Lectures aka Information Not in Pathoma

Anemia Lectures from Doll very well covered in Pathoma

Coberly Plasma Cell Dyscrasias

 Normal B cell development starts in the bone marrow, produces B cells with IgM/IgD and enters the lymph
node follicles
 Once they enter the follicles they find an antigen they bind to and cause a germinal center reaction
 The germinal center reaction can be separated into a dark zone and a light zone, in which the dark zone in
which plasma cells undergo proliferation and the light zone where they undergo selection and differentiation
via somatic hypermutation to create plasma cells and memory B-cells.

 distinguished between the mantle zone, light zone, and dark zone


 Once plasma cells become activated and produce memory B-cells and plasma cells they travel back to the
bone marrow
 Remember plasma cells make many immunoglobulins and more light chains (kappa and lambda) then heavy
chains so in multiple myeloma you have many, they are ineffective, MONOCLONAL chains.
 Mott cells (pockets of immunloglobulins push out nuclear contents) and Flame cells (IgA myeloma) have
been associated with multiple myeloma

 Picture of cast nephropathy from light chain deposition

o
 Picture of Ig Deposition in the glomerulus lowering glomerular function which contribute to kidney damage
and resultant anemia

o
 AL amyloidosis can occur to form BETA PLEATED SHEETS  can occur anywhere
 MGUS vs smoldering myeloma
o Smoldering myeloma
 Asymptomatic myeloma
 Serum M protein > 30 g/L or urinary M protein > 500 and clonal plasma cell percentage 10-
60%, no CRAB symptoms
o MGUS
 Serum M protein is < 30g/L and clonal bone marrow cells < 10% no CRAB symptoms
 Plasmacytoma
 o Single localized tumor of monoclonal plasma cells with no features of multiple myeloma (solitary
plasmacytoma of bone or exramedullary)
 Multiple myeloma can develop into a plasma cell leukemia in 1% of patients.
 Waldenstrom’s macroglobulinemia comes from MEMORY B CELLS rather than plasma cells and that is
why they have IgM instead of IgG/IgA as in multiple myeloma

Myelodysplastic/Myeloproliferative Disorders

Hematopoietic
Stem Cells

Genetic Mutations Epigenetic Alterations

AML

Myeloid
Neoplasms MDS

MPN

MW11-14

 (for a frame of reference)

 CML
o 9,22 translocation (ABL on 9, BCR on 22)

o
 Note FISH analysis shows combination of colors on one chromosome in 9,22 translocation
o Remember the myelocyte bulge is an important diagnostic clue here

o
 o

o Note the progressions of myeloblast to promyelocyte into myelocyte, and then meta myelocyte
(indented nucleus), bands (which make her dance), and then segmented granulocytes (eosinophil
showed). In CML all of these are increased, especially myelocyte (myelocyte bulge)
 CSF3R is a common mutation that is highly prevalent in chronic neutrophilic leukemia
 Polycythemia Vera
o Patients have a ton of RBCs but also a lot of platelets
 Essential Thrombocythemia
o Localized adjacent to sinuses
 Myelodysplastic Syndromes
o You have pancytopenia, higher blast percentage <20 vs <10 in myeloproliferative diseases,
ineffective hematopoiesis
o What is it?
 Stem-cell disorders involving ineffective hematopoiesis  defects in cell maturation of
nonlymphoid lineages.
 Caused by de novo mutations (50% such as 5q deletion or –Y deletion  meaning men are
more likely to have it as they age) or environmental exposures such as radiation, benzene or
chemotherapy (therapy related is 90% and also due to the 5q or 7q deletion)
 Huge difference is basically that myelodysplastic is a bunch of immature blast cells, whereas
myeloproliferative is an excessive production of usually one or more mature cells (ET 
platelets) (CML  myelocytes, basophils)
o A major anomaly associated with this condition is the Pseudo-pelger-huet anomaly  neutrophils
have bilobed or “duet” nuclei and are usually seen after chemotherapy

o
o Many treatments exist, one in which she highlighted is DNA methyltransferase inhibitors (5-
azzacytidine)

