Mediates allergic reaction. Densely basophilic granules contain heparin (anticoagulant) and histamine (vasodilator). Leukotrienes synthesized and released on demand. Basophilic is when stained with basic stains. Basophilia is uncommon, but can be a sign of myeloproliferative disease, particularly CML.
Mast cell
Mediates allergic reactions in local tissues. Mast cells contain basophilic granules and originate from the same precursor as basophils but are not the same cell type. Can bind the Fc portion of IgE to membrane. IgE cross-links upon antigen binding, causing degranulation, which releases histamine, heparin, and eosinophil chemotactic factors. Involved in type I hypersensitivity reactions. Cromolyn sodium prevents mast cell degranulation (used for asthma prophylaxis).
Dendritic cell
Highly phagocytic APC. Functions as link between innate and adaptive immune systems. Expresses MHC class II Fc receptors on surface. Called Langerhans cell in the skin.
Lymphocyte
Refers to B cells, T cells, and NK cells. B cells and T cells mediate adaptive immunity. NK cells are part of the innate immune response. Round, densely staining nucleus with small amount of pale cytoplasm.
B cell
Part of the humoral immune response. Originates from stem cells in bone marrow and matures in marrow. Migrates to peripheral lymphoid tissue (follicles of lymph nodes, white pulp of spleen, unencapsulated lymphoid tissue). When antigen is encountered, B cells differentiate into plasma cells (which produce antibodies) and memory cells. Can functions as an APC via MHC II. They have CD19, CD21, CD20. B=Bone marrow
T cell
Mediates cellular immune response. Originates from stem cells in the bone marrow, but matures in the thymus. T cells differentiate into cytotoxic T cells (express CD8, recognize MHC I), helper T cells (express CD4, recognize MHC II), and regulatory T cells. CD28 (co-stimulatory signal) necessary for T-cell activation. The majority of circulating lymphocytes are T cells (80%). T is for Thymus. CD4+ helper T cells are the primary target of HIV. MHCxCD=8 (eg MHC 2 x CD4=8, and MHC 1 x CD8=8).
Plasma cell
Produces large amounts of antibody specific to a particular antigen. Clock-face chromatin distribution, abundant RER, and well-developed Golgi apparatus. Multiple myeloma is a plasma cell cancer.
Group A blood
Group A antigens on RBC surface. Antibodies are IgM anti-B. If a patient receive B or AB, they have a hemolytic reaction.
Group B blood
Group B antigens on RBC surface. Antibodies are IgM anti-A. If a patient receive A or AB, they have a hemolytic reaction.
Group AB blood
Group A and B antigens on RBC surface. There are no antibodies. They are universal recipients of RBCs. If a patient receive B or AB, they have a hemolytic reaction.
Group O blood
No group antigens. They are universal donor of RBCs. Antibodies are IgM anti-B and anti-A. If a patient receive any non O blood, they have a hemolytic reaction.
Rh positive blood
There are Rh (D) antigens and no anti-D antibody.
Rh negative blood
There are no Rh (D) antigens. There are IgG anti-D. Rh negative mothers need to be treated with Rh (D) immunoglobulin after each pregnancy to prevent anti-D IgG formation.
Hemolytic disease of the newborn
IgM does not cross the placenta but IgG does cross placenta. Rh negative mothers exposed to fetal Rh positive blood (often during delivery) may make anti-D IgG. In subsequent pregnancies, anti-D IgG crosses the placenta causes hemolytic disease of the newborn (erythroblastosis fetalis) in the next fetus that is Rh positive. Prevented by administration of RhoGAM to Rh negative pregnant women during the third trimester, which prevents maternal anti-Rh IgG production. Rh negative mothers have anti-D IgG only if previously exposed to Rh positive blood.
Intrinsic coagulation pathway
The intrinsic pathway begins with Factor XII (Hageman factor), which is activated by subendothelial collagen. Factor XII activates factor XI, which activates IX. Factor IX requires Ca and VIII. Factor IX also activates factor X, the beginning of the combined pathway.
Extrinsic coagulation pathway
The extrinsic pathway begins with Factor VII (requires Ca), which is activated by tissue factor (aka Factor III or thromboplastin). Factor VII also activates factor X, the beginning of the combined pathway.
Combined coagulation pathway
The intrinsic and extrinsic pathway converge with the activation of Factor X. The common pathways begins with Factor X, and ends with the formation of fibrin polymers. Factor X requires Ca and V as cofactors and activates prothrombin to thrombin, which cleaves fibrinogen to form fibrin.
Fibrinolysis
Fibrinolysis is the dissolution of a clot. The clot releases the enzyme plasminogen activator (tPA), which activates plasminogen to plasmin. Plasmin lyses fibrinogen and fibrin, dissolving the clot slowly. tPA is inhibited by aminocaproic acid. It is activated by alteplase, reteplase, steptokinase, and tenecteplase.
Anticoagulants that target factor X
Includes LMWH (greatest efficacy), heparin, direct Xa inhibitors (apixaban, rivaroxaban), fondaparinux.
Anticoagulants that target factor II (thrombin)
Includes heparin (greatest efficacy), LMWH (dalteparin, enoxaparin), direct thrombin inhibitors (argatroban, bivalirudin, dabigatran).
Kinin cascade
Kallikrein converts HMWK to bradykinin, which causes an increase in vasodilation, permeability, and pain. HMWK also activates XII, the first step of the intrinsic coagulation pathway.
Vitamin K as a procoagulation cascade components
Oxidized vitamin K get converted to reduced vitamin K by epoxide reductase. Vitamin K acts as a cofactor for factors II, VII, IX, X, C, S. Warfarin inhibits the enzyme vitamin K epoxide reductase. Neonates lack enteric bacteria, which produce vitamin K. A vitamin K deficiency decreases synthesis of factors II, VII, IX, C, protein C, and protein S. vWF carries/ protects VIII.
Protein C
Protein C is activated by thrombin-thrombomodulin complex from endothelial cells, which cleaves and inactivates V and VIII with protein S as a cofactor. Factor V Leiden mutation produces a factor V resistant to inhibition by activated protein C.
tPA
tPA converts plasminogen to plasmin, which causes fibrinolysis by cleaving the fibrin mesh and destruction of coagulation factors.
Antithrombin
It inhibits activated forms of factors II, VII, IX, X, XI, XII. Heparin enhances the activity of antithrombin. The principal targets of antithrombin include thrombin and factor X.
Platelet plug formation (primary hemostasis)
Endothelial damage leads to a transient vasoconstriction via neural stimulation reflex and endothelin (released from damaged cell). vWF binds to exposed collagen. vWF is from Weibel-Palade bodies of endothelial cells and alpha-granules of platelets. Platelets bind vWH via GP1b receptor at the site of injury only, causing platelets to undergo conformational change. Platelets release ADP and Ca (necessary for coagulation cascade) and TXA2 (a derivative of platelet cyclooxygenase. ADP helps platelet adhere to endothelium. ADP binds to a receptor, which induces GpIIb/GpIIIa expression at platelet surface. Fibrinogen binds GPIIb/GpIIIa receptors and links platelets. Temporary plug stops bleeding but it is unstable and can easily be dislodged.
Pro-platelet aggregation factors
TXA2 (released by platelets, aspirin inhibits cyclooxygenase), decreased blood flow, and increased platelet aggregation.
Anti- platelet aggregation factors
PGI2 and NO (released by endothelial cells), increased blood flow, decreased platelet aggregation.
Drugs that inhibit ADP-induced expression of GpIIb/GpIIIa
Clopidogrel, prasugrel, and ticlopidine
Drugs that inhibit GpIIb/GpIIIa directly
Abciximab, eptifibatide, and tirofiban
Drugs that activate vWF to bind GpIb
Ristocetin. Failure of agglutination with ristocetin assay occurs in von Willebrand disease and Bernard-Soulier syndrome.
Acanthocyte
A spur cell, a form of red blood cell that has a spiked cell membrane, due to abnormal thorny projections. It is associated with liver disease, abetalipoproteinemia. Acantho=spiny.
