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Heme anemia etc grand overview
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39
Medical
Undergraduate 2
05/14/2013

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Term

What does Hepcidin do?

Definition

- it keeps ferroportin from releasing Fe into the blood stream.

- ferroportin is on the cell membranes of GI epi and macrophages

- hepcidin is inhibited when there are low Fe stores, hypoxia, HH and low erythropoeisis. It's stimulated by IL-6 and increased iron stores

- ppl with HFE gene mutations don't have funcitonning hepcidin, so they get too much Fe in their blood.

*DMT-1 receptors are on the GI lumen.

Term

What is porphyria?

Definition

- when you can't make heme

- rate limiting step is ALA synthase

- when you get stuff that would normally induce heme production, you get a bunch of toxic metabolites made instead

- neurotoxic (drowsy, abdom pain, psychosis, weakness) and photosensitive (blistering and scarring of sun-exposed areas)

- you get increased ALA and porphobilinogen in the urine during an acute attack

- tx by supplementing carbs, giving IV heme

*Pb poisoning inhibits sevral of these enzymes so it mimiks the neurotoxicity

Term

Tell the story of what makes jaundice and make the enzymes in bold

Definition

 Heme - heme oxygenase - Biliverdin - biliverdin oxygenase - Bilirubin

 

- increases in bilirubin cause jaundice. Bilirubin goes into the liver and gets conguated to glucuronide in the liver to make it soluble, then it gets excreted in bile.

- Jaundice is caused by increased RBC turnover, defective bilirubin conjugation (ex; drugs, Gilbert's disease, Crigler-Majjar syndrome of babies causing kernicterus and we do that blue light thing cause it's a non-enzymatic converstion of bilirubin to a soluble compound) and defective bile secretion.

Term

Two patients have jaundice, pt A has high indirect, pt B has high direct, what does that mean? What 3 groups of tests would you do?

Definition

indirect = unconjugated

direct = conjugated (so like, the longer word goes with the longer word)

- you can measure direct bilirubin and total, then calculate indirect

- increased indirect would be like Gilberts or hemolysis (ex; thalassemia and G6PDH)

- increased direct would by liver disease, cholestasis, biliary obstruction

1: hepatocellular disease: ALT, AST, INR and albumin

2: Bilary tract prob: ALP, GGT and imaging

3: Hemolysis: retic, LDH and haptoglobin

 

Term

What causes aplastic anemia?

*Aplastic anemia is sortof the same as pancytopenia, but sometimes it seens like maybe it's only the "hypo-production" causes are linked to aplastic anemia, and then the other things and more like low cells because of increased destruction!

Definition

- it's where all of the myeloid sten cells are hypoproliferating or destroyed. (the lymphocytes are ok)

- multiple hits causing hypoproliferative disease (loss of function of protoncogenes or gain of function of tumor supressor genes)

- Inherited: Fanconi's an (defective DNA repair, affects kidneys, spleen, bone hypoplasia)

- Aquired: chemical (anti-metabolites, benzene, chlorophinicol, alkylating agents)...

- Radiation

- Virus (EBV, CMV, Herpes)

 

Here are the bone marrow failure things

 

- immune destruction

- space occupying lesion (metastasis, granulomatous disease, myelofibrosis, myeloproliferative disorders and myelodysplasias)

- liver disease (mostly affects RBCs), this pretty much works through toxins causing the release of bm suppressing cytokines.

- kidney disease (lack of EPO and causes a more hemolytic environment)

- splenomegally

- SLE

- TB< AIDS< Leishmeniasis

Term

What would make you suspect aplastic anemia? What tests would you then do? How would you treat it?

Definition

- low RBCs would cause pallor, fatigue, SOB, weakness

- low plts would cause bleeding (petichiae) and bruising

- low WBCs would cause persistent or recurrent infections

 

- you would do a CBC and see lots of low values, then you would do a blood smear. Could also do a bone marrow aspiration or bx.

 

- in young adults, you treat with bmt. if they're over 50 you consider injection of ATGs, which are anti-thymocytic globulins. Also give cyclosporing to immunosuppress. Also treat with transfusion and Abios.

Term

What causes macrocytic, NON-MEGALLOBLASTIC, anemia?

Definition

- first the megalloblastic is caused just by B12 and folate (I think)

- newborns and pregnant women get this normally, otherwise:

- etoh

- liver disease

- obstructive jaundice,

- rapid RBC production

- aplastic anemia or marrow suppression

- myelodysplasic syndromes

- hypothyroidisn, absence of spleen, Downs, COPD

Term

If you see a high retic count, what is your ddx?

Definition

- hemolytic anemia

- recent blood loss

- myelosupression

- nutrient deficiency

Term

Someone comes in with a high retic count and jaundice. What do you suspect that they have? What other signs would you look for? How would you work them up?

