Flashcards in Hematology/Oncology Deck (173):
Agranulocytosis (drug reaction)
Aplastic anemia (drug reaction)
Direct Coombs-positive hemolytic anemia (drug reaction)
Gray Baby Syndrome (drug reaction)
Hemolysis in G6PD deficiency (drug reaction)
Megaloblastic anemia (drug reaction)
Thrombocytopenia (drug reaction)
Thrombotic complications (drug reaction)
hormone replacement therapy
Carries O2 to tissues and CO2 to lungs.
Anucleate and biconcave, with large surface area-to-volume ratio for rapid gas exchange.
Life span = 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
Polycythemia = portion of blood occupied by RBCs is higher
Erythrocytosis = polycythemia = higher hematocrit
Anisocytosis = varying sizes
Poikilocytosis = varying shapes
Reticulocyte = immature RBC; reflects erythroid proliferation
Involved in primary hemostasis. Small cytoplasmic fragment derived from megakaryocytes.
Life span = 8-10 days. When activated by endothelial injury, aggregates with other platelets and interacts with fibrinogen to form a platelet plug.
Contains dense granules (ADP, Ca) and alpha granules (vWF, fibrinogen).
About 1/3 of platelet pool is stored in spleen.
Thrombocytopenia (low platelet function) results in petechiae
vWF receptor: Gp1b
Fibrinogen receptor: Gp2b/3a
Divided into granulocytes (N, E, B) and mononuclear cells (M, L). Responsible for defense against infections. Normally 4000 - 10,000 cells/mm3
Differential from highest to lowest
Acute inflammatory response cell. Increased in bacterial infections. Phagocytic. Multilobed nucleus.
Specific granules contain ALP, collagenase, lysozyme, and lactoferrin. Azurophilic granules (lysosomes) contain proteinases, acid phosphatase, myeloperoxidase, and B-glucuronidase.
Hypersegmented polys (5 or more lobes) are seen in vitamin B12/folate deficiency
Increased band cells (immature neutrophils) reflect states of higher myeloid proliferation (bacterial infection, CML)
Important neutrophil chemotactic agents: C5a, IL-8, LTB4, kallikrein, platelet-activating factor
Differentiates into macrophage in tissues.
Large, kidney-shaped nucleus. Extensive "frosted glass" cytoplasm
It's a monocyte in the blood. Macro in tissues.
Phagocytoses bacteria, cellular debris, and senescent RBCs.
Long life in tissues. Macrophages differentiate from circulating blood monocytes. Activated by gamma interferon. Can function as antigen presenting cell via MHCII
Important component of granuloma formation (TB, sarcoidosis)
Lipid A from bacterial LPS binds CD14 on macrophages to initiate septic shock
Defends against helminthic infections (major basic protein).
Bilobate nucleus. Packed 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:
3) Allergic processes
4) Chronic adrenal insufficiency
5) Parasites (invasive)
Mediates allergic reaction. Densely basophilic granules contain heparin (anticoagulant) and histamine (vasodilator). Leukotrienes synthesized and released on demand.
Basophilia is uncommon, but can be a sign of myeloproliferative disease, particularly CML
Mediates allergic reaction 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 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 1 hypersensitivity reactions.
Cromolyn sodium prevents mast cell degranulation (used for asthma prophylaxis)
Highly phagocytic APC. Functions as link between innate and adaptive immune systems. Expresses MHC II and Fc receptors on surface.
Called Langerhans Cell in the skin
Refers to B cells, T cells, NK cells.
B and T mediate adaptive immunity.
NK are part of innate immune response.
Round, densely staining nucleus with small amounts of pale cytoplasm.
Part of 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 function as an APC via MHCII
CD19, CD20, CD21
Mediates cellular immune response. Originates from stem cells in bone marrow, but matures in the thymus. T cells differentiate into cytotoxic T cells (express CD8, recognize MHC1), helper T cells (CD4, recognize MHC2), and regulatory T cells.
CD28 (costimulatory signal) is necessary for T cell activation. The majority of circulating lymphocytes are T cells (80%)
CD4+ helper T cells are primary target of HIV
Th = CD3, CD4
Tc = CD3, CD8
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
Universal Donor of RBCs
Universal recipient of plasma
Universal Recipient of RBCs
Universal donor of plasma
Hemolytic disease of the newborn
IgM does not cross placenta; IgG does.
Rh(-) mothers exposed to fetal Rh(+) blood (often during delivery) may make anti-D IgG. In subsequent pregnancies, anti-D IgG crosses the placenta.
This leads to hemolytic disease of the newborn (erythroblastosis fetalis) in the next fetus that is Rh(+)
This is prevented by administration of RhoGAM to Rh (-) pregnant women during third trimester, which prevents maternal anti-Rh IgG production.
Rh(-) mothers have anti-D IgG only if previously exposed to Rh(+) blood.
Hemophilia A, B, C
A = factor 8 (XR)
B = factor 9 (XR)
C = factor 11 (AR)
Factor 10a anticoagulants
1) LMWH (greatest efficacy)
3) Direct 10a inhibitors (apixaban, rivaroxaban)
Factor 2a anticoagulants
2a = Thrombin
1) Heparin (greatest efficacy)
2) LMWH (dalteparin, enoxaparin)
3) Direct thrombin inhibitors (argatroban, bivalirudin, dabigatran)
Oxidized vitamin K becomes reduced vitamin K thanks to Epoxide reductase.
Reduced vitamin K acts as cofactor for conversion of immature 2, 7, 9, 10, C, S to mature forms.
Warfarin inhibits the enzyme Vitamin K epoxide reductase. Neonates lack enteric bacteria, which produce vitamin K
Vitamin K deficiency: Low synthesis of factors 2, 7, 9, 10, C, S
vWF carries/protects factor 8.