Basophilic stippling
Erythrocytes display small dots at the periphery. It is associated with lead poisoning.
Degamacyte
A bite cell. It is associated with G6PD deficiency
Elliptocyte
It is associated with hereditary elliptocytosis.
Macro-ovalocyte
An enlarged, oval-shaped erythrocytes (red blood cells). It is associated with megaloblastic anemia (also hypersegmented PMNs) and marrow failure.
Ringed sideroblast
An abnormal sideroblast with many iron granules in its mitochondria, found in a ring around the nucleus; seen in sideroblastic anemia.
Schistocyte
A helmet cell. It is associated with DIC, thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), HELLP syndrome (Hemolysis. Elevated Liver enzymes. Low Platelet count.), mechanical hemolysis (eg heart valve prosthesis).
Spherocyte
Sphere-shaped RBC, associated with hereditary spherocytosis, drug-and infection-induced hemolytic anemia.
Dacrocyte
Teardrop cell, associated with bone marrow infiltration (eg myelofibrosis). RBC sheds a tear because its mechanically squeezed out of its home in the bone marrow.
Target cell
It is associated HbC disease, Asplenia, Liver disease, and Thalassemia. (HALT, said the hunter to his target)
Heinz bodies
RBC with inclusions within red blood cells composed of denatured hemoglobin. Oxidation of Hb-SH groups to S-S causes Hb precipitation (Heinz body), with subsequent phagocytic damage to RBC membrane creating bite cells. It is associated with G6PD deficiency; Heinz body-like inclusions seen in alpha thalassemia.
Howell-Jolly bodies
Basophilic nuclear remnants found in RBCs. They are normally removed by splenic macrophages. They are seen in patients with functional hyposplenia or asplenia.
Microcytic anemia
Iron deficiency (late), anemia of chronic disease (late), thalassemias, lead poisoning, siderblastic anemia (late).
Nonhemolytic normocytic anemia
anemia of chronic disease, aplastic anemia, chronic kidney disease, iron deficiency (early).
Hemolytic normocytic anemia
Intrinsic causes include RBC membrane defect (hereditary spherocytosis), RBC enzyme deficiency (G6PD and pyruvate kinase), HbC defect, paroxysomal nocturnal hemoglobinuria, sickle cell anemia. Extrinsic causes include autoimmune, microangiopathic, macroangiopathic, and infections.
Megaloblastic macrocytic anemia
Folate deficiency, B12 deficiency, orotic aciduria
Non-megaloblastic macrocytic anemia
Liver disease, alcoholism, reticulocytosis.
Iron deficiency anemia
Microcytic, hypochromic anemia. A decrease in iron can occur due to chronic bleeding (eg GI loss, menorrhagia), malnurtion/absorption disorders, or an increase in demand (pregnancy), which causes there to be a decrease in the final step of heme synthesis. Findings include a decrease in iron, an increase in TIBC, a decrease in ferritin. Patients will have fatigue, conjunctival pallor, spoon nails (koilonychia). There will be microcytosis and hypochromia (central pallor). It may manifest as Plummer-Vinson syndrome.
Plummer-Vinson syndrome
It occurs due to iron deficiency anemia. It manifest as a triad of iron deficiency anemia, esophageal webs, and atrophic glossitis.
alpha-thalassemia
Microcytic, hypochromic anemia. The defect is a deletion of the alpha globin gene, which leads to a decrease in alpha globin synthesis. A cis deletion (αα/–) is prevalent in the Asian populations; trans deletion (α-/α-) prevalent in African populations. 1-2 allele deletion is less clinically severe anemia.
Hb Barts
4 alpha deletions. There is no alpha globin. Excess gamma-globin forms gamma four (Hb Barts). It is incompatible with life and leads to hydrops fetalis.
Hb H disease
This is 3 alpha deletion. There is very little alpha globin. Excess beta globin forms beta-4 (HbH).
Beta-thalassemia
Microcytic, hypochromic anemia. There are point mutations in the splice sites and promoter sequences, which leads to a decrease in beta-globin synthesis. There is high prevalence in mediterranean populations
Beta-thallassemia minor
Heterozygote in the beta gene. The beta chain is underproduced. It usually asymptomatic. It is diagnosed with an increase in HbA2 (above 3.5%) on electrophoresis.
Beta-thallassemia major
Homozygote in the beta gene. The beta chain is absent leading to severe anemia, requiring blood transfusions, which can lead to secondary hemochromatosis. On blood smear, there are anisocytosis, poikilocytosis, target cells, microcytosis, and schistocytes. Marrow expansion also occurs leading to skeletal deformities (crew cut on skull x-ray and chimunk facies). Extramedullary hematopoiesis, which leads to hepatosplenomegaly. This causes an increase risk of parvovirus B19-induced aplastic crisis. Major thallassemia also causes an increase in HbF (alpha2, gamma2). HbF is protective in the infant and disease becomes symptomatic only after 6 months.
Hb S/ Beta-thalassemia heterozygote
It causes mild to moderate sickle cell disease depending on amount of beta-globin production.
Lead poisoning anemia
Microcytic, hypochromic anemia. Lead inhibits the ferrochelatase and ALA dehydrogenase, leading to a decrease in heme synthesis and an increase in RBC protoporphyrin. It also inhibits rRNA degradation, causing RBCs to retain aggregates of rRNA, causing basophilic stippling. There is high risk in old houses with chipped paint. LEAD: Lead Lines gingiva (burton lines) and on metaphyses of long bones on x-ray. Encephalopathy and Erythrocyte basophilic stippling. Abdominal colic and sideroblastic Anemia. Drops- wrist and foot drop. Dimercaprol and EDTA are 1st line of treatment. Succimer used for chelation for kids. (It SUCks to be kid who eats lead).
Sideroblastic anemia
Microcytic, hypochromic anemia. Due to a defect in heme synthesis. Inheritable causes include X-linked defect in delta-ALA synthase gene. Other causes include myelodysplastic syndromes (aquired) and reversible (alcohol is most common; also vitamin B6 deficiency, copper deficiency, isoniazid). Ringed sideroblasts (with iron-laden, Prussian blue-stained mitochondria) are seen in bone marrow. Other findings include an increase in iron, normal/ decrease in TIBC, increase in ferritin. Treatment includes pryidoxine (B6, cofactor for delta-ALA synthase).
Megaloblastic anemia
Macrocytic anemia. It occurs due to impaired DNA synthesis, leading to maturation of nucleus of precursor cells in bone marrow delayed relative to maturation in cytoplasm. Findings include RBC macrocytosis, hypersegmented neutrophils, and glossitis.
Folate deficiency
Megaloblastic macrocytic anemia. Causes include malnutrition (eg alcoholics), malabsorption, drugs (eg methotrexate, trimethoprim, phenytoin), and increase requirement (eg hemolytic anemia and pregnancy). Findings include an increase in homocysteine and normal methylmalonic acid. There are no neurologic symptoms (vs B12 deficiency).
B12 (cobalamin) deficiency
Megaloblastic macrocytic anemia. Causes include insufficiency intake (eg veganism), malabsorption (eg Crohn disease), pernicious anemia, Diphyllobothrium latum (fish tapeworm), gastrectomy. Findings include an increase in homocysteine and methylmalonic acid. Neurologic symptoms include subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis), which affects the spinocerebellar tract, lateral corticospinal tract, and dorsal column dysfunction.
Orotic aciduria
Megaloblastic macrocytic anemia. Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) due to a defect in UMP synthase. It is autosomal recessive. It presents in children as failure to thrive, developmental delay, and megaloblastic anemia refractory to folate and B12. There is no hyperammonemia (vs ornithine transcarbamylase deficiency, which has an increase orotic acid with hyperammonemia). Findings include orotic acid in urine. Treatment includes uridine monophosphate to bypass mutated enzyme.
