all.txt

GnRH analog.
Pulsitile: agonist (infertility)
Continuous: antagonist (prostate cancer, fibroids)
Toxic: antiandrogen, nausea, vomit

Androgen R Agonist
Treats hypogonadism
Toxic: masculinization in females. Dec intratesticular testosterone in males (gonadal atrophy)
Premature closure of epiphyseal plates
Inc LDL, dec HDL

(propecia)
5 alpha reductase inhibitor (dec DHT production)
Used in BPH or to promote hair growth

Competitive inhibitor of testosterone receptor. Used in prostate carcinoma

Inhibits steroid synthesis (inhibits desmolase) Used for PCOS to prevent hirsutism due to SE of gynecomastia and amenorrhea

Inhibits steroid binding to androgen R. Used for PCOS to prevent hirsutism (gynecomastia and amenorrhea)

(ethinyl estradiol, DES, mestranol)
Used for hypogonadism or ovarian failure or HRT?
Used in men with androgen dependent prostate cancer
Toxic: inc risk of endometrial cancer. Bleeding in post-menopausal women. DES: clear cell adenocarcinoma of vagina. Inc risk of thrombi.

Physiology:
Ovary=17beta-estradiol (most potent) 50x inc in preg.
Placenta=estriol (least potent) 1000x inc in preg.
Blood= aromatization
Cytoplasmic receptors translocate to nucleus.

Function:
Development of genitalia and breast + fat distribution
Follicular growth, endometrial proliferation, inc. myometrail excitability
Upregulation of estrogen, LH and progesterone receptors
feedback inhibition of FSH, LH
Stimulates prolactin secretion (but blocks action at breast)
Inc transport proteins: SHBG (inc HDL, dec LDL)

SERM. Partial agonist of estrogen R in hpothal. Prevents normal feedback inhibition and inc. release of LH and FSH from pituitary to stimulate ovulation.
Used for infertility and PCOS.
Toxic: hot flashes, ovary enlargement, multiple pregnancies, vision problems

Antagonist on breast tissue to treat and prevent recurrence of ER psotive breast cancer

Agonist of bone, reduces resorption so used for osteoporosis

Aromatase inhibitors used in postmenopausal women with breast cancer.

Dec growth and Inc vascularization of endometrium
Used in oral contraceptives and to treat endometrial cancer and abnormal uterine bleeding

Physiology:
From Corpus luteum, placenta, adrenal cortex , testes (elevation indicates ovulation)
Functions:
Stimulation of endometrial glandular secretions and spiral artery development
Maintains pregnancy
Dec myometrial excitability
Production of thick cervical mucus inhibiting sperm entry into uterus
Inc body temp
Inhibition of LH and FSH
Uterine SM relaxation
Dec estrogen-R expressivity

(RU-486)
Progestin competitive inhibitor
Used to terminate pregnancy with misoprostol (PGE1)
Toxic: heavy bleeding, GI effects, abdominal pain

PGE2 analog causing cervical dilation and uterine contraction inducing labor

B2 agonists relaxing uterus reducing premature uterine contractions

Alpha 1 blocker for BPH. Specific for alpha 1 A's on prostate (alpha 1 B's on vessels)

cGMP phosphodiesterase inhibitors -> inc cGMP -> SM relaxation in corpus cavernosum -> inc blood flow -> erection.
Toxic: headache flushing dyspepsia impaired blue green vision. Risk of hypotension with nitrates

Testosterone and DHT (testes), androstenedione (adrenal)
DHT=most potent
Androsten.=least potent
Test -> DHT by 5alpha reductase (inhib by finasteride)
Converted to estrogen by aromatase in sertoli cells and adipose
Exogenous testosterone decreases testicular size (HPG axis inhibition)

Testosterone Functions:
Deifferentiation of internal genitalia except prostate (epididymis, vas def, seminal vesicles)
Growth spurt (penis, seminal vesicles, sperm, muscle, RBCs)
Deep voice, closed epiphyseal plates (estrogen), Libido

DHT Functions:
Early: differentiation of penis, scrotum, prostate
Late: prostate growth, balding, sebaceous gland activity

XXY tesitcular atrophy, eunichoid body, tall, long extremities, gynecomastia, female hair distribution, Barr body, hypogonadism.
Dysgenesis of seminiferous tubules (dec. inhibin and testosterone, inc FSH and LH so inc. estrogen)

XO short stature, ovarian dysgenesis (streak ovary so infertile), shield chest, bicuspid aortic valve, webbed neck (cystic hygroma), preductal coarctation of aorta. Most common cause of primary amenorrhea. Dec estrogen so inc. FSH and LH.

Normal phenotype, Tall, severe acne, antisocial in 1%. Normal fertility

XX. Ovaries present but virilized external genitalia. Due to CAH or exogenous androgens taken during pregnancy.

Testes present but ambiguous or female external genitalia. AIS most common (aka testicular feminization)

Both ovaries and testes are present (ovatestis)

46 XY. Normal appearing female. Androgen receptor mutation. Female external genitalia has rudimentary vagina, uterus and uterine tubes absent. No pubic hair, abdominal testis or in labia majora (removed to prevent malignancy). Increased testosterone, estrogen, LH

AR. Only in XY. Can't convert testosterone to DHT so ambiguous genitalia until normalizes as male at puberty. Guevadoces. Normal hormones and internal genitalia

Decrease syn of gonadotropin in anterior pituitary. Anosmia, lack of secondary sex characteristics.

46 XX or XY. Very large inc in hCG. Slight increase in uterine size. 2% convert to choriocarcinoma. Snowstorm appearance. No fetal parts. 2 sperm and empty egg. 15-20% malignant trophoblastic disease.