Protein C becomes activated Protein C via Thrombin-Thrombomodulin Complex (in endothelial cells).
Activated Protein C uses Protein S to cleave and inactivate 5a and 8a.
tPA converts plasminogen to plasmin which then leads to fibrinolysis (cleaves fibrin mesh, destroys coagulation factors)
Antithrombin inhibits activated forms of factors 2, 7, 9, 10, 11, 12.
Heparin enhances the activity of antithrombin.
Principal targets of antithrombin: thrombin and factor 10a
Factor 5 Leiden mutation produces a factor 5 resistant to inhibition by activated protein C.
tPA is used clinically as a thrombolytic
Platelet Plug formation (primary hemostasis)
1) Injury - endothelial damage leads to transient vasoconstriction via neural stimulation reflex and endothelin (released from damaged cell)
2) Exposure - vWF binds to exposed collagen. vWF is from Weibel-Palade bodies of endothelial cells and alpha-granules of platelets
3) Adhesion - Platelets bind vWF via Gp1b receptor at the site of injury only (specific). This induces a conformational change in platelets.
Platelets now release ADP and Ca (needed for coagulation cascade), as well as TXA2 (a derivative of platelet cycloxygenase). ADP helps platelets adhere to endothelium
4A) Activation - ADP binding to receptor induces Gp2b/3a expression at platelet surface.
4B) Aggregation - Fibrinogen binds Gp2b/3a receptors and links platelets.
There is a balance between
Pro-aggregation factors: TXA2 (released by platelets), reduced blood flow, and higher platelet aggregation
Anti-aggregation factors: PGI2 and NO (released by endothelial cells), higher blood flow, and lower platelet aggregation
This all leads to temporary plug that stops bleeding. It is unstable and easily dislodged. We then go on to secondary hemostasis - coagulation cascade
Formation of insoluble fibrin mesh
Aspirin inhibits cyclooxygenase (TXA2 synthesis)
Clopidogrel, Prasugrel and Ticlopidine inhibit ADP-induced expression of Gp2b/3a
Abiciximab, eptifibatide, and tirofiban inhibit Gp2b/3a directly
Ristocetin activates vWF to bind Gp1b. Failure of agglutination with ristocetin assay occurs in von Willebrand disease and Bernand-Soulier syndrome
1) Liver Disease
2) Abetalipoproteinemia (states of cholesterol dysregulation)
Acantho = spiny
1) Megaloblastic anemia (also hypersegmented PMNs)
2) Marrow failure
Sideroblastic anemia. Excess Fe in mitochondria = pathologic
3) HELLP Syndrome
4) Mechanical hemolysis (heart valve prosthesis)
Sickle Cell Anemia
Sickling occurs with dehydration, deoxygenation, and at high altitude
1) Hereditary spherocytosis
2) Drug and infection induced hemolytic anemia
Bone marrow infiltration (myelofibrosis)
RBC sheds a tear bc it's mechanically squeezed out of its home in the bone marrow
1) HbC disease
3) Liver disease
HALT said the Hunter to his target!
Oxidation of Hb-SH groups leads to Hb precipitation (Heinz bodies) with subsequent phagocytic damage to RBC membrane leading to bite cells.
1) G6PD deficiency.
2) Heinz body-like inclusions are seen in alpha-thalassemia
Basophilic nuclear remnants found in RBCs
They are normally removed from RBCs by splenic macrophages
seen in patients with functional asplenia or hyposplenia
1) Fe deficiency (late)
4) Pb poisoning
5) Sideroblastic anemia
1 and 2 may present as normocytic and progress to microcytic
Copper deficiency can cause a microcytic sideroblastic anemia
Anemia (MCV 80-100)
A) Nonhemolytic (Reticulocyte count normal or low)
- Aplastic anemia
- Chronic kidney disease
- Fe deficiency (early)
B) Hemolytic (Reticulocyte count high)
- RBC membrane defect
- RBC enzyme deficiency (G6PD, pyruvate kinase)
- HbC Defect
- Paroxysmal nocturnal hemoglobinuria
- Sickle cell anemia
Anemia (MCV > 100)
- Folate deficiency
- B12 deficiency
- Orotic aciduria
- Liver disease
Iron deficiency anemia
Low Fe due to chronic bleeding (GI loss, menorrhagia), malnutrition/absorption disorders, or higher demand (pregnancy) leads to reduction in final step of heme synthesis.
Low Fe, High TIBC, Low Ferritin.
Fatigue, conjunctival pallor, spoon nails (koilonychia)
Microcytosis and hypochromia (central pallor). May manifest as Plummer-Vinson Syndrome (triad of Fe deficiency anemia, esophageal webs, atrophic glossitis)
Triad of Fe deficiency anemia, esophageal webs, atrophic glossitis
Defect = alpha globin gene deletions leading to lower alpha globin synthesis.
cis deletion prevalent in Asians
trans deletion in blacks
1) 4 allele deletion: No a-globin. Excess gamma globin (y-globin) forms y4 (Hb Barts). Incompatible with life - causes hydrops fetalis
2) 3 allele deletion: HbH disease. Very little a-globin. Excess B-globin forms B4 (HbH)
3) 1-2 allele deletion: Less clinically severe anemia
Point mutations in splice sites and promoter sequences leads to lower B-globin synthesis. Prevalent in Mediterranean populations.
1) B-Thalassemia minor (heterozygote)
Beta chain is underproduced. Usually asymptomatic. Diagnosis confirmed by high HbA2 (more than 3.5%) on electrophoresis
2) Major (homozygote)
Beta chain is absent leading to severe anemia requiring blood transfusion (secondary hemochromatosis).
Marrow expansion ("crew cut" on skull XR) leads to skeletal deformities - "Chipmunk" facies
Extramedullary hematopoiesis (leads to hepatosplenomegaly). Higher risk of parvovirus B19-induced aplastic crisis.