Nonmegaloblastic macrocytic anemias
Macrocytic anemia in which DNA synthesis is unimpaired. Causes includes alcoholism, liver disease, hypothyroidism, and reticulocytosis. Findings include, RBC macrocytosis without hypersegmented neutrophils.
Normocytic normochromic anemia
Normocytic, bormochromic anemias are classified as nonhemolytic or hemolytic. The hemolytic anemias are further classified according to the cause of the hemolysis (intrinsic vs extrinsic to the RBC) and by location of the hemolysis (intravascular vs extravascular).
Intravascular hemolysis
Normocytic normochromic anemia. Findings include a decrease in haptoglobin, an increase in LDH, schistocytes, and reticulocytes on blood smear. Characteristic include hemoglobinuria, hemosiderinuria, and urobilinogen in urine. Notable causes include mechanical hemolysis (eg prosthetic valve), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias.
Extravascular hemolysis
Normocytic normochromic anemia. Macrophages in spleen clear RBCs. Findings include spherocytes in peripheral smear, an increase in LDH, no hemoglobinuria. hemosiderinuria, an increase in unconjugated bilirubin, which can cause jaundice.
Anemia of chronic disease
Nonhemolytic, normocytic anemia. Inflammation leads to an increase in hepcidin, which is released by the liver and binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport. The increase in hepcidin causes a decrease in release of iron from macrophages. It is associated with conditions like SLEm rheumatoid arthritis, neoplastic disorders, and chronic kidney disease. Findings include a decrease in iron and TIBC and an increase in ferritin. It can become microcytic anemia. Treatment includes EPO in chronic kidney disease only.
Aplastic anemia
Normocytic normochromic anemia. It is caused by failure or destruction of myeloid stem cells due to: radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites); viral agents (parvocirus B19, EBV, HIV, HCV), Faconi anemia (DNA repair defect); idiopathic (immune mediated, primary stem cell defect), may follow acute hepatitis. Pancytopenia is characterized by severe anemia, leukopenia, and thrombocytopenia. There is normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone marrow tap). Symptoms include malaise, pallor, purpura, mucosal bleeding, petechiae, and infection. Treatment includes withdrawal of offending agent, immunosuppressive regimens (eg antit-hymocyte globulin, cyclosporine), bone marrow allograft, RBC/platelet transfusion, bone marrow stimulation (eg GM-CSF).
Hereditary spherocytosis
Extravascular hemolytic normocytic intrinsic anemia. It occurs due to a defect in proteins interacting with RBC membrane skeleton and plasma membrane (eg ankyrin, band 3, protein 4.2, spectrin). This results in small round RBCs with less surface area and no central pallor (resulting in an increase in MCHC and red cell distribution width), which causes premature removal by spleen. Findings includes splenomegaly, aplastic crisis (eg due to parvovirus B19 infection). Labs include a positive osmotic fragility test and a normal to decrease in MCV. with an abundance of cells. Treatment includes splenectomy.
G6PD deficiency
Extravascular and intravascular intrinsic hemolytic normocytic anemia. It is the most common enzymatic disorder of RBCs. It is x-linked recessive. A defect in G6PD leads to a decrease in glutathione, which makes RBCs more susceptible to oxidant stress. Hemolytic anemia occurs following oxidant stress (eg sulfa drugs, antimalarials, infections, fava beans). Clinical findings include back pain, hemoglobinuria a few days after oxidant stress. A blood smear shows RBCs with heinz bodies and bite cells. “Stress makes me eat bites of fava beans with Heinz ketchup.
Pyruvate kinase deficiency
Extravascular intrinsic hemolytic normocytic anemia. It is autosomal recessive. A defect in pyruvate kinase, which catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate and one molecule of ATP, decreases ATP, causing RBCs to be rigid. It presents as hemolytic anemia in a newborn.
HbC defect
Extravascular intrinsic hemolytic normocytic anemia. Occurs due to a glutamic acid to lysine mutation in beta-globlin. Patients with HbSC (one of each mutant gene) have milder disease than HbSS.
Paroxysomal nocturnal hemoglobinuria
Intravascular intrinsic hemolytic normocytic anemia. An increase in complement-mediated RBC lysis due to an impairment in the synthesis of GPI anchor for decay-accelerating factor that protects RBC membrane from complement. This is due to an acquired mutation in a hematopoietic stem cell. There are also an increase incidence of acute leukemias. There is a triad of negative coombs hemolytic anemia, pancytopenia, and venous thrombosis. Labs show negative CD55/59 RBCs on flow cytometry. Treatment includes eculizumab (terminal complement inhibitor).
Sickle cell anemia
Extravascular intrinsic hemolytic normocytic anemia. HbS point mutation causes a single amino acid replacement in the beta chain (a substitution of glutamic acid with valine). Low O2, high altitude, or acidosis can precipitates sickling, which occurs due to deoxygenated HbS polymerization. This causes anemia and vaso-occlusive disease. Newborns are initially asymptomatic due to high levels of HbF and low levels of HbS. Heterozygotes (sickle cell trait) are resistant to malaria. 8% of Africans Americans carry an HbS allele. Xray will show a crew cut on the skull due to marrow expansion from an increase in erythropoiesis (this is also seen in thalassemia). Complications in sickle cell disease include: aplastic crisis (due to parvovirus B19), autosplenectomy (showing Howell-Jolly bodies with blood smear) that has an increase risk of infection from encapsulated bacteria, splenic infarct/ sequestration crisis, salmonella osteomyelitis, painful crises (a vaso-occlusive event, which can manifest as dactylitis (painful swelling of hands/ feet), acute chest syndrome, avascular necrosis, or stroke), renal papillary necrosis (due to a decrease in PO2 in papilla) and microhematuria (medullary infarcts). Diagnosis is based on hemoglobin electrophoresis. Treatment includes hydroxyurea (which increases HbF) and hydration.
Autoimmune hemolytic anemia
Extrinsic hemolytic normocytic anemia. Includes warm and cold agglutination. Many warm and cold AIDAs are idiopathic in etiology. Autoimmune hemolytic anemias are usually Coombs positive.
Warm agglutinin
Autoimmune hemolytic anemia, IgG mediated. Chronic anemia is seen in SLE and CLL and with certain drugs (eg alpha-methyldopa). Warm weather is Great.
Cold agglutinin
Autoimmune hemolytic anemia, IgM mediated. It is an acute anemia triggered by the cold. It is seen in CLL, Mycoplasma pneumonia infections, and infectious Mononucleosis (cold weather is MMMiserable).
Direct Coombs test
Anti-Ig antibody (Coombs reagent) is added to patients blood. RBCs agglutinate if RBCs are coated with Ig.
Indirect Coombs test
Normal RBCs are added to patient’s serum. If serum has anti-RBC surface Ig, RBCs will aggluntinate when Coombs reagent is added.
Microangiopathic anemia
Extrinsic hemolytic normocytic anemia. RBCs are damaged when they are passing through obstructed or narrowed vessel lumina. It is seen in DIC, TTP/HUS, SLE, and malignant hypertension. Schistocytes (helmet cells) are seen on blood smear due to mechanical destruction of RBCs.
Infections causing anemia
Extrinsic hemolytic normocytic anemia. Malaria or babesia among others can cause an increase destruction of RBCs.
Lab values seen in iron deficient anemia
A decrease in serum iron, an increase in transferrin or TIBC, a decrease in ferritin, and a large decrease in the precent of transferrin saturation (serum iron/ TIBC)
Lab values seen in anemia in chronic disease
A decrease in serum iron, a decrease in transferrin or TIBC, an increase in ferritin, and no change in the precent of transferrin saturation (serum iron/ TIBC)
Lab values seen in anemia due to hemochromatosis
An increase in serum iron, a decrease in transferrin or TIBC, an increase in ferritin, and a large increase in the precent of transferrin saturation (serum iron/ TIBC)
Lab values seen in anemia due to pregnancy or OCP use
No change in serum iron, an increase in transferrin or TIBC, no change in ferritin, and a decrease in the precent of transferrin saturation (serum iron/ TIBC)
Transferrin
Transports iron in blood.