69 XXY, slight increase in hCG, doesn't convert to choriocarcinoma, partial fetal parts, 2 sperm + 1 egg. Low risk of malignancy.

HTN, proteinuria, and edema. Eclampsia includes seizures. 7% of pregnant women from 20 weeks to 6 weeks postpartum.
Risk: HTN, diabetes, chronic renal disease, autoimmune disorders
Placental ischemia due to impairment of vasodilation of spiral arteries
HELLP Syndrome: hemolysis, elevated LFTs, low platelets.
Mortality due to cerebral hemorrhage and ARDS
Headache, blurred vision, abdominal pain, edema of face and extremities.
Treat: IV magnesium sulfatea nd diazepam (prevent and treat seizures)

Placenta detaches from site of implantation. Fetal death. Associated with DIC
Risk: smoking, HTN, cocaine
Painful bleeding in 3rd trimester

Placenta attaches to myometrium. No separation of placenta after birth
Risk: prior C-section, inflammation, and placenta previa.
Massive bleeding after delivery

Implants low in uterus. May occlude internal os
Risk: multiparity and prior C section
Painless bleeding in any trimester

Mostly in fallopian tubes. Suspect with high hCG and sudden lower abdominal pain. Check on US. Don't confuse with appendicitis.

may cause postpartum hemorrhage.

>1.5L of amniotic fluid.
Esophageal/duodenal atresia so can't swallow amniotic fluid. Anencephaly

<0.5L of amniotic fluid assoicated with placental insufficiency. bilateral renal agenesis or posterior urethral valves in males (can't excrete urine). Can give rise to potter's syndrome

CIN1,2,3
HPV 16,18
Vaccine available
May progress to invasive carcinoma if untreated
Risk: multiple sexual partners, smoking, early sexual intercourse, HIV infection

Squamous cell. Pap smear can catch dysplasia (koilocytes) before progresses to invasive carcinoma. Lateral invasion can block ureters causing renal failure.

Not neoplastic. Endometrial glands/stroma outside uterus. Cyclic bleeding leads to blood filled chocolate cysts. In ovary and peritoneum. Severe menstrual related pain. Infertility. Retrograde menstrual flow or ascending infection.

Endometrium within myometrium

Excess estrogen stimulation. Increases risk of endometrial carcinoma. Postmenopausal vaginial bleeding.
Risk: anovulatory cycles, HRT, PCOS, granulosa cell tumor

Most common gynecologic malignancy. Average age 60. Vaginal bleeding, Preceeded by hyperplasia.
Risk: prolonged estrogen w/o progestins, obesity, diabetes, HTN, nulliparity, late menopause
myometrial invasion gives worse prognosis

Fibroids. Myometrial tumor. Most common of all tumors in females!! Often multiple tumors, well demarcated, increase in blacks, benign SM tumor, rarely malignant
Estrogen sensitive so increase size in pregnancy and dec. size with menopause
Peaks in 20-40yo range.
Asymptomatic or if symptoms, multiple
Severe bleeding may lead to iron deficiency
Does NOT progress to leiomyosarcoma
Whorled pattern of SM bundles.

Bulky, irregularly shaped tumor with areas of necrosis and hemorrhage (de novo).
Inc. in blacks, aggressive tumor, recurs
May protrude from cervix and bleed. Commonly in middle aged women

Menopause before age 40. (Dec. estrogen, Inc FSH and LH)

Inc. LH production causes anovulation, hyperandrogenism (theca cells).
Amenorrhea, infertility, obesity, and hirsutism all from bilateral and enlarged ovaries filled with cysts.
Insulin resistanct, inc. risk of endometrial cancer,
Treat: weight loss, OCP, gonadotropin analogs, clomiphene, spironolactone to treat hirsutism or surgery

Follicular: unruptured graafian follicle
Corpus luteum: hemorrhage into persistent corpus luteum, regresses spontaneously
Theca-lutein: bilateral, multiple (choriocarcinoma and moles)
Chocolate cysts: blood cysts from endometriosis (menstrual cycle).

Ovarian germ cell tumor. malignant, like male seminoma (rarer). Sheets of uniform cells.
hCG and LDH

Rare and malignant. Develops during pregnancy in mother or baby. Large hyperchromatic syncytiotrophoblastic cells (hCG), increased frequency of theca-lutein cysts. Along with moles, "gestational trophoblastic neoplasia"

Endodermal sinus tumor. Aggressive and in ovaries or testes and sacrococcygeal area of young children. Yellow, friable solid masses
Schiller-Duval bodies that resemble glomeruli!
AFP

90% of ovarian germ cell tumors. 2 or 3 germ layers. Teeth and hair.
Mature: dermoid cyst, most frequent benign ovarian tumor
Immature: aggressively malignant
Struma ovarii: contains functional thyroid tissue (hyperthyroidism)

Ovarian non-germ cell tumor (20% of ovarian tumors). Bilateral, lined with fallopian tube-like epithelium, benign.

50% of ovarian tumors, malignant and frequently bilateral

Multilocular cyst lined by mucus secreting epithelium. Benign, intestine like tissue.

Malignant, pseudomyxoma peritonei. Intraperitoneal accumulation of mucinous material from ovarian or appendiceal tumor

Benign, bladder-like

Bundle of fibroblasts
Meig's syndrome: triad of ovarian fibroma, ascites, hydrothorax.
Pulling sensation in groin.