Hematopoietic
Stem Cell

Genetic Mutations Epigenetic Alterations

Over Proliferation Over Proliferation Increased Apoptosis

with maturation with Blasts Abnormal Maturation

Acute
Myeloproliferative Myelodysplastic
Myeloid
Neoplasm Syndromes
Leukemia

o
o Important to remember both can progress to AML
Transfusions – Good Madam Coberly
 Blood Bank Tests
o Type and Screen
 Patients blood is forward/reverse blood typed
 Antibody screen is performed
 New patient sample must be collected and retested every 3 days
o Crossmatching
 Basically you have packed RBC’s to set aside for future use by your patient with a
confirmatory type and screen
o Transfusion
 Forward typing
o Patient with B blood has B antigen on their surface so when you had B antibodies there will be
clumping
 Reverse typing
o Patient with B blood has A antibodies floating in serum. So when you add A blood, there should be
clumping in that test tube.

o
 Antibody Screen
o Purpose is to screen for ABO antibodies (usually IgG) in the patient’s plasma
o Patient’s plasma is added to RBCs with known antigen phenotypes  INDIRECT COOMBS!!
o Requires incubation so it takes longer
 What’s in a Bag of Blood?
o RBC: 200-350 mL
o Plasma: <50 mL
o Iron: 200-250 mg
o For every unit of transfused blood we expect a Hb increase of 1g/dL and a hematocrit increase of 3%
 A notable adverse event
o HYPOCALCEMIA!!!
o Blood is often anticoagulated with sodium citrate and citric acid and thus oftentimes blood
transfusions are accompanied by a large dose of citrate
o Citrate binds to free calcium leading to hypocalcemia
 Platelets
o Psoralen drug is activated by UV light inactivating most bacteria, viruses, and WBCs in the bag
o Reduced incidence of transfusion reactions
o CAN BE GIVEN TO ANY BLOOD TYPE!
o Remember to not give to patients ITP or TTP
o Uremic platelet dysfunction remember leads to increased bleeding time, but no change in platelet
count or PT/PTT would NOT help
 Plasma and Cryoprecipitate
 o Cryo is usually only ever used for a fibrinogen deficiency or sometimes a Hemophilia A
o Perform transfusions right before planned procedures as Factor 7 has a short half life

Ischemic Heart Disease – Kumar

 Important to remember that even when a patient has 100% occlusion in 2 or more arteries and feels fine,
if it happens slowly enough microcirculation can be recruited through VEGF and cause accessory blood
supply
 Chronic Stable Angina  relieved by rest + nitro
o Levine’s sign (clutching chest)
o Exercise capacity varies
o Relieved by nitrates
o Important concept is angina equivalents
 Dyspnea
 Epigastric discomfort
 Fatigue
o Non-cardiac causes of chest pain
 GERD, Chest infarction, PE, lung tumor, Tietz syndrome (MSK pain)
o Treatment: Aspirin, Statin, anti-anginal therapy (BB, Nitrates, CCB)


 Acute coronary syndrome 
o Unstable angina troponins are NEGATIVE
o NSTEMI  Positive troponins
 Acute management  O2, nitro, BB, ACEi, antiplatelet/antithrombotic therapy
(aspirin+clopidogrel (esp for patients who are allergic to aspirin)
o STEMI  Troponins + ST elevations
 The concept of Diversity of Lesions is UWORLD material
o A stenotic lesion has a thick cap, fibrotic, and there is less compensatory enlargement
o A nonstenotic lesion has a a lipid rich, thin cap, and there is compensatory enlargement
 TIMI risk score calculates 30 day mortality after a MI, also GRACE score
 
 CCS Classification (similar in terms of symptoms and severity to NYHA for CHF)
o Class I  Strenuous activity causes problems
o Class II  Slight limitation of ordinary activity (walking or climbing hills rapidly)
o Class III  Great limitation of physical activity
o Class IV  Can’t really to any physical activity
 Co-morbidities
o HTN + dyslipidemia are the 2 major ones
o Pts often have peripheral pulses, valvular disease, HTN, lung disease, S3, S4
 You can either perform a stress test or a noninvasive stress test (Adenosine PET being the highest
sensitivity and specificity)
 Treatment includes PCI, fibrinolytics, CABG
 COURAGE trial showed that death from MI, any cause of death, hospitalization for ACS, and rate of
acute MI was not changed significant with PCI vs medical therapy group
 PCI is preferred over lysis due to lower rates of reinfarction, hemorrhagic stroke, and total stroke