Total iron binding capacity (TIBC)
Indirectly measures transferrin.
Ferritin
It is the primary iron storage protein of body.
Corticoidsteroid effect on blood cells
Corticosteroids cause neutropenia, despite causing eosinophenia and lymphopenia. Corticosteroids decrease activation of neutrophil adhesion molecules, impairing migration out of the vasculature to sites of inflammation. in contrast, corticosteroids sequester eosinophils in lymph nodes and cause apoptosis of lymphocytes.
delta- aminolevulinic acid synthase
The first step in heme synthesis, also the rate limiting step. It catalyzes glycine and succinyl-CoA into delta aminolevulinic acid, with vitamin B6 as a cofactor. It is inhibited by glucose and heme. It is mutated in sideroblastic anemia.
delta- aminolevulinic acid dehydratase
The second step in heme synthesis. It occurs in the mitochondria. It converts delta-aminoleculinic acid into porphobilinogen. It is inhibited in lead poisoning.
Porphobilinogen deaminase
It is the third step in heme synthesis. It occurs in the mitochondria. It converts porphobilinogen into hydroxymethylbilane. It is mutated in acute intermittent porphyria.
Uroporphyrinogen decarboxylase
It is the fifth step in heme synthesis and occurs in the mitochondria. It converts uroporphyrinogen III into coproporphyrinogen III. It is mutated in porphyria cutanea tarda
Ferrochelatase
It is the 7th step in heme synthesis and occurs in the mitochondria. It converts protoporphyrin into heme by incorporating Fe. It is inhibited by lead poisoning.
Lead poisoning
The affected enzyme is ferrochelatase and ALA dehydratase. Protoporphyrin and delta-ALA becomes accumulated in the blood. It presents is microcytic anemia (showing basophilic stippling) and GI and kidney disease. It often occurs in children due to exposure to lead paint, which leads to mental deterioration. In adults, it often occurs due to environmental exposure (eg batteries or ammunition), which causes headache, memory loss, and demyelination.
Acute intermittent porphyria
Porphobilinogen deaminase is mutated. Porphobilinogen, delta ALA, and coporphobilinogen accumulates in urine. Symptoms include (the 5P’s): painful abdomen, port wine colored urine, polyneuropathy, psychological disturbances, and precipitated by drugs (eg cytochrome P-450 inducers), alcohol, and starvation. Treatment includes glucose and heme, which inhibit ALA synthase.
Porphyria cutanea tarda
Uroporphyrinogen decarboxylase is the mutated enzyme. Uroporphyrin becomes accumalted in urine, causing the urine to turn tea colored. Symptoms include blistering cutaneous photosensitivity. It is the most common porphyria.
Iron poisoning
There is a high mortality rate with accidental ingestion by children (adult iron tablets may look like candy). Cell death occurs due to peroxidation of membrane lipids. Symptoms include nausea, vomiting, gastric bleeding, lethargy, and scarring leadingy to GI obstruction. Treatment involve chelation (eg IV deferoxamine, oral deferasirox) and dialysis.
Prothrombin time (PT)
It tests the function of common and extrinsic pathway (factors I, II, V, VII, and X). A defect causes an increase in PT
Partial thromboplastin time (PTT)
It tests the function of the common and intrinsic pathway (all factors except VII and XIII). A defect causes an increase in PTT.
Hemophilia A
An intrinsic pathway coagulation defect in factor VIII, leading to an increase in PTT. It is x-linked recessive.
Hemophilia B
An intrinsic pathway coagulation defect in factor IX, leading to an increase in PTT. It is x-linked recessive.
Hemophilia C
An intrinsic pathway coagulation defect in factor XI, leading to an increase in PTT. It is autosomal recessive.
Macrohemorrhage in hemophilia
There can be hemarthroses (bleeding into the joints, such as knee), easy bruising, bleeding after trauma or surgery (eg dental procedures).
Treatment of hemophilia
Desmopressin and factor VIII concentrate (A); factor IX concentrate (B); or factor XI concentrate (C).
Vitamin K deficiency
Both PT and PTT increases. It causes a general coagulation defect. Bleeding time remains normal. There is a decrease in activation factors II, VII, IX, X, protein C, and protein S.
Platelet disorders
Defects in platelet plug formation causes there to be an increase in bleeding time (BT). Platelet abnormalities leads to microhemorrhage, which causes mucous membrane bleeding, epistaxis, petechiae, purpura, an increase in bleeding time, and possibly decreased platelet count.
Bernard Soulier syndrome
Due to a defect in platelet plug formation. There are large platelets. A decrease in GpIb causes there to be a defect in platelet to vWF adhesion. There is no agglutination on ristocetin cofactor assay. Platelet count is normal or decreased. Bleeding time is increased.
Glanzmann thrombasthenia
A defect in platelet plug formation. A decrease in GpIIb/IIIa leads to a defect in platelet to platelet aggregation. Labs will show no platelet clumping on blood smear. There is agglutination with ristocetin cofactor assay. There is no change in platelet count and an increase in bleeding time.
Immune thrombocytopenia
There are anti-Gp IIb/IIIa antibodies leading to splenic macrophage consumption of platelet-antibody complex. It is commonly due to viral illness. There are an increase in megakaryocytes on bone marrow biopsy. Platelet count is reduced and bleeding time is increased. Treatment includes steroids, intravenous immunoglobulin.
Thrombotic thrombocytopenic purpura
There is inhibition or deficiency of ADAMTS 13 (vWF metalloprotease), which causes there to be a decrease in degradation of vWF multimers. An increase in in large vWF multimers leads to an increase in platelet adhesion, causing platelet aggregation and thrombosis. Labs show schistocytes and an increase in LDH. Symptoms include a pentad of neurologic and renal symptoms, fever, thrombocytropenia, and microangiopathic hemolytic anemia. Platelet count decreases and bleeding time increases. treatment include plasmapheresis and steroids.
von Willebrand disease
It is an intrinsic pathway coagulation defect due to a decrease in vWF leading to a defect in platelet to vWF adhesion, which increases PTT. vWF normally acts to carry/ protect factor VIII. There is a defect in platelet plug formation because a decrease in vWF causes there to be a defect in platelet to vWF adhesion. It is autosomal dominant. It is mild but is the most common inherited bleeding disorder. It is diagnosed in most cases by ristocetin cofactor assay (a decrease in agglutination is diagnostic). Platelet count and PT are normal. Bleeding time and PTT are increased.
DIC
It occurs due to widespread activation of clotting factors causes there to be a deficiency in clotting factor, which increases bleeding state. Causes include Sepsis (gram-negative), Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome, and Transfusion (STOP Making New Thrombi). Labs will show schistocytes, an increase in fibrin split products (D-dimers), a decrease in fibrinogen, and a decrease in factors V and VIII. Platelet count in decreased. Bleeding time, PT, and PTT are all increased.
Antithrombin deficiency
An inherited deficiency of antithrombin. It has no direct effect on the PT, PTT, or thrombin time but diminishes the increase in PTT following heparin administration. It can also be acquired due to renal failure/ nephrotic syndrome, causing there to be antithrombin loss in urine leading there to be a decrease inhibition of factors IIa and Xa.
Factor V Leiden
Due to production of mutant factor V that is resistant to degradation by activated protein C. It is the most common cause of inherited hypercoagulability in whites.
Protein C or S deficiency
Due to a decrease in ability to inactivate factors Va and VIIIa. There is an increase risk of thrombotic skin necrosis with hemorrhage following administration of warfarin. Clinical symptoms will show skin and subcutaneous tissue necrosis after warfarin administration. Protein C Cancels Coagulation.
Prothrombin gene mutation
Due to mutation in 3’ untranslated region causes there to be an increase in production of prothrombin, increasing plasma levels and venous clots.
Packed RBCs transfusion therapy
It increases hemoglobin and O2 carrying capacity. It is used in acute blood loss and severe anemia.
Platelets transfusion therapy
It increases platelet count (by about 5000/mm3/unit). It is used to stop significant bleeding for thrombocytopenia and qualitative platelet defects.
