Heme/Onc Flashcards
What is the energy source for RBCs?
Glucose – undergo glycolysis. Cannot undergo TCA cycle and cannot use fatty acids or ketones since they do not have mitochondria
What activates macrophages?:
IFN gamma (released by Th1)
What Ig can cross the placenta?
IgG
Hemolytic disease of the newborn
in first pregnancy, Rh(-) mom with an Rh(+) fetus will make antibodies against Rh
o The first fetus is unaffected because IgM will not cross the placenta
o The next pregnancy (if Rh+) will be attacked because the anti Rh IgG will cross the placenta and target the fetal erythrocytes
o Tx: give Rh(-) mom anti-D IgG (RhoGAM) to prevent production of anti Rh IgG
What coag factors are affected by vitamin K deficiency?
2, 7, 9, 10
What vitamin deficiency can antibiotics cause?
Vitamin K deficiency → disruption of the vitamin K producing bacteria in the GI tract
Why do neonates need a shot of vitamin K after birth? What can happen if they dont receive this?
Newborns have an inherent lack of GI colonization and therefore can easily become Vitamin K deficient
Lack of clotting factors can lead to intraventricular hemorrhage
Liver failure and coagulation
The liver is responsible for making clotting factors → liver failure leads to dec production of clotting factors (will see bleeding)
Factor 5 Leiden
Autosomal dominant point mutation in F5, which makes it resistant to inactivation by Protein C → leads to thrombosis
Where does vWF come from?
vWF comes from the Weibel-Palade bodies of endothelial cells and a granules of platelets
vWF deficiency mechanism and treatment
most common inherited bleeding disorder (autosomal dominant)
o Normally, promotes platelet adhesion to subendothelial collagen through the GP1b receptor
Present with mucocutaneous bleeding
Is also responsible for carrying F8, so if it is deficient, there can be a deficiency in F8 –> inc aPTT
Treatment: vWF concentrate or desmopressin (DDAVP) – inc release of vWF and F8 from endothelial cells
What coag factors does Protein C/Protein S normally regulate?
F8 and F5
What coag factors does Antithrombin normally regulate?
Mainly thrombin and F10
Lupus anticoagulant aka Antiphospholipid antibody
Do patients present with bleeding or clotting
Clotting!
Patients have antiphospholipid antibody in serum and a hx of thrombosis or miscarriage
(Not always in Lupus patients)
How will a patient with a platelet disorder present?
mucocutaneous bleeding, petechiae, epistaxis, and inc bleeding time
6 year old child with a history of acute diarrhea presents with thrombocytopenia and renal failure. What do you suspect? How does this syndrome present?
Hemolytic Uremic Syndrome – thrombocytopenia, hemolytic anemia, and renal failure
Cytotoxin from bacteria (usually E coli and Shigella) causes endothelial damage and platelet aggregation → formation of microthrombi → decreased platelets and RBC lysis due to shearing
What type of RBCs do you see in a blood smear of someone with HUS or TTP?
Schistocytes – due to shearing
What causes thrombotic thrombocytopenic purpura?
TTP is caused by decreased ADAMTS13 enzyme – vWF isn’t cleaved to smaller monomers for degradation and instead the large strings of vWF cause abnormal platelet adhesion and formation of microthrombi
Treatment for immune thrombocytopenic purpura
IVIG, steroids, splenectomy – this is due to production of auto-antibodies against platelets which causes their destruction by splenic macrophages
Patient presents with widespread sepsis and undergoes antibiotic therapy. She then begins bleeding from her mouth and IV lines.
What do you suspect and what caused this?
What will you see on blood smear?
DIC!
Sepsis triggered widespread activation of the coagulation cascade which then led to a deficiency in clotting factors and caused widespread bleeding
Can also be due to trauma, OB complications, pancreatitis, malignancy, nephrotic syndrome, transfusion
Will see schistocytes
Why is vWF deficiency considered a mixed platelet and coagulation disorder?
Because it also is in charge of carrying F8, so if it is deficiency there is a deficiency of F8 –> impaired coagulation
Hemophilia A
Hemophilia B
A (more common): defect in F8 (A-ight)
B: defect in F9
What is the genetic cause of alpha thalassemia? B thalassemia?
Alpha- caused by a gene deletion
Beta - caused by a point mutation in a splice site or promoter sequence
Lead poisoning effects which enzymes in heme synthesis? What else does it do to cells?