Secretes estrogen leading to precocious puberty. Leads to endometrial hyperplasia or carcinoma in adults.
Call-Exner bodies: follicles filled with eosinophilic secretions. Abnormal uterine bleeding

GI malignancy mets to ovary.
Mucin secreting signet cell adenocarcinoma

Usually secondary to cervical SCC

Mother took DES while pregnant

Rhabdomyosarcoma variant. Vaginal tumor of girls < 4 yo with spindle shaped cells that are dermin positive (grapelike clusters)

Small, mobile, firm, sharp edges
Most common tumor < 25 yo
Estrogen sensitive
Not a precursor to breast cancer

Grows in lactiferous ducts beneath areola
Nipple discharge (maybe bloody).
Slight risk for carcinoma

Large bulky mass of CT. "leaf-like" projections
Mostly in 50s
May become malignant

Fills ductal lumen and arises from ductal hyperplasia
Early malignancy without basement membrane penetration

Firm, fibrous, hard mass with sharp margins
Worst and most invasive and most common (76%)

Orderly row of cells thats often multiple and bilateral

Fleshy cellular lymphocytic infiltrates with a good prognosis

Ductal with caseous necrosis (subtype of DCIS)

Lymphatic invasion and block drainage
Peau d'orange: breast skin resembles orange peel.
50% 5 years survival

Eczematous patches on nipple. Paget cells are large cells in epidermis w/ clear halo and suggests underlying carcinoma (ductal)

Most common cause of breast lumps 25 < age < menopause
Premenstrual pain, multiple and bilateral
Fluctuation in size, no increased risk of carcinoma
1. fibrosis: hyperplasia of stroma
2. cystic = blue dome. fluid filled
3. sclerosing adenosis: calcifications
4. epithelial hyperplasia: inc number of epithelial cell layers in terminal duct lobule. (inc risk of carcinoma)

Breast abscess during breast feeding. S. Aureus

benign painless lump due to trauma

Hyperestrogenism. Kleinfelters or drugs:
Spironolactone, Digitalis, Cimetidine, Alcohol, Ketoconozole. (Some drugs create awesome knockers)

Dysuria, frequency, lower back pain
Acute: e coli
Chronic: more common

Hyperplasia, >50yo. Sensitized to DHT. Specifically periurethral (lateral and middle) lobes compress urethra.
Risk of distention of bladder, hydronephrosis and UTI.
Inc PSA
Treat: alpha 1 block or finasteride

>50yo. Mostly from posterior lobe in peripheral zone.
Diagnosed w/ DRE + biopsy, PSA, alk phos
Bone mets in late stages

Undescneded testis due to lack of spermatogenesis due to inc body temp associated with inc risk of germ cell tumors.

Malignant, painless, homogenous testicular enlargement. Most common testicular tumor.
Mostly 15-35 yo.
Watery cytoplasm and fried egg appearance.
Radiosensitive
Excellent prognosis

Malignant, painful, bad prognosis. Glandular and papillary morphology. Differentiates to other tumors. Inc AFP, hCG

Endodermal sinus tumor. Yellow, mucinous. Schiller duval bodies resemble glomeruli (inc AFP)

Malignancy with inc. hCG. Disordered syncytio and cytotrophoblasts. Hematogenous mets

Mature teratoma is most often malignant (opposite in females)

Reinke crystals. Androgen producing, gynecomastia, precocious puberty. Gold

Androblastoma from sex cord stroma

Most common testicular cancer in older men

Transilluminates, bag of worms. dilated vein in pampiniform plexus

inc fluid due to incomplete fusion of processus vaginalis

Dilated epididymal duct

Gray crusty plaque on shaft of penis or scrotum. 40s. 10% become SCC

Red velvet plaques on glans

Younger age, multiple papular lesions, non-invasive

Asia, Africa and S. America.
HPV and lack of circumcision

Bent penis due to acquired fibrous tissue formation

Dec estrogen production due to decline in ovarian follicles as age (avg=51yo). (earlier in smokers)
Usually preceded by 4-5 years of abnormal menstrual cycles
Post: estrogen = estrone (peripheral conversion of androgens and weaker)
Inc. androgens cause hirsutism
Inc FSH is best way to confirm menopause (loss of negative feedback from estrogen)
Slightly inc. LH
(HHAVOC: hirsutism, hot flashes, atrophy of vagina, osteoporosis, coronary artery disease)
Early menopause may = premature ovarian failure

Inc. estrogen, inc. GnRH-R on anterior pituitary
Estrogen surge -> LH release -> ovulation (rupture of follicle)
Progesterone -> inc temp
Mittelshmerz = blood from ruptured follicle causes peritoneal irritation (appendicitis-like)

Anucleate, biconcave (surface area-gas exchange)
Energy: glucose 90% anaerobic degraded to lactate
Cl-bicarb antiport.
Physiologic chloride shift: RBC transports CO2 from periphery to lungs
Live 120 days
Erythrocytosis = polycythemia
Anisocytosis = varying sizes
Poikilocytosis = varying shapes
Reticulocyte = immature erythrocyte

Thrombocyte, Small fragment from megakaryocytes. primary hemostasis. Aggregate and form hemostatic plug.
Dense granules: ADP, Ca
Alpha granules: vWF, fibrinogen
1/3 in spleen
Live 8-10 days
Thrombocytopenia = petechiae
vWF-R=Gp1b
Fibrinogen-R=Gp2b3a

Granulocytes: basophils, eosinophils, neutrophils
Mononuclear cells: monocytes and lymphocytes
Defend against infections (4-10,000/uL)

Acute inflam. response
40-75% of wbc's
Phagocytic, multilobed nucleus, large spherical azurophilic granules (lysosomes). Contain hydrolytic enzymes lysozyme, MPO, and lactoferrin.
Hypersegmented PMNs = B12 or folate deficient

2-10% of leukocytes. Large, Kidney-shaped nucleus. Fxlensive "frosted glass" cytoplasm. Differentiates into macrophages in tissues.