Fresh frozen plasma transfusion therapy
It increases coagulation factor levels. It is used to treat DIC, cirrhosis, and immediate warfarin reversal.
Cryoprecipitate
It contains fibrinogen, factor VIII, factor XIII, vWF, and fibronectin. It is used to treat coagulation factor deficiencies involving fibrinogen and factor VIII.
Risks associated with blood transfusion
Risks include infection transmission (low), transfusion reactions, iron overload, hypocalcemia (citrate is a Ca chelator), and hyperkalemia (RBCs may lyse in old blood units).
Leukemia
Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood.
Lymphoma
A discrete tumor mass arising from lymph nodes. Presentations often blur types of lymphoma.
Leukemoid reaction
An acute inflammatory response to infection. There is an increase in WBC count with neutrophil and neutrophil precursors such as band cells (a left shift). There is also an increase in leukocyte alkaline phosphatase (LAP). In contrast with CML which also has an increase in WBC with left shift but a decrease in LAP.
Hodgkin lymphoma
It is characterized by localized single group of nodes. Extranodal manifestations are rare. Spread is contiguous (stage is the strongest predictor of prognosis). Prognosis is much better than non-Hodgkin lymphoma. It is characterized by Reed-Sternberg cells. There is a bimodal distribution, young adulthood and over 55 years. It is more common in men except for the nodular sclerosing type. It is strongly associated with EBV. There are constitutional (B) signs/ symptoms, including low-grade fever, night sweats, and weight loss.
Non-hodgkin lymphoma
It is characterized by multiple, peripheral nodes. Extranodal involvement is common. It spreads noncontiguous. The majority involve B cells (except those of lymphoblastic T-cell origin). Peak incidence for certain subtypes is from 20-40 years old. It may be associated with HIV and autoimmune disease. There are fewer constitutional signs/ symptoms than hodgkin lymphoma.
Reed Sternberg cells
Distinctive tumor giant cells seen in Hodgekin disease; it is binucleate or bilobed with the 2 halves as mirror images (owl eyes). RS cells are CD15+ and CD30+ of B cell origin. They are necessary but not sufficient for diagnosis of Hodgkin disease. There is a better prognosis with strong stomal or lymphocytic reaction against RS cells. The most common type that causes RS cells is nodular sclerosing form (affects women and men equally). The lymphocyte mixed or depleted forms have the worse prognosis.
Burkett lymphoma
A non-Hodhkin lymphoma of mature B cells. Occurs in adolescents or young adults. t(8;14) translocation of c-myc (8) and heavy chain Ig (14). Histology shows “Starry sky” appearance, sheets of lymphocytes with interspersed macrophages. It is associated with EBV. It is associated with jaw lesion in endemic form in Africa; pelvic and abdomen in sporadic form.
Diffuse large B-cell lymphoma
A non-Hodhkin lymphoma of mature B cells. It usually occurs in older adults, but 20% occurs in children. It is the most common type of non-Hodgkin lymphoma in adults.
Follicular lymphoma
A non-Hodhkin lymphoma of mature B cells. It occurs in adults. t(14;18) translocation of heavy chain Ig (14) and BCL-2 (18). There is an indolent course. Bcl-2 inhibits apoptosis. It presents with painless “waxing and waning” lymphadenopathy. Histology shows nodular, small cells, cleaved nuclei.
Mantle cell lymphoma
A non-Hodhkin lymphoma of mature B cells. It occur in older males due to a t(11;14) translocation of cyclin D1 (11) and heaving chain Ig (14). Cells express CD5+.
Adult T-cell lymphoma
A non-Hodhkin lymphoma of mature T cells. It occurs in adults and is caused by HTLV (human T-lymphotropic virus), which is associated with IV drug abuse. Adults will present with cutaneous lesions; it especially effects populations in Japan, West Africa, and the Caribbean. It causes lytic bone lesions and hypercalcemia.
Mycosis fungoides/ Sezary syndrome
A non-Hodhkin lymphoma of mature T cells. It occurs in adults. Mycosis fungoides presents with skin patches/ plaques (cutaneous T-cell lymphoma), characterized by atypical CD4+ cells with “cerebriform” nuclei. It may progress to Sezary syndrome (T-cell leukemia).
Multiple myeloma
It is a monoclonal plasma cell (fried egg appearance) cancer that arises in the marrow and produces a large amounts of IgG (55%) or IgA (25%). It is the most common primary tumor arising within bone in people over the age 40-50 years. It is associated with an increase susceptibility to infection, primary amyloidosis (AL), punched out lytic bone lesions on x-ray (leading to hypercalcemia), M spike (due to IgG) on serum protein electrophoresis, Ig light chains in urine (Bence Jones protein), Rouleaux formation (RBC stacked like poker chips in blood smear). There are numerous plasma cells with “clock face” chromatin and intracytoplasmic inclusions containing immunoglobulin. Symptoms include CRAB: hyperCalcermia, Renal involvement, Anemia, Bone lytic lesions/ Back pain. Multiple Myeloma= Monoclonal M protein spike.
Monoclonal gammopathy of undetermined significance (MGUS)
A monoclonal expansion of plasma cells. It is asymptomatic and made lead to multiple myeloma. There are no “CRAB” findings (hyperCalcermia, Renal involvement, Anemia, Bone lytic lesions/ Back pain). Patients with MGUS develop multiple myeloma at a rate of 1-2% per year.
Waldenstrom macroglobulinemia
It can be distinguished from multiple myeloma because the M spike is due to IgM, which leads to hyperviscosity syndrome (eg blurred vision, Raynaud phenomenon). There are no CRAB findings (hyperCalcermia, Renal involvement, Anemia, Bone lytic lesions/ Back pain)
Myelodysplastic syndromes
They are stem cell disorders involving ineffective hematopoiesis leading to defects in cell maturation of all nonlymphoid lineages. It is caused by de novo mutations or environmental exposure (eg radiation, benzene, chemotherapy). There is a risk of transformation to AML.
Pseudo Pelger Huet anomaly
Neutrophils are seen with bilobed nuclei. It is typically seen after chemotherapy.
Leukemias
It is unregulated growth and differentiation of WBCs in bone marrow, causing the marrow to fail, leading to anemia (a decrease in RBCs), infections (due to a decrease in mature WBCs), and hemorrhage (due to a decrease in platelets). There can be an increase or a decrease in the number of circulating WBCs.
Acute lymphoblastic leukemia/ lymphoma (ALL)
A lymphoid neoplasm. Occurs in those under the age of 15. T-cell can present as mediastinal mass (presenting as a SVC-like syndrome). It is associated with Down syndrome. Peripheral blood and bone marrow will have a large increase in lymphoblasts (purple stained with coarser chromatin and fewer nucleoli than myeloblasts). Markers include TdT+ (a marker of pre T and pre B cells) and CD10+ (pre B cells only). It is the most responsive leukemia to therapy. It may spread to CNS and testes. t(12,21) has a better prognosis.
Small lymphocytic lymphoma (SLL)/ chronic lymphocytic leukemia (CLL)
A lymphoid neoplasm. It occurs in those over the age of 60. It is the most common leukemia in adults. It is a CD20+ and CD5+ B-cell neoplasm. It is often asymptomatic and progresses slowly. Peripheral blood smear will show smudge cells. It is associated with autoimmune hemolytic anemia. SLL is the same as CLL except CLL has an increase in peripheral blood lymphocytosis or bone marrow involvement.
Hairy cell leukemia
A lymphoid neoplasm. It occurs in adults. It is a mature B-cell tumor in the elderly. Cells have a filamentous, hair-like projections. It causes marrow fibrosis which causes there to be a dry tap on aspiration. It stains tartate-resistant acid phosphatase positive (TRAP). TRAP stain has largely been replaced with flow cytometry. Treatment includes cladribine (a purine analog) and pentostatin (a purine analog).