Definition

- high LDH, hemoglobinuria, splenomegally (I think that would be a cause) and galstones. Those things you might expect to see

- so you're thinking hemolytic anemia, you should do an LDH, haptoglobin and indirect bilirubin as well as looking for free Hb and hemosiderin in the urine.

- haptoglobin is a prot that take up free Fe in the blood so that it can be recycled. If those levels are low, then it means that all the haptoglobin has been taken up by free Fe (and haven't either been re-made or returned to the general circulation in keeping up with the crazy Fe load). It will be low in intravascular hemolysis and normal in extravascular.

- you should also do a blood smear and then go from there

Term

Old Fred over there, he has hemolytic anemia the doc thinks, and the doc sends you to look at his blood smear. What might you see?

Definition

- polychromasia from high retic count

- schistocytes (fragmented RBCs indicating microangiopathic disease or high-shear fragmentation syndromes)

- spherocytes (H spherocytosis or autoimmune HA)

- Elliptocytosis/ovalocytes (blah)

- Sickle cells or Hb crystals (Hbopathy)

- RBC agglutination (cold agglutinin)

- bite cells and blister cells (oxidative hemolysis, esp in G6PD def)

- malarial parasites

Term

If you see spherocytes on the smear of someone with HA, what would you do next?

Definition

- DDx: H spherocytosis, autoimmune HA, burns, sepsis

- Coombs test to check for autoimmune

- osmotic fragility for H spherocytotsis

 

Term

If you see schistocytes on the smear of someone with HA, what would you do next?

Definition

- DDx: microangiopathic (DIC, HUS, TTP), malignant hypertension, weird heart valve, pre-eclampsia

- test Cr for HUS

- test platelets for TTP

- cardiac investigations for HTN

- INR, fibrinogen for DIC

Term

What if you saw target cells or sickle cells on the smear of someone with HA, what would you do?

Definition

- Ddx: sickle cell

- I don't understand the other one where you do a "Heinz body prep" and it will diagnose "unstable hemoglobin"

- but you would do a plasma Hb electrophoresis to see sickle cell

Term

How would you proceed in your tests if you swa that the smear fo your pt with HA was normal?

Definition

- Ddx: G6PDH def, pyruvate kinase def, Paroxysmal nocturnal hemoglobinuria (complement iduced RBC destruction)

- do a G6PD and PK screen and PNH assay.

- Then do a a Coomb's test to look for autoimmune cause that won't always present with spherocytosis

Term

You've exhausted your list of what could be caused HA, what else of the weird things are you left with?

Definition

- March Hburia

- oxidant drugs

- methmoglobin

- vasculitis

- giant hemangiomas, sepsis, burns

Term

What is hemosiderin?

Definition

- it's a bunch of ferritin stuck together

- in intravascular hemolysis (so in the blood), Hb that can no longer be taken up by haptogloben cause it's all used up, will get taken up by tubular epithelial cells, which will then become iron overloaded and slough off. You will then find hemosiderin in the urine. (common in PNH)

Term

One pt has dark stool and jaundice with normal coloured pee, the other has pale stool, jaundice and very dark urine. What's the diff?

Definition

- Pt A has lots of bilirubin product in their poo, and in their blood but the stuff in their blood is unconjugated. They will not have more conjugated bilirubin in their pee though, cause there's nothing stopping the conjugated bilirubin from going into the poo. Their urine will be high in urobilinogen, which is a super altered form of bilirubin that's being taken up from the GIT.

- Pt B has cholestasis or biliary obstruction. Their conjugated bilirubin is backing up and that is soluble so it can go in pee and make it dark. It will also go in blood and cause jaundice, but less will make it to the poop, so the poop is pale. *The conjugated bilirubin in the blood will also irritate mast cells in the skin and cause itching.

Term

What do you see in intravascular hemolysis that you do not see in extravascular?

Definition
- haptoglobin goes way down, then when it gets all used up, the free Hb will go up. It can then get oxidized to methemoglobin and cause methemoglobinemia. Free Hb can also get taken up with renal tubular cells and then cause acute tubular necrosis. Free Hb can also go into the urine.
Term

What is the story of Hb production from out fetal life to our adult life?

Definition

- it's Chx 16 that first makes the zeta peptide, then later in life makes the alpha-1 and alpha-2 peptides

- Chx 11 makes episilon, then G gamma, A gamma, then beta then delta. 