Phagocytoses bacteria, cell debris, and senescent red cells and scavenges dainaged cells and tissues. Long life in tissues. Macrophages differentiate from circulating blood monocytes (monocytes in blood, macrophages in tissue) Activated by gamma-interferon. Can function as Ag-presenling cell (APC) via MHC II.

1-6% of all leukocytes. Bilobate nucleus. Packed wilh large eosinophilic granules of uniform size. Defends against helminthic infections (major basic protein). Highly phagocytic for Ag-Ab complexes.
Produces histaminase and arylsulfatase (helps limit rxn post mast cell degranulation)
(NAACP cause eosinophilia: neoplasia, asthma, allergic rxn, collagen vascular disease, parasites)

Mediates allergic reaction. < 1% of all leukocytes. Bilobe nucleus. Densely basophilic granules containing heparin (anticoagulant), histamine (vasodilator) and other vasoactive amines, and leukotricncs (LTD-4). Found in the blood.
Stains w/ basic stains

Mediates allergic reaction. Degranulation — histamine, heparin, and eosinophil chemotactic factors. Can bind Fc portion of IgE lo membrane. Mast cells resemble basophils structurally and functionally but are not the same cell type. Found in tissue.
Type 1 hypersensitivity rxns.
Cromolyn sodium prvents degranulation (asthma)

Professional APCs. MHC2 and FcR on surface.
Induce primary antibody response
Skin=langerhans cells

Round, densely staining nucleus. Small amount of pale cytoplasm, B lymphocytes produce antibodies. T lymphocytes manifest the cellular immune response as well as regulate B lymphocytes and macrophages.

Part of humoral immune response. Arises from stem cells in bone marrow. Matures in"B"one 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 and produce antibodies. Has memory.
Can function as an APC via MHC II,

Off-center nucleus, clock-face chromatin distribution, abundant RER and well-developed Golgi apparatus, B cells differentiate into plasma cells, which produce large amounts of Ab specific to a particular antigen.

Mediates cellular iminune response. Originales from stem cells in the bone marrow, but matures in the thymus.
T cells differenliale inlo cytotoxic T cells (MHC I, CD8), helper T cells (MHC II, CD4), and suppressor T cells. The majority of circulating lymphocytes are T cells (80%).

Subsequent fetus taht is Rh+ to an Rh- mother already giving birth to a fetus that was Rh+.
Mother makes Ab against Rh during first pregnancy and they cross placenta during next causing hemolytic disease of newborn
Treat: rhogam (Rh Ag Ig at first delivery)

IgM does NOT cross placenta
IgG does (anti-Rh)

Deficient in Gp1b (platelet to collagen adhesion) Dec. Platelets, Inc Bleeding Time.

Deficiency in Gp2b3a (defect in platelet to platelet aggregation thru fibrinogen). No platelet clumping. Inc bleeding time

Spur Cell: liver disease, abetalipoproteinemia
(spiny)

Thalassemias, Anemia of chronic disease, iron deficiency, lead poisoning

(TAIL)

G6PD deficiency

Hereditary elliptocytosis

Megaloblastic anemia. Also hypersegmented PMNs, marrow failure

Sideroblastic anemia

Helmet cell: DIC, TTP/HUS, traumatic hemolysis

Sickle cell anemia

Hereditary spherocytosis, autoimmune hemolysis

Bone marrow infiltration (myelofibrosis)

HbC disease, asplenia, liver disease, thalassemia
(HALT)

Oxidation of iron from ferrous iron to ferric, denatured Hb precipitation and damage to RBC membrane. Leads to formation of bite cells
(Alpha thal, G6PD deficiency)

Basophilic nuclear remnants in RBCs
(Functional hyposplenia or asplenia)

Microcytic, hypochromic (MCV<80) anemia.
Dec iron due to chronic bleeding, malnutritrition/absorption disorders or inc demand (e.g., pregnancy) -> dec. heme synthesis (see Image 22).
May manifest as Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal web, and atrophic glossitis).

Microcytic, hypochromic anemia

Prevalent in Asia and Africa.
Defect: a-globin gene mutations -» a-globin synthesis. Deletion of 4 genes is incompatible with life —> Hb Barts (gamma4), which causes
hydrops fetalis. Deletion of 3 genes —> HbH disease (beta 4)
1-2 genes not associated with significant anemia

Deletion of 1-2 genes is not associated wilh anemia.

Prevalent in Mediterranean populalions.
Problems: point mutations in splice sites and promoter sequences.

Beta thalassemia minor (heterzygote);
1. Beta chain is underproduced. 2. Usually asymplomatic. 3. Diagnosis confirmed by inc HbA,

B-thalassemia major (homozygote): 1. P chain is absent —> severe anemia recurring blood

Betal thal minor transfusion
(2. hemochmatosis), 2. Marrow expansion ("crew cut" on skull x-ray) -»skeletal deformilies.
Chipmunk faeies, Both major and minor) T HbF (a.yj. HbS/P-thalassemia heterozygole: mild to moderate sickle cell disease
depending on amounl of B-glnbin production

Lead inhibits ferrochelalase and ALA dehydratase —> dec heme synthesis. Also inhibits rRNA degradation —> basophilic stippling (aggregation of ribosomes)
Accumulation of protoporphyrin in blood
Present with microcytic anemia, GI and kidney disease
Kids (lead paint -> mental deterioration)
Adults (environment -> headache, memory loss, demyelination)

(LEAD: Lead lines on gingivae = burton's lines...and on epiphyses of long bones. Encephalopathy and Erythrocyte basophilic stippling, Abdominal colic and sideroblastic anemia, Drops wrist and foot, Dimercaprol and EDTA are treatments or Succimer for kids)

Defect in heme bone syn.
Hereditan: X-linked defeel in S-aminolevulinic acid synthase gene. Treatment; pyridoxine (B6) therapy. Reversible etiologies: alcohol, lead, t iron, normal TIBC, T ferritin. Ringed sideroblasls (wilh iron-laden milochondrial.)