Acute myelogenous leukemia (AML)
A myeloid neoplasms. The median age of onset is 65 years. Cells have Auer rods. Peroxidase positive cytoplasmic inclusions are seen mostly in M3 AML. There is a large increase in circulating myeloblasts on peripheral smear. Risk factors include prior exposure to alkylating chemotherapy, radiation, myeloproliferative disorders, Down syndrome. t(15;17) translocation occurs in M3 AML subtype and responds to all-trans retinoic acid (vitamin A), which can restore the differentiation capacity of leukemic promyelocytes. DIC is a common presentation of M3 AML.
Chronic myelogenous leukemia (CML)
A myeloid neoplasms. The peak incidence is 45-85 years of age with the median age at diagnosis being 64 years. It is defined by the Philadelphia chromosome (t(9;22), BCR-ABL). It is marked by myeloid stem cell proliferation and presents with an increase in neutrophils, metamyelocytes (boomerang shaped), and basophils. There is also splenomegaly. It may accelerate and transform to AML or ALL (blast crisis). There is very low LAP (Leukocyte Alkaline Phosphatase) as a result of low activity in mature granulocytes (vs leukemoid reaction, in which LAP is increased). It responds to imatinib (a small molecule inhibitor of the bcr-abl tyrosine kinase).
t(8,14)
Burkitt lymphoma (c-myc activation)
t(9; 22)
Philadelphia chromosome. CML (BCR-ABL hybrid). Philadelphia CreaML cheese.
t(11;14)
Mantle cell lymphoma (cyclin D1 activation)
t(14;18)
Follicular lymphoma (BCL-2 activation)
t(15;17)
M3 type of AML. It responds to all-trans retinoic acid.
Langerhans cell histiocytosis
A collective group of proliferative disorders of dendritic (Langerhans) cells. It presents in a child as lytic bone lesions and skin rash or as recurrent otitis media with a mass involving the mastoid bone. Cells are functionally immature and do not effectively stimulate primary T cells via antigen presentation. Cells express S-100 (mesodermal origin) and CD1a. Birbeck granules (tennis rackets or rod shaped on EM) are characteristic.
Chronic myeloproliferative disorders
They are often overlapping in spectrum. JAK2 is involved in hematopoietic growth factor signaling. JAK2 gene mutation is often found in chronic myeloproliferative disorders except CML, which has BCR-ABL translocation.
Polycythemia vera
A chronic myeloproliferative disorder of increased hematocrit and is often associated with JAK2 mutation. It may present as intense itching after a hot shower (due to an increase in basophils). A rare but classic symptom is erythromelagia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities. Secondary polycythemia occurs due to a natural or artificial increase in EPO levels.
Essential thrombocytosis
A chronic myeloproliferative disorder similar to polycythemia vera but is specific for overproduction of abnormal platelets, which causes bleeding and thrombosis. Bone marrow contains enlarged megakaryocytes.
Myelofibrosis
A chronic myeloproliferative disorder, which involves obliteration of bone marrow due to an increase in fibroblast activity is response to proliferation of monoclonal cell lines. Teardrop RBCs and immature forms of the myeloid line are seen in a peripheral blood smear. Bone marrow is crying because its fibrosed and is a dry tap. It is often associated with massive splenomegaly.
Lab findings with polycythemia vera
There are increased RBCs, WBCs, and platelets. There is a JAK2 mutation and no Philadelphia chromosome. Plasma volume is increased. RBC mass is greatly increased. There is no change in O2 saturation. EPO levels decrease due to negative feedback suppressing renal EPO production.
Lab findings with essential thrombocytosis
There are no changes in RBCs and WBCs. There is an increase in platelets. There is a JAK2 mutation (30-50%) and no Philadelphia chromosome.
Lab findings with myelofibrosis
There is a decrease in RBCs. The amount of WBCs and platelets are variable. There is a JAK2 mutation (30-50%) and no Philadelphia chromosome.
Lab findings with CML
There is a decrease in RBCs and an increase in WBCs and platelets. There is a Philadelphia chromosome and no JAK2 mutation.
Lab findings with relative polycythemia
Occurs due to a decrease in plasma volume (dehydration and burns). There are no changes in RBC mass, O2 saturation, and EPO levels.
Lab findings with appropriate absolute polycythemia
An appropriate compensatory response to lung disease, congenital heart disease or high altitude. There is no change in plasma volume. RBC mass and EPO levels are increased while O2 saturation decreases.
Lab findings with inappropriate absolute polycythemia
An inappropriate compensatory response to renal cell carcinoma, hepatocellular carcinoma, hydronephrosis. It occurs due to ectopic EPO production. There is no change in plasma volume and O2 saturation. RBC mass and EPO levels are increased.
Mechanism of heparin
An activator of antithrombin, which decreases thrombin and factor Xa. It has a short life.
Clinical use of heparin
It is used for immediate anticoagulation for pulmonary embolism (PE) and acute coronary syndrome, MI, and deep venous thrombosis (DVT). It is used during pregnancy because it does not cross the placenta. It is followed with PTT.
Heparin toxicity
It causes bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin).
Low molecular weight heparin
For example enoxaparin and dalteparin. It acts more on factor Xa with better bioavailability and 2-4 times longer half life. It can be administered subcutaneously and without laboratory monitoring. It is not easily reversible.
Fondaparinux
It acts more on factor Xa with better bioavailability and 2-4 times longer half life. It can be administered subcutaneously and without laboratory monitoring. It is not easily reversible.
Heparin induced thrombocytopenia (HIT)
The developement of IgG antibodies against heparin bound platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets, which causes thrombosis and thrombocytopenia.
Argatroban
It inhibits thrombin directly. It is an alternative to heparin for anticoagulating patients with HIT.
Bivalirudin
It is related to hirudin, the anticoagulant used by leeches. It inhibits thrombin directly. It is an alternative to heparin for anticoagulating patients with HIT.
Mechanism of warfarin
It interferes with gamma-carboxylation of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C and S. Metabolism is affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1). In laboratory assay, has an effect on EXtrinsic pathway and increases PT. There is a long half life. The EX-PresidenT went to war(farin).
Clinical use of warfarin
It is used for chronic anticoagulation (eg venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation). It is not used in pregnant women (because warfarin, unlike heparin, crosses the placenta). It is monitored with PT/INR.
Warfarin toxicity
Includes bleeding, teratogenic, skin/ tissue necrosis, drug-drug interactions. Proteins C and S have shorter half lives than clotting factors II, VI, IX, and X, resulting in an early transient hypercoagulability with warfarin use. Skin/ tissue necrosis is believed to be due to small vessel microthromboses. For reversal of warfarin, give vitamin K. For rapid reversal, give fresh frozen plasma. Heparin bridging is frequently used when starting warfarin. Heparin’s activation of antithrombin enables anticoagulation during the initial, transient hypercoagulable state caused by warfarin and reduces the risk of recurrent venous thromboembolism and skin/ tissue necrosis.
Heparin vs warfarin
Heparin’s structure is large, anionic, acidic polymer, while warfarin is a small amphipathic molecule. Heparin is administered parenteral while warfarin is oral. Heparin site of action is in the blood, while warfarin acts in the liver. Heparin’s onset is rapid, while warfarin is slower and limited by the half-lives of normal clotting factors. The duration of action is acute in heparin and chronic in warfarin. Heparin inhibits coagulation in vitro but not with warfarin. Heparin is motored with PPT, while warfarin is monitored with PT/INR. Heparin does not cross the placenta while warfarin does.
Apixaban
A direct factor Xa inhibitor. Clinical use is treatment and prophylaxis for DVT and PE; stroke prophylaxis in patients with atrial fibrillation. Oral agents do not require coagulation monitoring. Toxicity includes bleeding (no reversal agent available.
Rivaroxaban
A direct factor Xa inhibitor. Clinical use is treatment and prophylaxis for DVT and PE; stroke prophylaxis in patients with atrial fibrillation. Oral agents do not require coagulation monitoring. Toxicity includes bleeding (no reversal agent available.