Major leads to higher HbF (a2y2). HbF is protective in the infant and disease becomes symptomatic only after 6 months.
3) HbS/B-Thalassemia heterozygote
Mild to moderate sickle cell disease depending on amount of B-globin production
A microcytic anemia
Lead inhibits ferrochelatase and ALA dehydratase leading to lower heme synthesis and higher RBC protoporphyrin
Also inhibits rRNA degradation causing RBCs to retain aggregates of rRNA (basophilic stippling)
high risk in old houses with chipped paint
L = Lead Lines on gingivae (Burton Lines) and on metaphyses of long bones on XR
E = Encephalopathy and Erythrocyte basophilic stippling
A = Abdominal colic and sideroblastic Anemia
D = Drops - wrist and foot drop. Dimercaprol and EDTA are 1st line Tx
Succimer used for chelation for kids.
Defect in heme synthesis. Hereditary X-linked defect in delta-ALA synthase gene.
Causes: Genetic, Acquired (myelodysplastic syndromes), and Reversible (alcohol is most common; also lead, B6 deficiency, Cu deficiency, isoniazid)
Ringed sideroblasts (with Fe-laden, Prussian blue-stained mitochondria) seen in bone marrow
Increased Fe, normal/low TIBC, high ferritin
Tx = pyridoxine (B6, cofactor for ALA synthase)
Impaired DNA synthesis leads to maturation of nucleus of precursor cells in bone marrow relative to maturation in cytoplasm.
RBC macrocytosis with hypersegmented neutrophils + glossitis
Causes: malnutrition (alcoholics), malabsorption, drugs (methotrexate, trimethoprim, phenytoin), increased requirement (hemolytic anemia, pregnancy)
You see: High homocysteine, normal methylmalonic acid, NO NEURO symptoms (vs B12)
B12 (cobalamin) deficiency
Causes: Insufficient intake (veganism), malabsorption (Crohn disease), pernicious anemia, Diphyllobothrium latum (fish tapeworm), gastrectomy
You see: High homocysteine, high methylmalonic acid
NEURO: subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis): spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction.
Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) bc of defect in UMP Synthase.
Autosomal recessive. Presents in children as failure to thrive, developmental delay, and megaloblastic anemia refractory to folate and B12.
No hyperammonemia (vs ornithine transcarbamylsae deficiency leading to high orotic acid with hyperammonemia)
You see: Orotic acid in urine.
Tx = uridine monophosphate to bypass mutated enzyme
Nonmegaloblastic macrocytic anemias
Macrocytic anemia in which DNA synthesis is unimpaired.
Causes: alcoholism, liver disease, hypothyroidism, reticulocytosis.
RBC macrocytosis without hypersegmented neutrophils
Normocytic, normochromic anemia
Normocytic, normochromic 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 the location of the hemolysis (intravascular vs extravascular)
You'd find low haptoglobin, high LDH, schistocytes and high reticulocytes on blood smear.
Characteristic hemoglobinuria, hemosiderinuira, and urobilinogen in urine.
Notable causes are mechanical hemolysis (prosthetic valves), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias.
Macrophages in spleen clear RBCs. Spherocytes in peripheral smear, high LDH, no hemoglobinuria/hemosiderinuria, high unconjugated bilirubin, which can cause jaundice.
Anemia of chronic disease
Nonhemolytic, normocytic anemia
Inflammation leads to high hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport)
This leads to depressed release of iron from macrophages. Associated with conditions such as RA, SLE, neoplastic disorders, and chronic kidney disease
Findings: Low Iron, Low TIBC, High ferritin
Normocytic, but can become microcytic
Tx = EPO (chronic kidney disease only)
Nonhemolytic, normocytic anemia
Caused by failure or destruction of myeloid stem cells due to:
1) Radiation and drugs (Benzene, alkylating agents, chloramphenicol, antimetabolites)
2) Viral agents (parvo B19, EBV, HIV, HCV)
3) Fanconi anemia (DNA repair defect)
4) Idiopathic (immune mediated, primary stem cell defect); may follow acute hepatitis
Pancytopenia characterized by severe anemia, leukopenia, and thrombocytopenia. Normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone marrow tap)
Symptoms: Fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection
Tx = Withdrawal of offending agent, immunosuppressive regimens (antithymocyte globulin, cyclosporine), bone marrow allograft, RBC/platelet transfusion, bone marrow stimulation (GM-CSF)
Hemolytic anemia - Intrinsic - Extravascular
Defect in proteins interacting with RBC membrane skeleton and plasma membrane (ankyrin, band 3, protein 4.2, spectrin)
Results in small, round RBCs with less surface area and no central pallor (high MCHC, high red cell distribution width) leading to premature removal by spleen
Findings: Splenomegaly, aplastic crises (parvo B19 infection).
Labs: osmotic fragility test (+). Normal to low MCV with abundance of cells.
Tx = splenectomy
hemolytic anemia - Intrinsic - Intra/Extravascular
Most common enzymatic disorder of RBCs
Defect in G6PD leads to low glutathione leading to high RBC susceptibility to oxidant stress. hemolytic anemia following oxidant stress (sulfa drugs, antimalarials, infections, fava beans)
Back pain, hemoglobinuria a few days after oxidant stress
Blood smear shows RBCs with Heinz Bodies and Bite Cells
Pyruvate kinase deficiency
Hemolytic anemia - intrinsic - Extravascular
Autosomal recessive. Defect in pyruvate kinase leads to lower ATP leading to rigid RBCs
Hemolytic anemia in a newborn*
Hemolytic anemia - Intrinsic - Extravascular
Glutamic acid to lysine mutation in B-globin
Patients with HbSC (1 of each mutant gene) have milder disease than HbSS patients.