ALA dehydratase (ALA –> PBG)
and
Ferrochetalase (Protoporphyrin –> Heme)
Also prevents rRNA degradation, leading to basophilic stippling in RBCs
How can you use labs to differentiate between folate deficiency and vitamin B12 (cobalamin) deficiency?
Folate: inc homocysteine
B12: inc homocysteine AND inc methylmalonic acid
What type of anemia does Methotrexate cause?
What drug can you give to reverse this?
Folate deficiency (macrocytic anemia). Methotrexate is a chemotherapy drug that blocks purine synthesis by inhibiting DHF reductase Reverse myelosuppression with leucovorin
Also trimethoprim and phenytoin cause anemia
Diphyllobothrium latum causes what type of vitamin deficiency
Vitamin B12
What is necessary for the absorption of vitamin B12?
Intrinsic factor produced by gastric parietal cells (Pernicious anemia= impaired absorption of vitamin B12)
Gastrectomy can also cause B12 deficiency due to lack of parietal cells
Why does B12 deficiency cause neurologic symptoms?
What parts of the spinal cord does it effect?
B12 is involved in myelin synthesis.
B12 deficiency will result in dysfunction of the spinocerebellar tract (ataxia), lateral corticospinal tract (weakness), and dorsal column dysfunction (sensory deficits)
How does chronic disease lead to anemia?
Production of hepcidin by the liver which sequesters iron in storage sites by binding to ferroportin on intestinal mucosal cells and macrophages, inhibiting iron transport
Dec release of iron from macrophages
Dec iron absorption from the gut
**leads to inc intracellular iron that is stuck there and dec serum iron
What does an elevated MCHC suggest?
Hereditary spherocytosis- round RBCs that cannot move through the splenic sinuosoids and are removed by splenic macrophages
Treatment is splenectomy
What do Heinz bodies and bite cells on blood smear suggest?
G6PD deficiency
Causes dec glutathione and inc RBC susceptibility to oxidative stress
What drugs can trigger hemolytic anemia in a person with G6PD deficiency?
Sulfa drugs
Fava beans
Antimalarials (Primaquine)
Anti leprosy drugs (Dapsone)
Paroxysmal Nocturnal Hemoglobinuria
Mechanism?
What do labs show?
complement mediated lysis of RBCs – impaired synthesis of GPI anchor for delay accelerating factor that protects RBC from complement
o Cells are negative for CD55 and CD59
What precipitates sickling of RBCs in sickle cell anemia?
Low O2
high altitude
Acidosis
Leads to anemia and vaso-occlusive disease
Patient presentation of acute intermittent porphyria
What causes symptoms?
What precipitates symptoms?
Treatment?
Abdominal Pain
Port wine urine
Psych disturbances
Polyneuropathy
Caused by a combination of porphobilinogen deaminase (PBG deaminase) deficiency and induction of ALA synthase
Precipitated by drugs (CYP450 inducers), alcohol, and starvation
Treat with heme and glucose (inhibit ALA synthase activity)
Patient presents with blistering cutaneous photosensitivity and has tea colored urine. Formation of what is likely impaired?
Heme synthesis (Porphyria cutanea tarda)
Due to a defect in uroporphyrinogen decarboxylase
Tea colored urine is due to accumulation of uroporphyrinogen
Autoimmune hemolytic anemias are usually Coombs positive or negative?
Positive
Warm vs cold autoimmune hemolytic anemia immunoglobulins
Warm (IgG) – warm weather is great
Cold (IgM) – cold weather is miserable
Warm vs cold autoimmune hemolytic anemia: presentation
Warm: chronic anemia seen in SLE and CLL and with certain drugs
Cold: acute anemia triggered by cold. Seen in CLL, Mycoplasma pneumonia infections, and mononucleosis – cam cause painful blue fingers and toes with cold exposure
Direct Coombs test
anti-Ig antibody (Coombs reagent) is added to patient blood. RBCs agglutinate if patient’s RBCs are coated with anti-RBC antibody
Indirect Coombs test
normal RBCs from a donor are added to the patient’s serum. If serum has anti-RBC surface Ig, the RBCs will agglutinate
Mutation in sickle cell anemia
Point mutation in the B globin gene (valine for glutamic acid)
Drugs used in tumor lysis syndrome to prevent uric acid induced renal dysfunction
Allopurinol (xanthine oxidase inhibitor)
Rasburicase (solubilizes uric acid to allantoin for excretion)
Complications in tumor lysis syndrome
K+ is released from cells and can cause a fatal arrhythmia
Uric acid formation due to breakdown of released nucleic acid can cause uric acid deposition in the kidney
Haptoglobin levels in hemolytic anemia (inc or dec?)