- first the zeta and episilon go together, then the alphas ad the deltas go together, then the alpha and beta (that's the most common normal adult Hb), then also some alpha will combine with delta in adult life

- Earliest Hb is "Gower's Hb" (2 zeta + 2 epsilon)

- Fetal Hb, or Hb F (2 alpha plus 2 gamma)

- Adult Hb, or Hb A (2 alpha plus 2 beta)

- Adult Hb2, of Hb A2 (2 alpha plus 2 delta)

Term

What is sickle cell anemia? What the heck is Hb C is that related to this?

Definition

- it's a problem with the beta chains, a point mutation turning a glutamic acid (GTG) to a valine (GAG) creating "Hb AS"

- certain factors induce sickling; low pO2, low pH, high pCO2

- HbC is another kindof mutated beta chain. Normally if you just have one HbC allelle and the other is A, you're fine. Homozygotes get mild hemolytic anemia.

- HbS + HbA = mild sickle cell (remember you have two alleles)

- HbS + HbC = moderate disease

- HbS + HbS = severe disease

Term

If a little baby has HbSS, how old will it be before it develops symptoms? Why? What will those symptoms be?

Definition

- about 5mo is the switch from gamma to beta chains from Chx 11.

- you get lots of breakdown of RBCs, so you can get jaundice and bilirubin gallstones, red bone marrow expands to compensate for the loss, renal damage from hemosiderin deposision

- acutely, you can get sickle, or vaso-occlusive attacks when sickles get stuck in the microcirculation and cause infarction. You could get this anywhere really (lungs, stroke, renal, prolonged erection). Often their spleens will first become enlarged but then shrink due to infarction. Autosplenectomy (or any splenectomy) makes them more prone to infection by capsulated bacteria like PNEUMOCOCCUS AND HIB

Term

How would you treat a poor person with sickle cell?

Definition

- exchange transfusion

- blood transfusion

- hydroxyurea to stimulate gamma globulin expression

- hydration (that's huge during the attacks)

- analgesics

- abios, immunizations for pneumococcus and Hib and prophylaxis abios.

Term

First, what test should we do to see if there's iron deficiency? Secondly, what test do we do in order to rule out anemia of chronic disease as a contributor?

Definition

- iron (ferritin) will be low in both iron def an and an of chronic dis.

- In IDA: serum iron is low and TIBC is high

- In ACD: serum iron is low and TIBC is also low. (transferrin is a negative acute phase reactant).

- transferrin sat = serum iron/TIBC

- if you really can't quite sort it out, you could do a trial of iron supplementation and see if it helps, or you could do a bone marrow aspirate and stain for iron (but that's inconvenient)

Term

What are some of the signs that someone has an inflammatory process going on?

Definition

Things that go high: CRP, ESR, fibrinogen and gamma globulins (causing Rouleaux), leukocytosis

Things that go low: albumin

Term

How do you calculate Hct, MCH and MCHC?

Definition

- Hct = MCV x # RBCs

- MCH = Hb/# RBCs

- MCHC = Hb/Hct

Term

Talk a bit about sickle cell anemia basic science. What processes (2) bring on the clinical manifestations of it?

Definition

- it's a point mutation in th ebta globin gene at residue 6 that changes Glutaminc acid (- charge) to a valine (neutral charge)

- this decreases solubility of DEOXY Hb, and causes formation of crystals in cytoplasm

- the red cells which are 7-8 um have to squeeze to fit through the capillaries (3um) and the spleic sinusoid (2um), but if it's all crystally then it gets stuck in both those places.

- it causes intravascular hemolysis (but also extravascular I would think!) and vas-occlusion, including of the spleen which is what cause autosplenectomy.

Term

What causes the anemia of sickle cell anemia? Talk about some other clinical manifestations

Definition

- the hemolysis!

- the heart has to work harder chronically, so you may get dilated cardia myopathy

- increased bilirubin can cause stones

- if they get infections or something and get just a bit of supression of the bone marrow, that can cause a super big problem for them.

- they also get a reduction in nitric oxide (a vasodilator) cause free Hb is around, and arginase is released from the RBC cytosol. Those things decrease NO and you get a tendancy to vasconstrict which is not helpful at all.

- stroke is a big one. MCA is affected fairly often, but even moreso it's small vessels. Peak incidence of stroke is in kids! You have to transfuse them a lot to try to dilute the HbS

- nephropathy

- ischemic proliferative retinopathy

- avascular necrosis

- dactylitis

- pain crisis and chest crisis. *triggered by infection, dehydration, hypoxia

Term

How would you manage a sickle cell pain crisis? Chest syndrome?

Definition

- Analgesia with short acting narcotics or NSAIDs

- Hydration

- O2

- transfusion if not settling

 

- Prevention: avoid dehydration and other triggers, increase HbF with Hydroxyurea, chronic transfusion, bone marrow transplant.