Paroxysmal nocturnal hemoglobinuria
Hemolytic anemia - Intrinsic - Intravascular
Increased complement-mediated RBC lysis (impaired synthesis of GPI anchor for decay-accelerating factor that protects RBC membrane from complement)
Acquired mutation in a hematopoietic stem cell. Higher incidence of acute leukemias.
Triad: Coombs (-) hemolytic anemia, pancytopenia, and venous thrombosis.
Labs: CD55/59 (-) RBCs on flow cytometry
Tx = eculizumab (terminal complement inhibitor)
Sickle Cell Anemia
Hemolytic anemia - Intrinsic - Extravascular
HbS point mutation causes a single amino acid replacement in B chain (substitution of glutamic acid with valine)
Pathogenesis: Low O2, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerizes) leading to anemia and vaso-occlusive disease.
Newborns are initially asymptomatic bc of increased HbF and lower HbS.
Heterozygotes (sickle cell trait) also have resistance to malaria.
8% of blacks carry an HbS allele.
Sickle cells are crescent shaped RBCs.
"Crew Cut" on skull XR due to marrow expansion from increased erythropoiesis (also seen in thalassemias)
1) Aplastic crisis (due to Parvo B19)
2) Autosplenectomy (Howell-Jolly bodies) leading to increased risk of infections by encapsulated organisms
3) Splenic infarct/sequestration crisis
4) Salmonella osteomyelitis
5) Painful crises (vaso-occlusive): dactylitis (painful swelling of hands/feet), acute chest syndrome, avascular necrosis, stroke.
6) Renal papillary necrosis (low P O2 in papilla) and microhematuria (medullary infarcts)
Dx: hemoglobin electrophoresis
Tx = hydroxyurea (increases HbF), hydration
Autoimmune hemolytic anemia
Hemolytic anemia - Extrinsic
1) Warm agglutinin (IgG) - chronic anemia seen in SLE and CLL and with certain drugs (alpha methyldopa)
2) Cold agglutinin (IgM) - acute anemia triggered by cold; seen in CLL, Mycoplasma pneumonia infections and infectious Mononucleosis
Many warm and cold AIHAs are idiopathic in etiology
Autoimmune hemolytic anemia is usually Coombs (+)
Direct and Indirect Coombs test
Direct Coombs - anti-Ig antibody (Coombs reagent) added to patient's blood. RBCs agglutinate if RBCs are coated with Ig.
Indirect Coombs - normal RBCs added to patient's serum. If serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent added.
Hemolytic anemia - Extrinsic
RBCs are damaged when passing through obstructed or narrowed vessel lumina. Seen in DIC, TTP/HUS, SLE, and malignant HTN
Schistocytes are seen on blood smear due to mechanical destruction of RBCs
Hemolytic anemia - Extrinsic
Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia secondary to mechanical destruction.
Schistocytes on peripheral smear
Infections and anemia
Hemolytic - Extrinsic
Increased destruction of RBCs (malaria, Babesia)
Differentiating various anemias with labs
1) Iron Deficiency
Low Fe (primary)
Much lower % transferrin saturation (Fe/TIBC)
2) Chronic Disease
Low Transferrin/TIBC (pathogens use circulating iron to thrive. The body has adapted a system in which Fe is stored within cells of body and prevents pathogens from acquiring circulating Fe)
High Ferritin (Primary)
Flat % transferrin saturation (Fe/TIBC)
High Fe (Primary)
Much higher %transferrin saturation (Fe/TIBC)
4) Pregnancy/OCP use
High Transferrin/TIBC (Primary)
Low % Transferrin saturation (Fe/TIBC)
Transferrin transports Fe in the blood
TIBC - indirectly measures transferrin
Ferritin - primary Fe storage protein in body
Absolute neutrophil count
Absolute lymphocyte count
1) Cushing Syndrome
Heme synthesis, porphyrias, and lead poisoning
The porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the accumulation of heme precursors.
Lead inhibits specific enzymes needed in heme synthesis, leading to a similar condition.
Lead poisoning (enzyme targeted)
Enzyme: Ferrochelatase and ALA Dehydratase
Accumulation of: Protoporphyrin, Delta-ALA (blood)
Microcytic anemia (basophilic stippling), GI and kidney disease
Children - exposure to lead paint leads to mental deterioration
Adults - environmental exposure (batteries, ammunition) leads to HA, memory loss, demyelination
Acute Intermittent Porphyria
Enzyme: Porphobilinogen deaminase
Symptoms = 5 P's
1) Painful abdomen
2) Port wine-colored urine
4) Psychological disturbances
5) Precipitated by drugs (cytochrome P450 inducers), alcohol, starvation
Tx = glucose and heme, which inhibit ALA Synthase
Porphyria Cutanea Tarda
Enzyme: Uroporphyrinogen Decarboxylase
Accumulation of: Uroporphyrin (tea-colored urine)
Blistering cutaneous photosensitivity. Most common porphyria***
High mortality rate with accidental ingestion by children (adult iron tablets may look like candy)
Cell death due to peroxidation of membrane lipids
Nausea, vomiting, gastric bleeding, lethargy, scarring leading to GI obstruction
Tx = Chelation (IV deferoxamine, oral deferasirox) and dialysis
Tests function of common and extrinsic pathway (1, 2, 5, 7, 10).
Coagulation disorder = high PT
Partial Thromboplastin Time
Tests function of common and intrinsic pathway (all factors but 7 and 13)
Coagulation disorder = high PTT
Hemophilia A, B, C (more detail)
Intrinsic pathway coagulation defect.