Decreased
As the RBC is lysed and hemoglobin is released into the blood, it is scaveneged by haptoglobin (“suicide protein”) → haptoglobin (+hemoglobin) is engulfed by macrophages, which leads to decreased serum levels of haptoglobin
diagnosis of vWF deficiency
Dx with ristocetin aggregation test:
Ristocetin activates GP1b receptors on platelets and makes them available for vWF bindings → When the vWF level is decreased, there is poor platelet aggregation in the presence of ristocetin
Child presents with bleeding gums. Has small wide thumbs and small eyes and pigmented patches on abdomen. He has not met cognitive milestones. Labs show pancytopenia and high fetal hemoglobin levels. What is this congenital disorder?
Fanconi anemia
The most common cause of inherited aplastic anemia and is characterized by defective DNA repair that results in inc chromosomal breakage, rearrangements, and deletions → causes bone marrow failure
o Patients have short stature, ic incidence of tumors/leukemia, café au lait spots and thumb/radial defects
What is the cause of almost all of the Myeloproliferative Neoplasms?
JAK2 kinase mutation: cytoplasmic tyrosine kinase
(Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis, but NOT seen in Chronic Myelogenous Leukemia)
CML is t(9,22) philadelphia chromosome
Erythropoitetin levels in polycythemia vera
Decreased. Due to negative feedback that suppresses renal EPO production
- In contrast, EPO is elevated in malignancy (renal cell carcinoma, hepatocellular carcinoma) due to ectopic EPO production
Patient has a platelet levels >450,000. What myeloproliferative neoplasm do you suspect?
Essential Thrombocythemia (JAK2 kinase mutation)
Patient presents with intense itchiness after taking a warm shower. She also reports episodes of burning pain in her hands with red discoloration. What do you suspect and what is a common complication of this disorder?
Polycythemia vera (inc risk of venous thrombosis, like Budd Chiari syndrome)
t(9,22)
Chronic myelogenous leukemia (CML)
Philadelphia chromosome t(9,22) which generates a BCR-ABL fusion protein with inc tyrosine kinase activity – drives overproduction of neoplastic cells
Teardrop RBCs on bloodsmear
Primary myelofibrosis
(JAK2 kinase mutation)
Obliteration of the bone marrow with fibrosis (due to inc fibroblast activity)
Auer rods seen on histo
Needle shaped cytoplasmic structures (crystal aggregates of myeloperoxidase)
Seen in Acute Myelogenous Leukemia
t(15, 17)
Acute promyelocytic leukemia (M3 subtype of AML)
Defect is in retinoic acid receptor (PML/RARA fusion protein blocks maturation)
treat with vitamin A derivatives
Cells express TdT (terminal deoxynucleotidyl transferase)– what does this indicate about the cells? What is the role of TdT?
They are immature B or T cells (mature cells do not express TdT)
TdT is responsible for adding nucleotides to the V, D, and J regions of the antibody gene for antibody diversity
A young male presents with an anterior mediastinal mass involving thymic tissue. What do you suspect?
T cell acute lymphoblastic lymphoma (T-ALL)
symptoms of superior vena cava syndrome
“Crew cut” on skull Xray
due to marrow expansion from inc erythropoiesis – seen in Sickle cell and B thalassemia major
Where can ALL spread?
To the CNS or to the testes
Histo shows smudge cells
Chronic lymphocytic leukemia
CLL = Crushed Little Lymphocytes
What can happen with CLL/SCL in terms of progression?
Richter transformation: CLL/SCL can transform into an aggressive lymphoma (diffuse large B cell lymphoma)
What stains TRAP positive?
Hairy cell leukemia (mature B cell tumor)
What are heme/onc causes of a dry tap?
Primary myelofibrosis (obliteration of the bone marrow with fibrosis- inc fibroblast activity)
Hairy cell leukemia (mature B cell tumor)
Reed Sternberg cells are positive for which cytologic markers
CD15 and CD30
(2 owls eyes x 15 = 30)
Seen in Hodgkin Lymphoma
What drugs can you give to help tx Sickle Cell patients and how do they work?