Alteplase
tPA. It helps with the conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. They will increase PT, PTT with no change in platelet count. It is used in early MI, early ischemic stroke, direct thrombolysis of severe PE. Toxicities include bleeding. It is contraindicated in patientswith active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
Reteplase
rPA. It helps with the conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. They will increase PT, PTT with no change in platelet count. It is used in early MI, early ischemic stroke, direct thrombolysis of severe PE. Toxicities include bleeding. It is contraindicated in patientswith active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
Streptokinase
It helps with the conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. They will increase PT, PTT with no change in platelet count. It is used in early MI, early ischemic stroke, direct thrombolysis of severe PE. Toxicities include bleeding. It is contraindicated in patientswith active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
Tenecteplase
TNK-tPA. It helps with the conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. They will increase PT, PTT with no change in platelet count. It is used in early MI, early ischemic stroke, direct thrombolysis of severe PE. Toxicities include bleeding. It is contraindicated in patientswith active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
Aspirin
It irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) enzyme by covalent acetylation. Platelets cannot synthesize new enzyme so the effect lasts until new platelets are produced, which causes an increase in bleeding time and a decrease of TXA2 and prostaglandins. There is no effect on PT or PTT. It is used as an antipyretic, analgesic, anti-inflammatory, and antiplatelet (by decreasing aggregation).
Aspirin toxicity
Toxicities include gastric ulceration, tinnitus (CNVIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Reye syndrome can occur in children with viral infection. Overdose initially causes hyperventilation and respiratory alkalosis, but transition to mixed metabolic acidosis-respiratory alkalosis.
Clopidogral
It inhibits platelet aggregation by irreversibly blocking ADP receptors. It prevents expression of glycoproteins IIb/IIIa on platelet surface. It is used for acute coronary syndrome; coronary stenting. There is a decrease incidence or recurrence of thrombotic stroke. Toxicities include thrombotic thrombocytopenic purpura (TTP).
Prasugrel
It inhibits platelet aggregation by irreversibly blocking ADP receptors. It prevents expression of glycoproteins IIb/IIIa on platelet surface. It is used for acute coronary syndrome; coronary stenting. There is a decrease incidence or recurrence of thrombotic stroke. Toxicities include thrombotic thrombocytopenic purpura (TTP).
Ticagrelor
It inhibits platelet aggregation by reversibly blocking ADP receptors. It prevents expression of glycoproteins IIb/IIIa on platelet surface. It is used for acute coronary syndrome; coronary stenting. There is a decrease incidence or recurrence of thrombotic stroke. Toxicities include thrombotic thrombocytopenic purpura (TTP).
Ticlopidine
It inhibits platelet aggregation by reversibly blocking ADP receptors. It prevents expression of glycoproteins IIb/IIIa on platelet surface. It is used for acute coronary syndrome; coronary stenting. There is a decrease incidence or recurrence of thrombotic stroke. Toxicities include neutropenia and thrombotic thrombocytopenic purpura (TTP).
Cilostazol
It is a phosphodiesterase III inhibitor, which increases cAMP in platelets, resulting in inhibition of platelet aggregation. It also causes vasodilation. It is used for intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), and angina prophylaxis. toxicities include nausea, headache, facial flushing, hypotension, and abdominal pain.
Dipyridamole
It is a phosphodiesterase III inhibitor, which increases cAMP in platelets, resulting in inhibition of platelet aggregation. It also causes vasodilation. It is used for intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), and angina prophylaxis. toxicities include nausea, headache, facial flushing, hypotension, and abdominal pain.
Abciximab
It binds to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abciximab is made from monoclonal antibody Fab fragments. It is used for unstable angina, percutaneous transluminal coronary angioplasty. Toxicities include bleeding and thrombocytopenia.
Eptifibatide
It binds to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. It is used for unstable angina, percutaneous transluminal coronary angioplasty. Toxicities include bleeding and thrombocytopenia.
Tirofiban
It binds to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. It is used for unstable angina, percutaneous transluminal coronary angioplasty. Toxicities include bleeding and thrombocytopenia.
Cancer drugs that inhibit G2
bleomycin, etoposide, teniposide
Cancer drugs that inhibit DNA synthesis
etoposide, teniposide, and antimetabolites (azathrioprine, cladribine, cytarabine, 5-fluorouracil, hydroxyurea, methotrexate, 6-mercaptopurine, and 6-thioguanine)
Cancer drugs that inhibit mitosis
Microtubule inhibitors (paclitaxel), vinca alkaloids (vinblastine and vincristine)
Cancer drugs that inhibit G1
Alkylating agents and nitrosoureas (carmustine, cisplatin, and lomustine)
Cancer drugs that decrease thymidine synthesis
Mthotrexate and 5-fluorouracil
Cancer drugs that decrease de novo purine synthesis
6-mercaptopurine
Cancer drugs that inhibit ribonucleotide reductase
hydroxyurea
Cancer drugs that cross link DNA
alkylating agents and cisplatin
Cancer drugs that break DNA strands
bleomycin
Cancer drugs that intercalates DNA
Dactinomycin and doxorubicin
Cancer drugs that inhibit topoisomerase II
Etoposide
Cancer drugs that inhibit topoisomerase I
Irinotecan
Cancer drugs that inhibit microtubule formation
Vinca alkaloids
Cancer drugs that microtubule disassembly
Paclitaxel
Azathioprine
A purine (thiol) analog, which decreases de novo purine synthesis. It is activated by HGPRT. It is metabolized into 6-mercaptopurine. It is used in preventing organ rejection, rheumatoid arthritis, IBD, and SLE. It is also used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease. Toxicities include myelosuppression, GI, and liver problems. It is metabolized by xanthine oxidase and therefore has an increase toxicity with allopurinol or febuxostat.
6-mercaptopurine (6-MP)
A purine (thiol) analog, which decreases de novo purine synthesis. It is activated by HGPRT. It is used in preventing organ rejection, rheumatoid arthritis, IBD, and SLE. It is also used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease. Toxicities include myelosuppression, GI, and liver problems. It is metabolized by xanthine oxidase and therefore has an increase toxicity with allopurinol or febuxostat.
6-thioguanine (6-TG)
A purine (thiol) analog, which decreases de novo purine synthesis. It is activated by HGPRT. It is used in preventing organ rejection, rheumatoid arthritis, IBD, and SLE. It is also used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease. Toxicities include myelosuppression, GI, and liver problems.
Cladribine (2-CDA)
It is a purine analog that causes inhibition of DNA polymerase and breaking of DNA strands). It is used to treat Hairy cell leukemia. Toxicities include myelosuppression, nephrotoxicity, and neurotoxicity.
Cytarabine (arabinofuranosyl cytidine)
It is a pyrimidine analog that inhibits DNA polyermase. It is used to treat leukemia (AML) and lymphomas. Toxicities include leukopenia, thrombocytopenia, megaloblastic anemia. CYTarabine causes panCYTopenia.
5-fluorouracil (5-FU)
A prymidine analog that is bioactivated to 5f-dUMP, which covalently complexes folic acid. This complex that inhibits thymidylate synthase, which decreases dTMP and therefore decreasing DNA synthesis. It is used to treat colon cancer, pancreatic cancer, and basal cell carcinoma (topical). Toxicity includes myelosuppression, which is not reversible with leucovorin (folinic acid).
Methotrexate (MTX)
A folic acid analog that competitively inhibits dihydrofolate reductase, which decreases dTMP and thereby decreasing DNA synthesis. It is used to neoplastic conditions such as treat leukemias (ALL), lymphoma, choriocarcinoma, sarcomas. It is also used to treat ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, and vasculitis. Toxicities include myelosuppression, which is reversible with leucocorin (folinic acid). It can also cause hepatotoxicity, mucositis (eg mouth ulcers), and pulmonary fibrosis.
Cancer drugs that inhibit thymidylate synthase
5-fluorouracil (5-FU), which prevents dUMP with CH2-THF being converted into dTMP.