1) A - deficiency in factor 8 leads to high PTT (X-Recess)
2) B - deficiency of factor 9 leads to high PTT (XR)
3) C - deficiency of factor 11 leads to high PTT (AR)
Macrohemorrhage in hemophilia - hemarthroses (bleeding into joints, such as knee), easy bruising, bleeding after trauma or surgery (dental procedures)
Tx = desmopressin + factor 8 concentrate (A); factor 9 concentrate (B), factor 11 concentrate (C)
Vitamin K deficiency (PT, PTT)
General coagulation defect. Bleeding time normal. Lower activation of factors 2, 7, 9, 10, C, and S
Defects in platelet plug formation leads to increased bleeding time (BT)
Platelet abnormalities lead to microhemorrhage; mucous membrane bleeding, epistaxis, petechiae, purpura. Increased BT, possibly decreased platelet count (PC)
1) Bernard-Soulier Syndrome
2) Glanzman Thrombasthenia
3) Immune Thrombocytopenia
4) Thrombotic Thrombocytopenic Purpura
Defect in platelet plug formation. Large platelets.
Low Gp1b leads to defect in platelet-to-vWF adhesion.
No agglutination on ristocetin cofactor assay
Defect in platelet plug formation
Low Gp2b/3a leads to defect in platelet-to-platelet aggregation
Blood smear shows no platelet clumping
Agglutination with ristocetin cofactor assay
Anti-Gp2b/3a antibodies leads to splenic macrophage consumption of platelet-antibody complex.
Commonly due to viral illness.
Labs show high megakaryocytes on bone marrow biopsy
Tx = steroids, IV IG (intravenous immunoglobulin)
Thrombotic Thrombocytopenic Purpura
Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease) leads to lower degradation of vWF multimers
Elevated large vWF multimers leads to increased platelet adhesion leading to more platelet aggregation and thrombosis.
Labs: Schistocytes, High LDH
Symptoms: Pentad of
1) Neuro symptoms
2) Renal symptoms
5) Microangiopathic hemolytic anemia
Tx = plasmapheresis and steroids
What are the mixed platelet and coagulation disorders?
von Willebrand Disease
von Willebrand Disease
High PTT (may be normal/flat too)
Intrinsic pathway coagulation defect: Low vWF leads to high PTT (vWF acts to carry/protect factor 8)
Defect in platelet plug formation: Low vWF leads to defect in platelet-to-vWF adhesion.
Mild but most common inherited bleeding disorder. Diagnosed in most cases by ristocetin cofactor assay (lower agglutination is diagnostic)
Tx = desmopressin, which releases vWF stored in endothelium
Widespread activation of clotting leads to deficiency in clotting factors leading to bleeding state
Causes: STOP Making New Thrombin
S = Sepsis (gram neg)
T = Trauma
O = Obstetric complications
P = Pancreatitis
M = Malignancy
N = Nephrotic Syndrome
T = Transfusion
Labs: Schistocytes, high fibrin split products (D-Dimers), low fibrinogen, low factors 5 and 8.
Hereditary thrombosis syndromes leading to hypercoagulability
1) Antithrombin deficiency
2) Factor 5 Leiden
3) Protein C or S deficiency
4) Prothrombin gene mutation
Inherited deficiency of antithrombin
has no direct effect on PT, PTT or thrombin time but diminishes the increase in PTT following heparin administration
Can also be acquired: renal failure/nephrotic syndrome leads to antithrombin loss in urine leading to lower inhibition of factors 2a and 10a
Factor V Leiden
Production of mutant factor 5 that is resistant to degradation by activated protein C
Most common cause of inherited hyper-coagulability in whites
Protein C or S deficiency
Lower ability to inactivate factors 5a and 8a
Increased risk of thrombotic skin necrosis with hemorrhage following administration of warfarin
Skin and subcutaneous tissue necrosis after warfarin administration - think protein C deficiency
Protein C Cancels Coagulation
Prothrombin gene mutation
Mutation in 3' untranslated region leads to higher production of prothrombin which leads to high plasma levels and venous clots
Given for acute blood loss, severe anemia
Increases Hb and O2 carrying capacity
Increases platelet count (increase of 5000/mm3/unit)
Used to stop significant bleeding (thrombocytopenia, qualitative platelet defects)
Fresh frozen plasma
Increases coagulation factor levels
Immediate Warfarin reversal
Contains fibrinogen, factor 8, factor 13, vWF, and fibronectin
Use for: Coagulation factor deficiencies involving fibrinogen and factor 8.
Blood transfusion risks
1) Infection transmission (low)
2) Transfusion reactions
3) Fe overload
4) Hypocalcemia (citrate is a Ca Chelator)
5) Hyperkalemia (RBCs may lyse in old blood units)
Leukemia vs Lymphoma
Leukemia: lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood.
Lymphoma: Discrete tumor mass arising from lymph nodes. Presentations often blur definitions
Acute inflammatory response to infection.
Increased WBC count with High neutrophils and neutrophil precursors such as band cells (left shift)
Increased leukocyte alkaline phosphatase (LAP)
Contrast with CML (also high WBC with left shift, but LOW LAP)
Localized, single group of nodes
Extranodal is rare
Contiguous spread (Stage is strongest predictor of prognosis)
Prognosis is much better than non-Hodgkin
Characterized by Reed-Sternberg Cells
Bimodal distribution - young adulthood and > 55 years; more common in men except for nodular sclerosing type
Strongly associated with EBV
Constitutional (B) signs/symptoms: Low-grade fever, night sweats, weight loss
Multiple, peripheral nodes
Extranodal involvement common
Majority involve B cells (except those of lymphoblastic T cell origin)
Peak incidence for certain subtypes at 20-40 yrs
May be associated with HIV and autoimmune diseases
Fewer constitutional signs/symptoms
Distinctive tumor giant cell seen in Hodkin disease
Binucleate or bilobed with the 2 halves as mirror images ("owl eyes"). RS cells are CD15+ and CD30+ B Cell origin.