Beta Thal.
Alpha Thal.
Iron deficiency
Lead poisoning
Sideroblastic anemia

(BAILS)

Megaloblastic anemia (folate + B12 deficiency)

Nonmegaloblastic anemia:
1. Liver diseased
2. Alcoholism: bone marrow suppression
3. Reticulocytosis: larger than mature RBCs
4. Metabolic disorder: orotic aciduria (purine + pyrimidine synthesis)
5. Drugs (5FU, AZT, hydroxyurea)

Findings: hypersegmented neutrophils, glossitis, dec. folale, Inc homocysteine but normal methylmalonic,
Etiologies: malnutrition (e.g., alcoholics) malabsorption, impaired metabolism (e.g.. methotrexate, trimethoprim), Inc requirement (e.g., hemolylic anemia, pregnancy).

Findings: hypersegmented neutrophils, glossilis, dec. B12, Inc homocysleine, Inc methylmalonic acid.
Etiologies: malnutrition (e.g., alcoholics), malabsorption (e.g., Crohn's disease). pernicious anemia, Diphyllobothrium latum (fish tapeworm).
Neurologic symptoms: subacute combined degeneration (due to involvement of B12 in fatty acid pathways).
1. Peripheral neuropathy with sensorimotor dysfuction
2. Posterior columns lost
3. Lateral corticospinal loss (spasticity)
4. Dementia

Nonhemolytic: Anemia of chronic disease (ACD), aplastic anemia, kidney disease.

Hemolytic:
Intravascular Hemolysis: Paroxysmal noctumal hemoglobinuria, auloimmune (cold agglutinins), mechanical
destruction (eg., aortic stenosis, prosthetic valve), G6PD deficiency.
Findings: Dec. haptoglobin, inc. LDH

Extravascular Hemolysis: Hereditary spherocytosis, pyruvale kinase deficiency, sickle cell
anemia, HbC defect, autoimmune (warm agglutinins), microangiopathic (eg. DIC, TTP-HUS).
Findings: macrophage in spleed clears RBCs. Inc LDH and Inc UCB (jaundice).

Nonhemolytic, normocytic anemia
Inflammation -> Inc hepcidin —> Inc release of iron from macrophages
Inc iron, Dec TIBC, Inc ferritin.
Can become microcytic, hypochromic in long-standing disease.

Nonhemolytic Normocytic anemia
Pathologic features: pancytopenia characterized by severe anemia, neutropenia, and thrombocytopenia. Normal cell morphology, but hypocellular bone marrow with fatty
infiltration.

Causes: failure or destruction of myeloid stein cells due to:
1. Radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites)
2. Viral agents (parvovirus B19, EBV, HIV)
3. Fanconi's anemia (inherited defect in DNA repair)
4. Idiopathic (immune mediated. 1° stem cell defect); may follow acute hepatitis

Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, pelechiae. infection.
Treatment: witlidrawal of offending agent, immunosuppressive regimens (antithymocyte
globulin, cyclosporine), allogeneic bone marrow transplantation, RBC and platelet
transfusion, G-CSF or GM-CSF.

Nonhemolytic normocytic anemia
Dec EPO -> Dec Hematopoiesis

Intrinsic hemolytic normocytic anemia-Extravascular

Defect in proteins interacting with RBC membrane skeleton and plasma membrane (eg ankyrin, band 4.1, or spectrin).

Pathogenesis: less membrane causes small and round RBCs with no central pallor (Inc MCHC, Inc RDW) -> premature removal of RBGs by spleen.

Findings: splenomegaly, aplastic crisis (B19 infection). Howell-Jolly bodies present after splenectomy.
Labs: positive osmotic fragility test.

Intrinsic hemolytic normocytic anemia-Intravascular
X-linked. Defect in G6PD —> dec glutathione -> inc RBC susceptibility to oxidant stress. (eg: sulfa drugs, infections, fava beans)
Symptoms: back pain, hemoglobinuria a couple days later
Labs: blood smear shows RBCs with Heinz bodies and bite cells

Intrinsic hemolytic normocytic anemia- extravascular.
Autosomal recessive, defect in pyruvate kinase -> dec. ATP -> rigid RBCs
Presentation: hemolytic anemia in newborn

Intrinsic hemolytic normocytic anemia- extravascular

8% of African-Americans carry the HbS trait; 0.2% have the disease. Sickled cells are crescent-shaped RBCs. "Crew cut" on skull x-ray due to marrow expansion from Inc EPO (also in thalassemias)
Newborns are initially asymptomatic owing to inc HbF and dec HbS.
Mulation: HbS mulalion is a single amino acid replacement in P chain (substitution of normal glutamic acid with valine).
Pathogenesis: deoxygenated HbS polymerizes. Low O2 or dehydration precipitates sickling. Heterozygotes (sickle cell trait) have resistance to malaria, Complicalions in homozygotes (sickle cell disease)
1. Aplastic crisis (due to parvovirus B19)
2. Autosplenectomy —» T risk of infection with encapsulated organisms
3. Salmonella osteomyelitis
4. Painful crisis (vaso-occlusive)
5. Renal papillary necrosis (clue to low O2 in papilla)
6. Splenic sequestration crisis