Hypertension – Bostick
 We care about HTN because CV mortality doubles with each 20 mmhG SBP or 10 mmhg DBP
increment (115/75  135/85)
 End organ damage can occur to the
o heart leading to LVH, MI, HF
o PAD
o Brain  TIA, dementia
o CKD, retinopathy
 Pathophysiology of HTN
o Disorder of sodium metabolism  leads to increased EC fluid volume
o Imbalance of RAAS system
o Endothelial dysfunction
o Sympathetic overactivity
o Mosaic theory
 CAD, Stroke, PAD, CF go way down with proper BP control (Framingham heart study)
 Basic testing you want to get when a patient has high BP  Fasting Blood Glucose, Lipid profile, serum
creatinine with eGFR, serum sodium, potassium
 Although many more Americans now qualify as hypertensive under the new JNC7 guidelines, only a
fraction require additional pharmacologic therapy
 Use ACSVD Risk calculator to determine their lifetime complication of developing a cardiac event
 In a young female patient with sudden change in BP, suspect a secondary HTN cause (RAS,
fibromuscular dyplasia etc)
 We often give chlorthalidone a long acting HCTZ medication as a baseline treatment for HTN
 Difference between MASKED HTN and WHITE COAT HTN
 o Masked coat HTN  BP is fine in clinic, but elevated at home checks
o White coat HTN  BP is fine at home, but elevated in clinic
 In a patient with stage II HTN  2 medications are needed, but stage I HTN  start one and then adjust
 In African Americans  CCB + Thiazide diuretics (also more likely to require 2 meds)
o Beta blockers are not really recommended unless they have had an MI or you want to help
angina symptoms
o If he has kidney issues  consider an ACEi or ARB


Valvular Heart Disease

 45-year-old man develops new symptoms of sudden-onset flushing involving his head and neck lasting a
few minutes. He also notices watery diarrhea and abdominal pain when the flushing occurs. Serotonin
and its metabolites are elevated in his urine and serum.
o Carcinoid syndrome
o The cardiac lesions of gastrointestinal carcinoids are almost exclusively in the right side of
the heart and occur only when there are hepatic metastases. Fibrous plaques are found on
the endothelium of the cardiac chambers, valves, and great vessels. These plaques can
distort cardiac valves; tricuspid regurgitation and pulmonic stenosis are the most common
valvular problems.
 73-year-old man has angina pectoris on exertion, but an angiogram reveals non critical stenosis of the
coronary arteries. This occurs most frequently with which of the following valvular heart diseases?
o Aortic stenosis
 79-year-old man presents with syncope. On physical examination, he has a slow upstroke in his carotid
pulse and a diamond-shaped systolic murmur at the base. His chest is clear. Which of the following
findings is his CXR most likely to reveal?
o In aortic stenosis, there is normal overall cardiac size, but dilatation of the proximal
ascending aorta and blunt rounding of the lower left cardiac contour.
 32-year-old asymptomatic woman has a rapidly rising, forceful pulse that collapses quickly. Which of
the following is the most likely diagnosis?
o Aortic regurgitation
 25-year-old woman develops exertional dyspnea and fatigue. Her past history is significant for
rheumatic fever as a child. Auscultation of the heart reveals a loud first heart sound and a low-pitched
mid diastolic sound.
o Mitral stenosis
o The notched P wave is most prominent in lead II. In lead V1, the P wave has a negative
terminal deflection.
 Patient with new-onset syncope has a blood pressure of 110/95 mm Hg and a harsh systolic ejection
murmur at the base, radiating to both carotids. Auscultation of the second heart sound at the base might
reveal which of the following findings?
o Aortic stenosis
o In aortic stenosis, the first sound is usually normal; the second sound is characteristically
diminished because of the increased ventricular pressure and the stenotic valve is less
mobile. There can be a single S2 either because A2 and P2 are superimposed or A2 is
absent or very soft. Severe aortic stenosis may be accompanied by paradoxical splitting of
S2.