Necessary but not sufficient for a diagnosis of Hodkin disease. Better prognosis with strong stromal or lymphocytic reaction against RS cells.
Nodular sclerosing form most common (affects women and men equally).
Lymphocyte rich form as best prognosis.
Lymphocyte mixed or depleted has worse prognosis
Non-Hodgkin lymphomas (6)
Neoplasms of mature B cells
1) Burkitt lymphoma
2) Diffuse Large B Cell Lymphoma
3) Follicular Lymphoma
4) Mantle Cell Lymphoma
Neoplasms of mature T cells
5) Adult T Cell Lymphoma
6) Mycosis Fungoides/Sezary Syndrome
A NH Lymphoma (B cells)
Adolescents or young adults
t(8;14) - translocation of c-myc (8) and heavy chain Ig (14)
"Starry Sky" appearance, sheets of lymphocytes with interspersed macrophages
Associated with EBV
Jaw lesion in endemic form in Africa; Pelvis or abdomen in sporadic form
Diffuse Large B-Cell Lymphoma
A NH Lymphoma (B Cells)
Usually in older adults, 20% in children
Most common type of NH Lymphoma in adults
A NH Lymphoma (B Cells)
t(14;18) - translocation of heavy chain Ig (14) and BCL-2 (18)
Indolent course; Bel-2 inhibits apoptosis. Presents with painless "waxing and waning" lymphadenopathy. Nodular, small cells; cleaved nuclei
Mantle Cell Lymphoma
A NH Lymphoma (B Cells)
t(11;14) - translocation of cyclin D1 (11) and heavy chain Ig (14)
Adult T Cell Lymphoma
A NH Lymphoma (T Cells)
Caused by HTLV - human t lymphotropic virus (associated IV drug abuse)
Adults present with cutaneous lesions; especially affects populations in Japan, West Africa, and the Caribbean
Lytic bone lesions; hypercalcemia
Mycosis Fungoides/Sezary Syndrome
A NH Lymphoma (T Cells)
Mycosis fungoides presents with skin patches/plaques (cutaneous T cell lymphoma), characterized by atypical CD4+ cells with "cerebriform" nuclei. May progress to Sezary Syndrome (T Cell Leukemia)
Monoclonal plasma cell (fried egg appearance) cancer that arises in the marrow and produces large amounts of IgG (55%) or IgA (25%). Most common primary tumor arising within bone in people older than 40-50 years old.
1) Higher susceptibility to infection
2) Primary amyloidosis
3) Punched out lytic bone lesions on XR
4) M Spike on serum protein electrophoresis
5) Ig light chains in urine (Bence Jones protein)
6) Rouleaux formation (RBCs stacked like poker chips in blood smear)
Numerous plasma cells with "clock face" chromatin and intracytoplasmic inclusions containing immunoglobulin
Bone lytic lesions/Back pain
Multiple Myeloma Monoclonal M protein spike
Monoclonal gammopathy of undetermined significance (MGUS)
Monoclonal expansion of plasma cells, asymptomatic, may lead to multiple myeloma
No CRAB findings (unlike MM)
Patients with NGUS develop multiple myeloma at rate of 1-2% per year.
M spike = IgM
Hyperviscosity syndrome (blurred vision, Raynaud phenomenon)
No CRAB findings (unlike MM)
Stem-cell disorders involving ineffective hematopoiesis leads to defects in cell maturation of all nonlymphoid lineages. Caused by de novo mutations or environmental exposure (radiation, benzene, chemotherapy). Risk of transformation to AML.
Pseudo-Pelger-Huet anomaly - neutrophils with bilobed nuclei. Typically seen after chemotherapy.
Unregulated growth and differentiation of WBCs in bone marrow leads to marrow failure leading to anemia (low RBCs), infections (low mature WBCs) and hemorrhage (low platelets). High or Low number of circulating WBCs
Leukemic cell infiltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible.
List the Leukemias (5)
1) Acute Lymphoblastic Leukemia/lymphoma (ALL)
2) Small lymphocytic lymphoma (SLL)/Chronic lymphocytic Leukemia (CLL)
3) Hairy Cell Leukemia
4) Acute myelogenous Leukemia (AML)
5) Chronic myelogenous Leukemia (CML)
Acute Lymphoblastic Leukemia/Lymphoma (ALL)
Age is less than 15
T Cell ALL can present as mediastinal mass (presenting as SVC-like syndrome). Associated with Down Syndrome
Peripheral blood and bone marrow have wayyyy higher lymphoblasts
TdT+ (marker of pre-T and pre-B cells), CD10+ (pre B cells only)
Most responsive to therapy
May spread to CNS and testes
t(12;21) = better prognosis
Small Lymphocytic Lymphoma (SLL)/ Chronic Lymphocytic Leukemia (CLL)
Age older than 60
Most common adult leukemia. CD20+ CD5+ B cell neoplasm.
Often asymptomatic, progresses slowly; smudge cells in peripheral smear; autoimmune hemolytic anemia
SLL same as CLL except CLL has increased peripheral blood lymphocytosis or bone marrow involvement
Hairy Cell Leukemia
Mature B Cell tumor in the elderly. Cells have filamentous, hair-like projections. Causes marrow fibrosis leading to dry tap on aspiration
Stains TRAP (Tartrate-resistant acid phosphatase +) TRAP stain largely replaced with flow cytometry.
Tx = cladribine, pentostatin
Acute Myelogenous Leukemia (AML)
Age: Median onset 65 years. Auer rods; peroxidase + cytoplasmic inclusions seen mostly in M3 subtype of AML; Much higher circulating myeloblasts on peripheral smear; adults.