- Chest syndrome ppl with have pain, fever, pulm infiltrated, cough, SOB, wheeze, manage with Abios covering pneumo, hemophilis and atypicals, give O2, hydration and alagesia and do RBC exchange transfusion

Term

Talk about thalassemia

Definition

- it's where there's an imbalance of alpha and beta chain synthesis

- excess free chains are unstable and get oxidized. (beta chains can get together and form beta4, so 4 beta chains together, and that is called Hb H!)

- shortened RBC survival, can have ineffective erythropoesis or intramedullary death.

- thalassemia minor is when one beta allele is messed up, and there are really no clinical consequences.

- thalassemia intermedia is when there's HbH disease, then you get moderate anemia and gradual iron overload

- thalassemia major makes profound anemia, crazy stuff really bad. skeletal malformation and massive splenomegally, osteoporosis.

Term

Hemoglobin E

Definition

- a certain type of beta globin mutation

- Hb EE is benign, but Hb E and beta thalassemia gives a thalassemia intermedia phenotype.

Term

What will iron overload do to the body? How do we treat it?

Definition

- dilated cardiomyopathy

- cirrosis and hepatocellular ca

- insulin dependent DM due to pancreatic damage

- hypogonadotrophic hypogoniadism due to hypothalamus/pituitary damage

- slate colour to the skin

 

- treat with iron chelation (ex; Deferoxamine or deferasirox)

Term

What is the "leukoerythroblastic reaction"?

Definition

- it's what you see when the marrow is being infiltrated by something (ex; leukemic cells, tumor cells, infectious granulomatta, lipid storage cells, fibrous tissue

RBCs: anemia with anisocytosis (variation is size) and poikilocytosis (tear drop cells)

WBCs: more often leukocytosis than leukopenia. Often with many immature cells.

Plts: all over the map

*you can see cytopenia...

- this all seems sortof confusing, so just remember that you should do bone marrow aspiration and biopsy to see what's going on.

Term

Someone has symptoms of B12 deficiency and their B12 comes back low. What do you do next? What could have caused that?

Definition

- first remember that other things can cause megalloblastic appearance (folate, antimetabolites) and macrocytosis (liver dis, etoh, myelodysplasia)

- also remember that macrocytosis, esp megalloblastic, causes hemolysis of those weird RBCs, and so indices of hemolysis will be high (Haptoglobin may not be super low, and that might tip you off that it's not intracellular), this is extracellular and it's a normal response to the underlying megallobloastic disease! Don't get confused, always look at the size first.

- causes of B12 def other than dietary:

Long-standing strict vegeterian diet, gastrectomy, congenital lack of intrinsic factor, pancreatic insufficiency, diseases of terminal ileum (Crohn’s disease,  ileal resection), blind loop syndrome. Lack of intestinal receptors for vitamin B12,fish tapeworm infestation...

Term

What special "new" test makes it so that we catch more infections in the donor pool?

Definition
- NAT: nucleic acid testing, and it's cause the window between infection and NAT showing up it shorter than IgM or IgG
Term

Who is the universal donor and who is the universal acceptor?

Definition

- O is the universal dOnOr for RBCs. But I think the thing that mixes me up is that you would not want to give type O plasma to just anyone, cause type O plasma will have both A and B antibodies! So here we know that before we give the O blood, we wash out the O plasma which would contain A and B antibodies which may react with the recipient's RBCs. So the "reaction" you're mostly worried about it the recipient's plasma's attack on the new RBCs

- AB is the universal Acceptor, (they are greedy), cause they don't have any antigens so their plama would not react against any new RBCs.

 

*For plasma, it's almost the opposite!

Term

What's the deal with The Rh thing?

Definition

- 85% of ppl are Rh+, and 15% are Rh-

- being an Rh- woman could be bad if you have an Rh+ baby, cause then the mom can make Abs that attack the baby (if not during the 1st pregnancy then maybe during a second one)

- we give Rh immunoglobulin to Rh- pregnany women to prevent this

- for non-pregnany Rh- women, they should get Rh- (so that they don't develop Abs that they will then later attack their baby with). Also older women could get Rh+ and then develop those Abs, but then they shouldn't get a second Rh+ transfusion cause they'll just react to that!

Term

When should you transfuse someone?

Definition

- they say that until your Hb drops like up to 75% you're probably not showing symptoms. Do transfuse when they show serious symptoms.

- Hb of 70 is when you start to conisder it. Under 60 is highly recommended.

- if we're talking platelets, you'd do it when they're less than 10 and it's non-immune thrombocytopenia.

Term

What is TRALI? TACO?

Definition

- transfusion related acute lung injury, related to neutrophil activation.

- pregnancy women more likely to get TRALI, you get acute onset hypoxemia, O2 sat goes below 90, bilateral lung infiltrates, no evidence of circulatory overload. 

- transfusion associated cardiac overload

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