Hemodynamics - Aggarwal

 Swan-Ganz Catheter
o 1cc of air is injected into the catheter and inflate the balloon which takes the free air to the left
atrium
o 10 cc of saline can be injected to determine temperature changes


 

Hemodynamics in AMI
Normal hemodynamics Pulmonary Congestion
PCWP <18 PCWP >25
CI >2.2 CI >2.2

Warm & wet

Pulm congestion & periph
Peripheral
hypoperfusion
hypoperfusion
PCWP >25
PCWP <10
CI <2.2
CI <2.2
Cold & wet
Cold & dry

Evaluation and Management of CHF

 Biggest risk factor now is HTN  LVH and failure
  HF should be evaluated as decreased forward perfusion + pulmonary congestion
 AHA guidelines (NOT REVERSIBLE just progression)
o Stage A  you’re chilling
o Stage B  insult to the heart that predisposes a patient to HF but they have no current symptoms
o Stage C  Heart disease is present AND symptoms have occurred
o Stage D  Presence of heart disease with HF symptoms requiring aggressive medical therapy
 NYHA guidelines (REVERSIBLE)

o
 ACE inhibitors are usually first line for mortality benefit
 Sacubitril  neprolysin inhibitor (BNP degradation inhibitor) + ARB

Hyperlipidemia
 Evolocumab  statin + PCSK9 inhibitor is even better then just a stain in reducing LDL cholesterol
 Any statin is better than none and more potent is better than less potent
 Statins cause myalgias and increase risk for type 2 DM, while decreasing exercise tolerance
 Cholesterol Synthesis
o Important part of cell membranes and precursor to hormones, vitamin D, and bile acids
o Esterified by LCAT  allows it to be stored in micelles so it can be transported

o
 Lipids are transported via apolipoproteins  combinations form HDL, IDL, LDL, VLDL
 o
 Pancreatic lipase degrades dietary TG in the lumen of the small intestine
o FFA enter enterocytes, re-esterify, and that transported as chylomicrons
 Lipoprotein lipase is a vascular endothelium that degrades TG from chylomicrons so that their
degradation products can be absorbed  remainder is transported to liver
 Hormone sensitive lipase degrades stored TG
 Hepatic TG lipase  converts IDLs into LDLs



 Lipid Lowering Agents
o HMG-CoA reductase inhibitors (lovostatin)
 Greatly decrease LDL, slightly increase HDL, and decrease TG
 MOA: Inhibit conversion of HMG-CoA reductase to mevalonate
 Side effects: Hepatotoxicity, myopathy
o Bile acid resins (cholestyramine, colestipol)
 Decrease LDL, slightly increase HDL and TG
 MOA: Prevent intestinal reabsorption of bile acids, liver must now use cholesterol to
make more
 GI upset, decreased absorption of other drugs and fat soluble vitamins
o Ezetimibe
 Prevents cholesterol absorption at brush border  can lead to diarrhea
o Fibrates (gemfibrozil, bezafibrate)
 Decrease LDL, increase HDL, and greatly decreased TG
 MOA: Upregulate LDL  increase TG clearance
 Activates PPAR-a to induce HDL synthesis
 Side effects: Myopathy, cholesterol gallstones (inhibits cholesterol 7a hydroxylase)
o Niacin (vitamin B3)
 Decreases LDL, increases HDL, decreases TG
 MOA: Inhibits lipolysis (hormone sensitive lipase) in adipose tissue, reduces hepatic
VLDL synthesis
 Side effects: Red, flushed face, decreased by NSAIDS or long-term use, hyperglycemia,
hyperuricemia
o PCSK9 inhibitors (alirocumab, evolocumab)
 Greatly decrease LDL
 Inactivate LDL receptor degradation, increasing the amount of LDL removed by the
blood stream
 Side effects: Myalgias, delirium, dementia
Nutritional Deficiencies and Eating Disorders
 > 100cm Resection = Bile salt deficiency & fat malabsorption
 < 100cm Resection = Bile-acid induced diarrhea (secretory diarrhea with hyperabsorption of oxalate 
kidney stones)