Risk factors: Prior exposure to alkylating chemotherapy, radiation, myeloproliferative disorders, Down Syndrome. t(15;17) leads to M3 subtype - responds well to all-trans retinoic acid (Vitamin A), inducing differentiation of myeloblasts; DIC is a common presentation
Chronic Myelogenous Leukemia (CML)
Age: Peak incidence 45-85 years, median age at diagnosis is 64. Defined by Philadelphia Chromosome (t[9;22], BCR-ABL); myeloid stem cell proliferation; presents with increased neutrophils, metamyelocytes, basophils; splenomegaly; may accelerate and transform to AML or ALL ("blast crisis")
Very low LAP as a result of low activity in mature granulocytes (vs Leukemoid reaction, in which LAP is elevated)
Responds to imatinib (a small-molecule inhibitor of the bcr-abl tyrosine kinase)
1) t(8;14) = Burkitt Lymphoma
2) t(9;22) = Philadelphia = CML (BCR-ABL hybrid)
3) t(11;14) = Mantle Cell Lymphoma (cyclin D1 activation)
4) t(14;18) = Follicular Lymphoma (BCL-2 activation)
5) t(15;17) = M3 Subtype of AML - responds to all trans Retinoic Acid
Langerhans cell histiocytosis
Collective group of proliferative disorders of dendritic (Langerhans) cells. Presents in a child as lytic bone lesions and skin rash or 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
These disorders represent an often-overlapping 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)
Disorder of increased hematocrit, often associated with JAK2 mutation. May present as intense itching after hot shower (due to increased basophils).
Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of extremities
Secondary polycythemia is via natural or artificial increase in EPO levels.
Similar to polycythemia vera, but specific for overproduction of abnormal platelets leading to bleeding, thrombosis.
Bone marrow contains enlarged megakaryocytes
Obliteration of bone marrow due to increased fibroblast activity in response to proliferation of monoclonal cell lines
Teardrop RBCs and immature forms of the myeloid line.
"Bone marrow is crying bc it's fibrosed and is a dry tap"
Often associated with massive splenomegaly
Chronic Myeloproliferative Disorder findings
1) Polycythemia vera
(-) Philadelphia Chromosome
(+) JAK2 mutations
2) Essential thrombocytosis
(+) JAK2 (30-50%)
(+) JAK2 (30-50%)
Different Polycythemia findings
Low plasma volume
Normal RBC mass
Normal O2 Sat
Normal EPO levels
Associated with low plasma volume (dehydration, burns)
2) Appropriate Absolute
Normal plasma volume
High RBC mass
Low O2 Sat
Associated with Lung disease, congenital heart disease, high altitude
3) Inappropriate Absolute
Normal plasma volume
High RBC mass
Normal O2 Sat
Associated with RCC, hepatocellular carcinoma, hydronephrosis. Due to ectopic EPO.
4) Polycythemia vera
High plasma volume
Very high RBC mass
Normal O2 sat
Associated with: EPO is low in PCV due to negative feedback suppressing renal EPO production.
Activates antithrombin; lowers thrombin and lowers factor 10a. Short half life
Use: Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT. Used during pregnancy (does not cross placenta). Follow PTT levels.
Toxicity: Bleeding! Thombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin)
Low molecular weight heparins (enoxaprin, dalteparin) and fondaparinux act more on factor 10a, have better bioavailability, and 2-4 times longer half life; can be administered subcutaneously and without lab monitoring. Not easily reversible.
Heparin-Induced Thrombocytopenia (HIT)
development of IgG antibodies against heparin-bound platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets leading to thrombosis and thrombocytopenia
Argatroban, Bivalirudin, Dabigatran
Bivalirudin is related to hirudin, the anticoagulant used by leeches
Inhibits thrombin directly. Alternatives to heparin for anticoagulating patients with HIT
Interefers with y-carboxylation of Vit K-dependent clotting factors 2,7,9,10,C,S. Metabolism affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1).
In lab assay, has effect on extrinsic pathway and increases PT. Long half-life
Use: Chronic anticoagulation (venous thromboembolism prophylaxis, and prevention of stroke in AFib). Not used in pregnant women (crosses placenta). Follow PT/INR
Toxicity: Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions. Proteins C and S have shorter half-lives than clotting factors 2,7,9,10. This results in early transient hypercoagulability with Warfarin use. Skin/Tissue necrosis beleived to be due to small vessel microthromboses.
For reversal of warfarin, give Vit K
For rapid reversal, give fresh frozen plasma.
Heparin bridging: Heparin is frequently used when starting warfarin. Heparin's activation of antithrombin enables anticoagulation during initial, transient hypercoagulable state caused by warfarin. Initial heparin therapy reduces risk of recurrent venous thromboembolism and skin/tissue necrosis.
Site of action of Warfarin = Liver
Direct Factor 10a inhibitors
Bind to and directly inhibit 10a
Use: Tx and prophylaxis for DVT and PE (rivoraxaban); stroke prophylaxis in patients with AFib
Oral agents do not usually require coagulation monitoring
Toxicity: Bleeding (no reversal agent available)
Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. Increased PT and PTT. No change in Platelet count
Use: Early MI, early ischemic stroke, direct thrombolysis of severe PE
Toxicity: Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe HTN.
Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies
Irreversibly inhibits COX1 and COX2 by covalent acetylation. Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced: Increased BT, lower TXA2 and prostaglandins. No effect on PT or PTT
Use: Antipyretic, analgeic, anti-inflammatory, antiplatelet (lowers aggregation)
Gastric ulceration, tinnitus (CN 8). Chronic use can lead to acute renal failure, interstitial nephritis and upper GI bleeding.
Reye Syndrome in children with viral infection.
OD initially causes hyperventilation and respiratory alkalosis, but transitions to mixed metabolic acidosis-respiratory alkalosis
ADP receptor inhibitors
Inhibit platelet aggregation by irreversibly blocking ADP receptors. Prevent expression of glycoproteins 2b/3a on platelet surface
Use: Acute coronary syndrome, coronary stenting. Lowers incidence of recurrence of thrombotic stroke.