Hydroxyurea: increases production of HbF
Gardos channel blockers (calcium dependent K+ channel): hinders the efflux of K+ and water from the cell, preventing the dehydration and RBCs and reducing the polyermization of HbS
Electrolyte changes in blood transfusion
Hypocalcemia: citrate is a calcium chelator (will also see dec Mg for the same reasons)
Hyperkalemia: RBCs may lyse in older blood unites
SLE effects on RBCs
Autoimmune hemolytic anemia
Warm hemolytic anemia (IgG)
t(8;14)
Burkitt lymphoma
translocation of c-myc (8) and heavy chain Ig(14)
Transcription factor that causes rapid tumor cell proliferation
How to differentiate between benign neutrophilia (leukemoid reaction) and chronic myelogenous leukemia?
CML has a low leukocyte alkaline phosphatase due to low activity of malignant neutrophils
Benign neutrophilia will have high LAP
Cells express S-100 and CD1a
Langerhans cell histiocytosis
Have characteristic Birbeck granules in the cytoplasm
Blotting procedures: Southern vs Western vs Northern
SNoW DRoP
Southern = DNA sample Northern = RNA sample Western = protein sample
Multiple myeloma key clinical presentation
CRAB hyperCalcemia Renal dysfunction Anemia Bone lesions and back pain
t(14, 18)
Follicular lymphoma
translocation of heavy Ig chain and BCL2
Inhibition of apoptosis
t(11; 14)
Mantle cell lymphoma
Translocation of cyclin D1 and heavy chain Ig
Why are people with multiple myeloma at inc risk of infection?
They overproduce abnormal Igs and do not produce enough normal Igs
Heparin: use, mechanism and antidote
Use for immediate anticoagulation
activates antithrombin, which then decreases the activity of thrombin and factor 10a (monitor PTT)
o Rapid onset, short t ½
o Safe to use in pregnancy
o Antidote = protamine sulfate
LMWH (Enoxaparin, Dalteparin) and Fondaparinux
act more on factor 10a, have better bioavailability, and have a longer half life
Warfarin mechanism of action and antidote
Warfarin: interferes with γ-carboxylation of vitamin K-dependent clotting factors (2, 7, 9, 10) and Protein C/S
o Inc PT
o Not safe for pregnancy
o Antidote: Vitamin K and fresh frozen plasma
o Can cause a transient hypercoagulable state due to inhibition of protein C and S – start patients on Heparin first and then warfarin
Factor 10 inhibitors
Factor X inhibitors: Rivaroxaban, Apixaban
o have an X in the name
Heparin Induced Thrombocytopenia:
IgG is formed against the heparin-platelet factor 4 complex and results in platelet activation and aggregation → clotting
o Can see DVT and PE in this patient
o Seen 5-14 days after exposure to heparin
DO NOT GIVE PATIENTS WARFARIN - inhibition of protein C and S can worsen the clotting
B thalassemia trait
Inc HbA2 (a2d2)
Coarse basophilic stippling in RBCs seen in blood smear
Lead poisoning
Lead prevents the breakdown of rRNA
Which neoplasm has a common presentation of DIC?
Acute myelogenous leukemia (AML) - especially the acute promyelocytic leukemia subtype
B symptoms
Reed Sternberg cells (Hodgkin lymphoma) secrete cytokines which can cause fever, chills, weight loss, and night sweats
How do RBCs generate NADPH
via the HMP shunt, necessary to maintain glutathione in a reduced state by the action of glutathione reductase
o HMP shunt is the only major pathway that makes NADPH in erythrocytes so if there are defects then the RBC is susceptible to free radical and oxidant stress
What factors promote angiogenesis in neoplastic and granulation tissue?
VEGF and Fibroblast growth factor (FGF)
o Pro-inflammatory cytokines can indirectly promote angiogenesis through inc VEGF production
What cells stain positive for major basic protein?
Eosinophils
helps defend against parasites
What cells stain positive for peroxidase?
Myeloblasts (auer rods)
CML treatment
Imantinib (inhibits the BCR-ABL fusion protein)
Blood smear shows stacked RBCs
Multiple myeloma (Rouleaux formation)
What are thymomas associated with?
Myasthenia gravis and pure red cell aplasia
Are multiple myeloma bone lesions osteolytic or osteoblastic? What other cancers can cause this type of lesion?
Osteolytic
Non small cell lung cancer (squamous cell carcinoma secretes PTHrP)
Renal cell carcinoma (secretes PTHrP)
Melanoma
Non hodgkin lymphoma
What type of bone lesions are caused by prostate cancer?