Cancer drugs that inhibit dihydrofolate (DHF) reductase
Methotrexate (MTX), which prevents dihydrofolate (DHF) to be converted into tetrahydrofuran (THF)
Bleomycin
It induces free radical formation leading to breaks in DNA strands. It is used to treat testicular cancer, Hodgkin lymphoma. Toxicities include pulmonary fibrosis, skin hyperpigmentation, and mucositis. There is minimal myelosuppression.
Dactinomycin (actinomycin D)
It intercalates in DNA. It is used to treat Wilms tumor, Ewing sarcoma, rhabdomyosarcoma. It is used for childhood tumors (children ACT out). Toxicity includes myelosuppression.
Doxorubicin
It generates free radicals, which intercalate DNA causing breaks in DNA and decreasing replication. It is used to treat solid tumors, leukemia, and lymphomas. Toxicities include cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. It is toxic to tissues following extravastion. Dexrazoxane (iron chelating agent) is used to prevent cardiotoxicity.
Daunorubicin
It generates free radicals, which intercalate DNA causing breaks in DNA and decreasing replication. It is used to treat solid tumors, leukemia, and lymphomas. Toxicities include cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. It is toxic to tissues following extravastion. Dexrazoxane (iron chelating agent) is used to prevent cardiotoxicity.
Busulfan
It cross links DNA. It is used to treat CML. It is also used to ablate patients bone marrow before bone marrow transplantation. Toxicities include severe myelosuppression (in almost all cases), pulmonary fibrosis, and hyperpigmentation.
Cyclophosphamide
It cross-link DNA at guanine N-7. It requires bioactivation by the liver. It is used to treat solid tumors, leukemia, lymphomas. Toxicity includes myelosuppression and hemorrhagic cystitis, which can be partially prevented with mesna (thiol group of mesna binds toxic metabolites).
Ifosfamide
It cross-link DNA at guanine N-7. It requires bioactivation by the liver. It is used to treat solid tumors, leukemia, lymphomas. Toxicity includes myelosuppression and hemorrhagic cystitis, which can be partially prevented with mesna (thiol group of mesna binds toxic metabolites).
Nitrosoureas (carmustine, lomustine, semustine, streptozocin)
It requires bioactivation. It crosses the blood-brain barrier into the CNS and cross-link DNA. It is used to brain tumors (including glioblastoma multiforme). Toxicities include CNS toxicity (convulsions, dizziness, and ataxia).
Paclitaxel and other taxols
It hyperstabilizes polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur). It is TAXing to break down microtubules. It is used to treat ovarian and breast carcinomas. Toxicities include myelosuppression, alopecia, and hypersensitivity.
Vincristine
It is a vinca alkaloids that bind beta-tubulin and inhibit its polymerization into microtubules and thereby preventing mitotic spindle formation (M-phase arrest). It is used to treat solid tumors, leukemias, and non-Hodgkin lymphomas. Toxicities include neurotoxicity (areflexia, peripheral neuritis) and paralytic ileus.
Vinblastine
It is a vinca alkaloids that bind beta-tubulin and inhibit its polymerization into microtubules and thereby preventing mitotic spindle formation (M-phase arrest). It is used to treat solid tumors, leukemias, and Hodgkin lymphomas. VinBLASTine blasts bone marrow (suppression).
Cisplatin
It cross-links DNA. It is used to treat testicular, bladder, ovary, and lung carcinomas. Toxicities include nephrotoxicity and ototoxicity. Amifostine (a free radical scavenger) can prevent the nephrotoxicity and chloride (saline) diuresis.
Carboplatin
It cross-links DNA. It is used to treat testicular, bladder, ovary, and lung carcinomas. Toxicities include nephrotoxicity and ototoxicity. Amifostine (a free radical scavenger) can prevent the nephrotoxicity and chloride (saline) diuresis.
Etoposide
eTOPOside inhibits TOPOisomerase II, leading to DNA degradation. It is used to treat solid tumors (particularly testicular and small cell lung cancer), leukemias, and lymphomas. Toxicities include include myelosuppression, GI upset, and alopecia.
Teniposide
It inhibits topoisomerase II, leading to DNA degradation. It is used to treat solid tumors (particularly testicular and small cell lung cancer), leukemias, and lymphomas. Toxicities include include myelosuppression, GI upset, and alopecia.
Irinotecen
It inhibits topoisomerase I and prevents DNA unwinding and replication. It is used to treat colon cancer. Toxicities include severe myelosuppression and diarrhea.
Topotecan
It inhibits topoisomerase I and prevents DNA unwinding and replication. It is used to treat ovarian and small cell lung cancer. Toxicities include severe myelosuppression and diarrhea.
Hydroxyurea
It inhibits ribonucleotide reductase, leading to a decrease in DNA Synthatesis (S-phase specific). It is used to treat melanoma, CML, sickle cell disease (it increases HbF). Toxicities include severe myelosuppression and GI upset.
Prednisone
There are various mechanism of action including binding of intracytoplasmic receptor and altering gene transcription. It is one of the most commonly used glucocorticoids in cancer chemotherapy. It is used to treat CLL, non-Hodgkin lymphoma (part of combination chemotherapy regimen). Also is used as an immunosuppressants (eg in autoimmune disease). Toxicities include cushing like symptoms, weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosism hypertension, peptic ulcers, hyperglycemia, and psychosis.
Prednisolone
There are various mechanism of action including binding of intracytoplasmic receptor and altering gene transcription. It is one of the most commonly used glucocorticoids in cancer chemotherapy. It is used to treat CLL, non-Hodgkin lymphoma (part of combination chemotherapy regimen). Also is used as an immunosuppressants (eg in autoimmune disease). Toxicities include cushing like symptoms, weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosism hypertension, peptic ulcers, hyperglycemia, and psychosis.
Bevacizumab
It is a monoclonal antibody against VEGF, which inhibits angiogenesis. It is used to treat solid tumors such as colorectal cancer and renal cell carcinoma. Toxicity includes hemorrhage, blood clots, and impaired wound healing.
Erlotinib
It inhibits EGFR tyrosine kinase and is used to treat non-small cell lung carcinoma. Toxicity includes rash.
Imatinib
It is a tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors). Toxicity includes fluid retention.
Rituximab
It is a monoclonal antibody against CD20, which is found on most B-cell neoplasms. it is used to treat non-hodgkin lymphoma, CLLm IBD, rheumatoid arthritis. Toxicity includes an increase risk of progressive multifocal leukoencephalopathy.
Tamoxifen
It is a selective estrogen receptor modulator (SERMs)- a receptor antagonist in breast and an agonist in bone. It blocks the binding of estrogen to ER positive cells. It is used to treat breast cancer and prevention. There is toxicity due to it being a partial agonist in endometrium, which increases the risk of endometrial cancer and causes hot flashes.
Raloxifene
It is a selective estrogen receptor modulator (SERMs)- a receptor antagonist in breast and an agonist in bone. It blocks the binding of estrogen to ER positive cells. It is used to prevent osteoporosis. There is no increase in endometrial carcinoma because it is an estrogen receptor antagonist in endometrial tissue.
Trastuzumab (Herceptin)
It is a monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. It helps kill cancer cells that overexpress HER-2, through inhibition of HER-2 initiated cellular signaling and antibody-dependent cytotoxicity. It is used to treat HER-2 positive breast cancer and gastric cancer. It can cause cardiotoxicity (Heartceptin damages the heart).
Vemurafenib
It is a small molecule inhibitor of BRAF oncogene positive melanoma and is used to treat metastatic melanoma.
Cancer drugs that cause acoustic nerve damage and nephrotoxicity
Cisplatin and carboplatin
Cancer drugs that cause peripheral neuropathy
Vincristine
Cancer drugs that cause pulmonary fibrosis
Bleomycin and busulfan
Cancer drugs that cause cardiotoxicity
Doxorubicin and trastuzumab
Cancer drugs that cause hemorrhagic cystitis
Cyclophosphamide
Cancer drugs that cause myelosuppression
Methotrexate, 5-FU and 6-MP