Trace Minerals
ZINC SELENIUM
DEFICIENCY TOXICITY DEFICIENCY TOXICITY
Taste Loss N/V & Diarrhea Cardiomyopathy Hair Loss
Hair Color Change and Loss Abdominal Pain Skeletal Muscle Dysfunction Tooth Decay
Rash (Acro-orificial) Copper Deficiency Nail Changes
Neurologic
(MS changes, peripheral
neuropathy)
Lab = Plasma Zinc Lab = Serum Selenium
Lab = Blood Glutathione Peroxidase Activity
IODINE COPPER
DEFICIENCY TOXICITY DEFICIENCY TOXICITY
Hypothyroidism Hyper- or Hypothyroidism Pancytopenia Hepatic Necrosis
Mental Slowing Goiter Fractures Renal Failure
Delayed Development Neurologic (Ataxia, Neuropathy) N/V & Abdominal Pain
Coma
Lab = Urine Iodine Lab = Serum Copper
Lab = TSH Lab = Plasma Ceruloplasmin
CHROMIUM MANGANESE
DEFICIENCY TOXICITY DEFICIENCY TOXICITY
Glucose Intolerance Rash with Skin Ulcers Hair Color Change Neurologic (Parkinson's-like)
Bronchogenic CA Sexual Dysfunction
Lab = Serum Chromium Cramps
Lab = Glucose Tolerance Test Lab = Serum Manganese
IRON FLUORIDE
DEFICIENCY TOXICITY DEFICIENCY TOXICITY
Anemia N/V & Diarrhea Tooth Decay N/V & Diarrhea
(microcytic, hypochromic) Hepatic Necrosis Hypersalivation
Shock (all 3) Seizures
Lab = Serum Fe, TIBC, Ferritin CP Arrest
 Pazirandeh S & Burns DL. UpToDate – 2006

Arrythmias
 Anything that is above the His bundle is considered Supraventricular and anything below is called
ventricular
 Sinus arrhythmia
o Irregularity of the normal sinus rhythm that originates from the sinus node, usually in young and
healthy individuals and is not pathologic but a product of vagal tone
 Sinus bradycardia
o Secondary to vagal tone or sinus node disease
 Sinus tachycardia
o Physiolgoy response to exercise usually, dehydration
 Inappropriate sinus tachycardia
o Persistent, rate is high, cannot be explained by physiologic demands
 Sick Sinus Syndrome
o Tachycardia, Bradycardia
o Pts can have chronotrophic incompetence  inappropriately low HR responses to physiologic
demands
 If someone has an arrhythmia of sinus origin IF they have symptoms  put in a pacemaker
 Tachyarrhythmia
 o
o Remember that tachyarrhythmias occur from usually 2 reasons
 Focal arrhythmias: repetitive firing of a group of cells
o Reentry: the continuous cycling of an electrical impulse in any cardiac tissue

o
 A flutter vs A fib
o A flutter is a reentry circuit that keeps looping around hence producing the saw-tooth pattern
 Ablation is the preferred method and has a very high success rate as compared to AF
o A fib is not it is just multiple foci firing at once
 No P waves on EKG and patients have an irregular rhythm
 o
o Treatment: Rate control over rhythm  BB, CCB, Digoxin
 Long term  ablation or cardioversion

o
 REMEMBER if they have valvular afib you should immediately start them on warfarin
 Paroxysmal SVT

o
  AVRT vs AVNRT

o Treatment patients can usually do carotid sinus massage to slow the AV node and bring
themselves out of their tachycardia
o Definitive treatment is ablation
 AV Block

o
Congenital Heart Disease
 
 Older the patient is at the time of CoA repair the higher the incidence of systemic HTN after surgery is
Transfusion 2
 The Most Common transmitted infection is bacterial contamination!
 Septic Tranfusion Reaction/Bacterial Contamination of the Product
o Most commonly from platelets, then RBCs, uncommonly plasma
o Abrupt and severe onset
o Treatment: STOP TRANFUSION, NOTIFY BLOOD BANK, BROAD SPECTRUM
ANTIBIOTICS
 Alloimmunization
o Allo vs autoantibodies
 Alloantibodies  Antibodies against foreign RBC antigens that the patient doesn’t
express
 Autoantibodies  Antibodies against self RBC antigens that are present on the patient’s
own RBCs
o Can be clinically significant  Antibody is capable of causing hemolytic transfusion rxns,
hemolytic disease of the fetus
o Alloimmunization is highest in sickle cell disease patients!!
o IgM antibodies against RBC antigens are usually naturally occurring (intravascular hemolysis)
o IgG antibodies against foreign antigens are from transfusion or pregnancy (extravascular 
delayed hemolysis)
o