Osteoblastic bone lesions
What causes cachexia in cancer patients?
Cytokine release (TNFa, IL1, IL6)
TNFa acts on the hypothalamus to dec appetite and increase metabolic rate
Mechanism of apoptosis
How does translation of apoptotic proteins occur?
Bcl2 in the cytoplasm is inactivated, cytochrome c can exit the mitochondria and enter the cytoplasm where it activates caspases that initiate apoptosis
Caspases are proteolytic enzymes that destroy cell components. They contain cysteine and are able to cleave aspartic acid residues (cysteine-aspartic-acid-proteases)
o In order to translate proteins necessary for apoptosis, an alternative method known as internal ribosome entry is used → a distinct nucleotide sequence called the internal ribosome entry site attacts the eukaryotic ribosome to mRNA and allows translation to begin in the middle of the mRNA sequence
What drugs have increased activity when given with Allopurinol or Febuxostat? Why?
6-Mercaptopurine and Azathioprine
These drugs are also metabolized by xanthine oxidase – thus have increased toxicity when taken with allopurinol or Febuxostat (because less xanthine oxidase is available to metabolize 6-MP or Azathioprine)
Heme precursors
Glycine and Succinyl CoA
Tumor invasion of basement membrane
- Tumor cells detach from surrounding cells due to decreased expression of E-cadherin
- Tumor cells adhere to the basement membrane via increased expression of laminin and other adhesion molecules
- Tumor cells invade the basement membrane via enhanced secretion of proteolytic enzymes (metalloproteinases)
Patient ingests rat poison – what should you do to treat them?
Rat poison = super warfarin – give them FFP!
Retinoblastoma is associated with what other cancer?
Osteosarcoma
Both have mutation in RB gene (G1/S transition inhibitor)
Warfarin induced skin necrosis: mechanism and treatment
happens in patients who are protein C or S deficient – following the initiation of warfarin, a rapid drop in factor 7 and protein C levels occurs. If a protein C deficiency is present, the transient procoagulant/anticoagulant balance is futther exaggerated, causing a hypercoagulable state with thrombotic occlusion of microvasculature and skin necrosis
Tx: stop warfarin and give FFP to replenish protein C concentrations
What cytokine stimulates the release of acute phase reactants?
IL-6
Inheritance of G6PD
X linked recessive
What is the mechanism by which the human multidrug resistance (MDR1) gene works in chemotherapy resistance?
The MDR1 gene codes for P-glycoprotein, a transmembrane ATP dependent pump protein that increases efflux of drugs from the cytosol and decreases influx of drugs into the cytosol
What is responsible for converting pro-carcinogens into carcinogens – promoting the formation of cancers?
Cytochrome P450 monooxygenase
Li Fraumeni
Mutation in TP53 (tumor suppressor)
Autosomal dominant – inc risk of cancer in childhood or as yound adults
SBLA syndrome: sarcomas, breast/brain tumors, leukemia, and adrenocortical carcinoma
Uremic platelet dysfunction
Cause?
Labs?
Tx?
due to renal failure
Accumulation of uremic toxins impair platelet aggregation and adhesion, resulting in prolonged bleeding time with normal platelet count, PT, and aPTT
Can be improved with dialysis as it removes the toxins and partially reverses the bleeding abnormality
How do the RBCs of alcoholic look?
Macrocytic with or without anemia (usually due to poor diet – folate)
Role of Kallikrien in the coagulation cascade
accelerates the activation of F12
o Positive feedback: starts being made when there is some F12 present, and then induces more formation of activated F12
Sideroblastic anemia
defect in heme synthesis due to defect in ALA synthase
Can be caused by genetic defect (X linked), alcohol abuse, lead, vitamin B6 deficiency, copper deficiency, isoniazid
o Treatment: vitamin B6 (cofactor for ALA synthase)
o Histo shows ringed siderblasts with iron laden, Prussian blue-stained mitochondria
Which microcytic anemia can cause hydrops fetalis?
alpha thalassemia
–/– = severe anemia, stillborn – Hydrops fetalis
Roles of transferrin and ferritin?
Transferrin: transports iron in blood (transferrin transports)
- Inc in iron deficiency anemia (looking for more iron)
- Dec in anemia of chronic disease
Ferritin: stores iron in cells
- Dec in iron deficiency anemia (not a lot of iron intracellularly)
- Inc in chronic disease anemia (hepcidin sequesters iron in cells and prevents release)