Treatment: hydroxyurea (Inc HbF) and bone marrow transplant

Intrinsic hemolytic normocytic anemia
Glutamic acid to lysine mutation
Pts. with HbSC (1 of each mutant) have milder disease than HbSS

Intrinsic hemolytic normocytic anemia- Intravascular

Decay accelerating factor inhibits complement on RBC membrane
Impaired synthesis of GPI anchor, decay accelerating factor and all GPI linked proteins in the RBC membrane
Labs: inc urine hemosiderin

Extrinsic hemolytic normocytic anemia
Warm agglutinin (IgG)—chronic anemia seen in SLE, in CLL, or with certain drugs (alpha methyldopa)
(Warm = GGGreat)
Cold aggluliuin (IgM)—acute anemia triggered by cold; seen wilh Mycoplasma pneumoniae infections or infectious mononucleosis.
(Cold = MMM)

Erythroblastosis fetalis—seen in newborns due to Rh or other blood antigen incompatibility —> mother's antibodies attack fetal RBCs.
Autoinmiune hemolytic anemias are usually Coombs positive:

•Direct Coombs' test —auto-Ig antibody added to patient's RBCs agglutinate if RBGs are coated with Ig.
• Indirect Coombs' test—normal RBCs added to patient's serum agglutinate if serum has anti-RBC surface Ig.

Extrinsic Hemolytic Normocytic Anemia.
Pathogenesis: RBCs are damaged when passing through obstructed or narrowed vessel lumina. Seen in DIC, TTP-HUS, SLE, and malignant hypertension.
Schistocytes (helmet cells) are seen on blood smear due to mechanical destruction of RBCs

Extrinsic hemolytic normocytic anemia
Inc destructions of RBCs (malaria, babesia)

Extrinsic Hemolytic Normocytic Anemia
Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia 2° to mechanical destruction.

Porphobiligen deaminase (uropophyrinogen-I-synthase) affected. Accumulate porphobilinogen, delta-ALA, uroporphyrin.
Symptoms: painful abdomen, red urine, polyneuropathy, psych disturbances, drug use precipitates.
Treat: Glucose and heme (block ALA synthesis)

Uroporphyrinogen decarboxylase affected so build up uroporphyrin (tea colored urine)
Blistering cutaneous photosensititivity
most common porphyria

Inc. PTT. intrinsic pathway coagulation defect.
A: deficiency of factor 8
B deficiency of factor 9
Macrohemorrhage in hemophilia (hemarthroses: bleed into joints)
Easy bruising

Inc PT and PTT
General coagulation defect with dec. syn of factors 2,7,9,10, protein C and S

idiopathic thrombocytopenic purpura.
Dec platelets, inc bleeding time
Dec. platelet survival. Anti-Gp2b3a Ab destroys peripheral platelets
Inc megakaryocytes

Thrombotic thrombocytopenia purpura. Dec. platelets, inc bleeding time. Dec. platelet survival
Deficiency of ADAMTS 13 (vWF metalloprotease) so decreased degradation of vWF multimers
Inc number of large multimers leads to inc platelet aggregation and thrombosis
Schistocytes, inc LDH
Pentad: Neuro, renal, fever, thrombocytopenia, microangiopathic hemolytic anemia

Intrinsic pathway coagulation delect: dec vWF leads to normal or inc PTT (depends on severity; vWF acts to carry/protect factor VIII).
Defect in platelet plug formation: dec vWF -> defect in platelet-to-collagen adhesion.
Mild but most common inherited bleeding disorder (AD).
Treat: DDAVP (desmopresin) releases vWF stored in endothelium

Dec. platelets, Inc bleeding time, PT, PTT
Widespread aclivation ofclotting leads to a deficiency in clotting factors, which creates a bleeding state.
Causes: Sepsis (gram-negative). Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome. Transfusion (STOP Making New Thrombi).
Labs: schistocytes, inc fibrin split producls (D-dimers), dec fibrinogen, dec factors V and VIII.

Production of mutant factor V that cant be degraded by protein C, most common cause of inherited hypercoagulability

Mutation in 3' untranslated region associated with venous clots

Inherited deficiency of AT
Reduced inc in PTT after heparin

Dec ability to inactivated factors 5 and 8
Inc risk of thrombotic skin necrosis with hemorrhage following administration of warfarin

Presence of Reed-Sternberg cells
Localized, single group of nodes; extranodal rare;
contiguous spread (stage is strongest predictor
of prognosis)
Constitutional ("B") signs/symptoms—low-grade
fever, night sweats, weight loss
Mediastinal lymphadenopathy
50% of cases associated with EBV; bimodal distribution
—young and old; more common in men except for
nodular sclerosing type
Good prognosis = inc lymphocytes, dec RS cells (binucleate bilobed owl eyes: CD30+, 15+ B cell in origen)

Nodular sclerosing (65-75%):Excellent prognosis, collagen banding. Primarily young adults
Mixed cellularity (25%): RS cells!! Intermediate prognosis
Lympliocyte predominant (6%) Excellent prognosis
Lymphocyte depleted (rare): Poor disease process (in older men w/ disseminated disease)

Hodgkin's Lymphoma

Adolescents or young adults. t(8;14), cmyc gene moves to next heavy chain Ig. Starry sky appearance (lymphocytes w/ interspersed macrophages). Associated with EBV. Jaw lesion in endemic form in Africa, pelvis or abdomen in sporadic form