TTP may be seen.
Phosphodiesterase III inhibitors; raise cAMP in platelets, resulting in inhibition of platelet aggregation; vasodilators
Use: Intermittent claudication, coronary vasodilation, prevention of a stroke or TIAs (combined with aspirin), angina prophylaxis
Nausea, HA, facial flushing, hypotension, abdominal pain
Gp 2b/3a inhibitors
Bind to Gp 2b/3a on activated platelets, preventing aggregation. Abciximab is made from monoclonal antibody Fab fragments
Use: Unstable angina, percutaneous transluminal coronary angioplasty
Purine (thiol) analogs leading to reduced de novo purine synthesis. Activated by HGPRT. Azathioprine is metabolized into 6-MP.
Use: Preventing organ rejection, RA, IBD, SLE; used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease
Myelosuppression, GI, Liver. Azathioprine and 6-MP are metabolized by XO; thus both have higher toxicity with allopurinol or febuxostat.
Pure analog with multiple mechanisms (inhibition of DNA polymerase, DNA strand breaks)
Use: Hairy cell leukemia
Myelosuppression, nephrotoxicity, and neurotoxicity
Cytarabine (arabinofuranosyl cytidine)
Pyrimidine analog - inhibition of DNA polymerase
Use: Leukemias (AML), Lymphomas
Leukopenia, thrombocytopenia, megaloblastic anemia. So a pancytopenia
Pyrimidine analog bioactivated to 5F-dUMP which covalently complexes folic acid. This complex inhibits thymidylate synthase leading to lower dTMP and lower DNA synthesis
Use: Colon cancer, pancreatic cancer, basal cell carcinoma (topical)
Myelosuppression, which is not reversible with leucovorin (folic acid)
Folic acid analog that competitvely inhibits dihydrofolate reductase leading to lower dTMP leading to lower DNA Synthesis
Use: Cancers - Leukemias (ALL), Lymphomas, Choriocarcinoma, Sarcomas.
Nonneoplastic - ectopic pregnancy, medical abortion (with misoprostol), RA, psoriasis, IBD, vasculitis
Myelosuppression, which is reversible with leucovorin (folic acid) rescue.
Mucositis (mouth ulcers)
Induces free radical formation leading to breaks in DNA strands
Use: Testicular cancer, Hodgkin Lymphoma
Dactinomycin (Actinomycin D)
Intercalates in DNA
Use: Wilms Tumor. Ewing Sarcoma. Rhabdomyosarcoma. Used for childhood tumors
Generate free radicals. Intercalate into DNA leading to breaks in DNA leading to lower replication
Use: Solid tumors, leukemias, lymphomas
Cardiotoxic (dilated cardiomyopathy)
Toxic to tissues following extravasation
Dextrazoxane (iron chelating agent) used to prevent cardiotoxicity
Cross links DNA
Use: CML. Also to ablate patient's bone marrow before bone marrow transplantation
Severe myelosuppression (almost all cases)
Cross link DNA at Guanine N-7. Requires bioactivation by liver.
Use: Solid tumors, leukemia, lymphomas
Hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolites)
Alkylating agents, Nitrosoureas
Require bioactivation. Cross BBB into CNS. Cross link DNA
Use: Brain tumors (including glioblastoma multiforme)
CNS toxicity (convulsions, dizziness, ataxia)
Paclitaxel, other taxols
Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur)
Use: Ovarian and Breast carcinomas
vinca alkaloids that bind B-tubulin and inhibit its polymerization into microtubules leading to the prevention of mitotic spindle formation (M phase arrest)
Use: Solid tumors, leukemias, Hodgkin (Vinblastine) and non-Hodgkin (Vincristine) lymphomas
neurotoxicity - areflexia, periheral neuritis
blasts bone - marrow suppression
Cross link DNA
Use: Testicular, bladder, ovary, lung carcinomas
Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis
Etoposide inhibits topoisomerase II leading to more DNA degradation
Use: Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas
Inhibit topoisomerase I and prevent DNA unwinding and replication
Use: Colon cancer (irinotecan); ovarian and small cell lung (topotecan)
Inhibits ribonucleotide reductase leading to reduced DNA Synthesis (S-Phase specific)
Use: Melanoma, CML, sickle cell disease (raises HbF)
Various mechanisms. Binds intracytoplasmic receptor and alters gene transcription
Use: Most commonly used glucocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin (part of combo chemo regimen). Also used as immunosuppressants (in autoimmune diseases)
Cushing-like symptoms - weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosis, HTN, peptic ulcers, hyperglycemia, psychosis
Monoclonal antibody against VEGF. Inhibits angiogenesis
Use: Solid tumors (colorectal, RCC)
Hemorrhage, blood clots, impaired wound healing
EGFR tyrosine kinase inhibitor
Use: Non-small cell lung cancer
Tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors)
Use: CML, GI stromal tumors
Monoclonal antibody against CD20, which is found on most B cell neoplasms
Use: NH Lymphoma, CLL, IBD, RA
Higher risk of progressive multifocal leukoencephalopathy
Selective estrogen receptor modulators (SERMs) - receptor antagonists in breast and agonist in bone. Block the binding of estrogen to ER + cells.
Use: Breast cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent osteoporosis
Tamoxifen - partial agonist in endometrium - increases risk of endometrial cancer; hot flashes
Raloxifene - no increase in endometrial carcinoma bc it is an estrogen receptor antagonist in endometrial tissue
Monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER2, through inhibition of HER2-initiated cellular signaling and antibody-dependent cytotoxicity
use: HER2 + Breast cancer and gastric cancer
Small molecule inhibitor of BRAF oncogene + melanoma
Use: Metastatic melanoma