Burkitt Lymphoma

Usually older adults (20% in kids). Most common adult NHL (mature T cell in origin

Diffuse large B cell lymphoma

Older males t(11;14). Poor progosis, CD5+

Mantle cell lymphoma

Adults, t(14;18) bcl2 expression. Difficult to cure, indolent course. bcl2 inhibits apoptosis

Follicular lymphoma

Adults, HTLV1. Adults present with cutaneous lesions especially affects population in japan, west africa, carribean aggressive

Adults T cell lymphoma

aka: sezary syndrome. Adults, Adults prevent w. cortaneous patches / nodules. Indolent CD4+

Myscosis fungiodis:

Monoclonal plasma cell ("fried-egg" appearance) cancer that arises in the marrow and produces large amounts of IgG (55%) or IgA (25%), Most common 1° lumor arising within bone in the elderly (> 40 - 50 years of age).
Associated:
Inc suscptibility to infect
Primary amyloidosis
Punched out lytic bone lesion on tuesday
M spike on protein electrophoresis
Ig light chains in urine (bence jones)
reuleaux formatoin RBCs stacked like powder chipes in blood sugar.
Disting from waldenstroms macrow
RBCs stacked like poker chips in blood smear
Distinguish from waldenstomr

Multiple Myeloma

Monoclonal 4 bayby ur so smart
Monoclonal grammophathy of undetermined significance.

MGUS

Upregulated growth of leukocytes in bone marrow. (anemia).
Infection

Leukemias

ALL. Occurs in children.
Children: Bone marrow involvement
Adolescent males: mediastinal mass
Bone marrow filled with huge increase in lymphocytes
TdT+ (marker of pre-T and pre-B cells), CALLA +
Most responsive to therapy
May spread to CNS and testes
t(12;21) leads to better prognosis

Occurs in older adults > 60yo
Often asymptomatic, smudge cells in peripheral blood smear
Warm Ab autoimmune hemolytic anemia
CLL has peripheral blood lymphocytosis

Elderly. Mature B-Cell tumor. Cells have filamentous hairlike projections
Stains TRAP + (tartrate-resistant acid phosphatase)

60-70yo
Auer rods; way increased circulating myeloblasts on peripheral smear. M3 (APL) responds to all-trans retinoic acid (ATRA-vitamin A) inducing differentiation of myeloblasts.
APL: t(15;17) PML-RARa. latin american 40yo

Philadelphia chromosome t(9;22), bcr-abl. myeloid stem cell proliferation.
Increased neutrophils, metamyelocytes, basophils, platelets, and splenomegaly.
Dec. RBCs
bcr-abl leads to inc cell division and inhibition of apoptosis.
Can transform to AML or ALL (blast crisis)
Very low leukocyte alk phos
Responds to imatinib (anti bcr-abl tyrosine kinase)

proliferative disorder of dendritic (Langerhans) cells.
Defective cells express S-100 and CD1a
Birbeck granules ("tennis rackets" on EM) are classic

Inc. RBCs, WBCs, Platelets
JAK2 mutation
Abnormal clone of hematopoietic stem cells are increasingly sensitive to growth factors
"Lenny kravitz"

Inc. platelets. Jak2 mutation in 30-50%
Specific to megakaryocytes

Dec. RBCs. JAK2 mutation in 30-50%
FIbrotic obliteration of bone marrow. Teardrop cell.

Cofactor for the activation of antithrombin, dec thrombin and Xa. Short half-life
Immediate anticoagulation for PE, stroke, acute coronary syndrome.
Ml, DVT.
Used during pregnancy (does not cross placenta). Follow PTT
Toxicities: Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal of heparinization, use protamine sulfate (positively charged molecule that acts by binding negatively charged heparin).

HIT: heparin binds to platelets, causing
autoantibody production that binds to and activates platelets leading to their clearance and resulting in a thrombocytopenic hypercoagulable state

Newer low-molecular-weight heparins (e.g., enoxaparin) act more on Xa. have better bioavailability and 2-4 times longer half-life, can be administered subcutan. and without laboratory monitoring.
Not easily reversible.

Hirudin derivatives,
Direct thrombin inhibitors
use as alternative to heparin for patients with HIT

Interferes with normal syn and gamma-carboxylation of vitamin K-dependent clotting (factors 2,7,9,10,C,S).
Metabolized by the cytochrome P-450 palhway. In laboratory assay, has
effect on EXtrinsic pathway and inc PT. Long half-life.

Used for: Chronic anticoagulation. Not used in pregnant women (because warfarin, unlike heparin, can cross the placenta). Follow PT/INR values.

Toxic: Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions.

Long term reverse: give vit. K
Short term reverse: Fresh frozen plasma

Streptokinase, urokinase, tPA (alteplase), APSAC (anistreplase)
Directly or indireclty aid conversion of plasminogen to plasmin which cleaves thrombin and fibrin clots.
Inc PT and PPT but no change in platelet count
Early MI or ischemic results.
Toxic: Bleeding, contraindicated in patients w/ bleed

Acetylates and irreversibly inhibits cox (COX-2 and Cox1) to prevent conversion of arachidonic acid to TxA2
Inc bleeding time, no change in PT or PTT
Antipyretic, analgeisic , antiinflammatory, antiplatelet drugs
Toxic: gastric ulcer, bleed, hyperventilation, Reyes syndrome, tinnits (CN8)

inhibit platelet aggregation (irreversible block of ADP reeptors) inhibit fibinogen binding by preventing gp2b3a expression
ACS, Coronary stenting. Dec. incidence of recurrent thrombotic stroke.
Neutropenia (ticlopidine)

Monoclonal Ab binds to gp 2b3a on activated platelets preventing aggregation.
ACS percutaneous transluminal cornoary angioplasty
Toxic: bleeding, throbocytopenia.

antimetabolite
Inhibits DHFR (folate analog). Dec dTMP, dec DNA and protein syn

Used for leukemia, lymphoma, choriocarcinoma, sarcoma. Abortion, ectopic, rheumatoid arthritis, psoriasis.

Toxic: myelosuppression (reversible by leucovorin = folinic acid "rescue")
Macrovesicular fatty change in liver, mucositis, teratogenic

Antimetabolite. Pyrimidine analog
5FU -> 5F-dUMP which complexes folic acid
Inhibits thymidylate synthesis so dec dTMP, DNA and protein syn

Used for: colon cancer, basal cell carcinoma
Synergy w/ MTX

Toxic: myelosuppresion, not reversible w/ leucovorin (only for MTX). Instead rescue is with thymidine
Photosensitivity!

Antimetabolite. Purine Analog
Decreased de Novo purine synthesis
Activated by HGPRTase

Use: leukemias, lymphoma (not CLL or hodgkins)

Toxic: Bone marrow, GI, liver, metabolized by xantine oxidase (inc toxic w/ allopurinol)

Antimetabolite. purine analog (same pathway as 6-MP -> dec de novo purine synthesis)

Use: ALL

Toxi: bone marrow depression, liver
Can be given with allopurinol as opposed to 6-MP

antimetabolite. Pyrimidine antagonist (inhibition of DNA polymerase)

use: AML, ALL, high grade NHL

toxic: leukopenia, thrombocytopenia, megaloblastic anemia

Antitumor antibiotics
Intercalates in DNA.

Use: wilm's tumor, ewing's sarcoma, rhabdomyosarcoma. Childhood tumors!

Toxic: myelosuppression

Antitumor antibiotics. Generates free radicals
Intercalate and break up dna to dec. replication

(A in ABVD)
Use: combo regimen (ABVD) for hodgkins. Also for myeloma, sarcoma and solid tumors)

Toxic: cardiotoxic. also myelosuppression and alopecia. Toxic to Extravasation tissues

Antitumor antibiotics
G2 phase specific (free radical formation w/ breaks in DNA strands)

Use: Testicular cancer, hodgkins

Toxic: pulmonary fibrosis, skin changes, minimal myelosuppresion

Antitumor antibiotics
Late S-G2 specific
Inhibits topoisomerase II (DNA degradation)

Use: small cell carcinoma of lung and prostate, testicular cancer

Toxic: myelosuppression, GI irritation, alopecia

Alkylating agents
X-link covalently (interstrand) DNA at guanine N-7. Requires bioactivation by liver

use: NHL, breast and ovarian carcinomas. Immunosuppressants.

Toxic: myelosuppression, hemorrhagic cystitis (prevention w/ mesna -> thiol group of mesna binds toxic metabolite)

Carmustine, lomustine, semustine, streptozocin
Alkylating agents
Require bioactivation. Cross BBB (CNS)

Use: brain tumors (GBM)

Toxic: CNS toxicity (dizzy, ataxia)

Alkylating agents (alkylates DNA)

Use: CML, ablating bone marrow before bone marrow transplant

Toxic: pulmonary fibrosis, hyperpigmentation

Microtubule inhibitor. Alkaloids that bind tubulin in M phase and block polymerization of MTs so mitotic spindle can't form.
"MTs are the vines of cells"

Use: Hodgkin's lymphoma, Wilm's tumor, choriocarcinoma

Toxic:
vincristine: neurotoxic (areflexia, peripheral neuritis) paralytic ileus
Vinblastine: bone marrow suppression

MT inhibitor. Hyperstabilizes polymerized MTs in M phase so mitotic spindle can't break down (anaphase can't occur).
"It's taxing to stay polymerized"

Use: ovarian and breast cancer

Toxic: myelosuppression and hypersensitivity

Mech: Cross-link DNA.
Use: Testicular, bladder, ovary, and lung carcinoinas.
Toxic: Nephrotoxicity and acoustic nerve damage.

Mech: Inhibits Ribonucleotide Reductase —» dec DNA Synthesis (S-phase specific)

use: Melanoma, CML, sickle cell disease (inc HbF)

Toxic: Bone marrow suppression, GI upset.

Mech: May trigger apoptosis. May even work on nondividing cells.

use: Most commonly used glucocorticoid in cancer chemo. Used in CLL, Hodgkins (part of the MOPP regimen). Also an immunosuppressant used in autoimmune diseases.

Toxic: Cushing-like symptoms; immunosuppression, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia. psychosis

Mech: SERMs receptor antagonists in breast, agonists in bone; block the binding of estrogen to estrogen receptor-positive cells

use: Breast cancer. Also useful to prevent osteoporosis.

Toxic: Tamoxifen may inc the risk of endometrial carcinoma via partial agonist effects; "hot
flashes." Raloxifene does not cause endometrial carcinoma because it is an endometrial antagonist.

Monoclonal Ab against HER2 (erb B2). helps kill breast cancer cells that overexpress HER2 possibly thru Ab-depenent cytotoxicity

use: metastatic breast cancer

toxicity: cardiotoxicity

philadelphia chromosome, bcr-abl tyrosine kinase inhibitor

use: CML, GI stromal tumors

toxic: fluid retention

Monoclonal Ab against CD20 (B cell neoplasms)

use: NHL, rheumatoid arthritis (w/ MTX)