MD

Antiplatelet Drugs

Aspirin/ASA

- Works on Cyclo-oxygenase (AA -> thromboxane)

- Low dose (80-160 mg/day) irreversibly inhibits plt COX, and they can’t make new COX b/c they have no nucleus

- Some inhibition of endothelial COX but not much, therefore prostacyclin (anti-coag) synthesis isn’t  affected much
- Benefit is greater after thrombolysis

- SE is bleeding

- Prophylaxis for MI or TIA (80mg/day), higher doses for post-MI/TIA (160-325mg/day)

- Contraindications (bleeding risk):  Vit. K def., Hemophilia, Hypoprothombinemia, pregnancy & childbirth

Clopidogrel/Plavix

- ADP antagonist

- Competes with ADP for P2Y receptor (prevents lowering of cAMP)

- Less incidence of neutropenia/thrombocytopenia

- Used in combo with ASA

 Ticlopidine

- ADP antagonist, prodrug

- Often used in combo with ASA (synergistic)

- May cause severe neutropenia (1%)

 

Dipyridamole

- phosphodiesterase inhibitor (prevents cAMP breakdown)

 

GpIIb-IIIa inhibitors

-  Eptifibatide, Abciximab, Tirofiban

-  Block the receptor for fibrinogen blocking plt Aggregation

 

Heparin (& derivatives)

- Stimulates natural anticoags (antithrombin)

Heparin

- Monitor using aPTT (add negative charges)

- Negatively charged, therefore cannot cross membranes (given IM, IV, parentally)

- Good for pregnancy

- Eliminated by RES & macrophages

- Potentiates AT III (in the plasma) – inhibits IIa, Xa, IXa and VIIa

- Toxicity – hemorrhage

- Antidote – protamine sulfate (1mg for every 100 units of heparin)

Heparin-Induced Thrombocytopenia (HIT) – occurs 5-10 days after, stop heparin immediately;  use alternatives lepirudin/danaparoid

- Good for PE and DVT and during pregnancy

 

LMWH – better bioavailability, can be given subcut. w/o lab monitoring as outpatient, less risk of bleeding

- More expensive, not good in renal failure, not for pregnancy

- DOES NOT inhibit IIa (but inhibit Xa)

- Good for DVT, PE and UA

Danaparoid – promotes inhibition of Xa by AT (for HIT)

Lepirudin – direct thrombin inhibitor (for HIT)

 

Coumarin (Oral) anticoags

Warfarin

- Monitored using PT (add tissue factor)

- Inhibit Vit. K Epoxide reductase in liver

-Prevents carboxylation of Vit.K dependent factors

-Takes 4-5 days to get effective (carboxylated fx’s in plasma need to be cleared before inactive ones take over)

-Small volume of distribution, steep dose-response curve (small therapeutic window)

-Teratogenic

- For DVT and PE, prosthetic heart valves or Afib, MI

-Metabolized by CYP1A and CYP2C9

-Efficacy measured by INR, pt’s PT time divided by PT time in pooled plasma

- INR = (PTpt/PTref)^ISI (target is 2.0 – 3.0)

- Warfarin overdose

- Give Excess Vit.K, goes through a diff  enzyme that isn’t inhibited by warfarin  (Diaphorase)

Fibrinolytics (lyse formed thrombi)

Streptokinase – turns plasminogen -> plasmin

-Plasmin breaks down fibrin (lysis of formed clot) Dissolves clots post-MI/DVT/PE

- SE – bleeding (systemic plasminogen activation), allergy, hTN, fever

- Streptokinase has an additive effect with ASA

Tissue plasminogen activator (tPA) – acts on fibrin and circulating plasminogen -> plasmin

- Less systemic plasmin

- Same indications as streptokinase

- More expensive

 Abetalipoproteinemia: decrease ApoB-48, Apo B-100; pigmentary degeneration of retina, acanthocytes, steatorrhea, cerebellar ataxia.
   
 Acute Fatty Liver of Pregnancy: microvesicular steatosis in the liver, mitochondrial dysfunction in the oxidation of fatty acids leading to an accumulation in hepatocytes
   
  Alkaptonuria: homogentisate oxidase deficiency, increase homogenistic acid, ochronosis, dark blue urine.
   
  AcylCoA Dehydrogenase deficiency (MCAD): fasting hypoglycemia, no ketone bodies, dicarboxilic acidemia.
   
  Bernard Soulier Sd: gp1b deficiency, prolonged bleeding time
 
  Bloom Sd: chromosome 15, Ashkenazi Jews, BLM gene.
 
  Carpenter Sd: craniosynostosis, acrocephaly, craniofacial asymmetry, increased ICP, cutaneous syndactyly, polydactily, mild-profound MR.
 
  Chediak Higashi Sd: Lyst gene mutation, microtubule polymerization defect, no phagolysosome formation, albinism.
 
  Chondrodystrophy: normal-sized trunk and abnormally short limbs and extremities (dwarfism)
 
  Congenital Adrenal Hyperplasia: 17alpha or 21beta or 11 beta hydroxylase deficiency; enlargemente od adrenal glands due to increase ACTH
 
  Congenital Hepatic Fibrosis: hepatic (periporta) fibrosis, irregularly shaped proliferating bile duct, portal hypertension, renal cystic disease.
 
  Cystic Fibrosis: CFTR gene, Phe508, defective Chloride channel, chromosome 7.
 
  Dubin-Johnson Sd: direct hyperBbnemia, cMOAT deficiency, black liver
 
  Endocardial Fibroelastosis: restrictive/infiltrative cardiomyopathy, thick fibroelastic tissue in endocardium of young children, <2yo
 
Familial Mediterranean Fever: chromosome 16, recurrent autoinflammatory disease, characterized by F°, PMN disfx, sudden attacks pain/inflammation (7 types of attacks (abdominal, joints, chest, scrotal, myalgias, erysipeloid, fever). Complication: AA-amyloidosis
 
  Fanconi Anemia: genetic loss of DNA crosslink repair, often progresses to AML, short stature, ↑incidence of tumors/leukemia, aplastic anemia
 
  Friedreich’s Ataxia: GAA triplet repeat, chromosome 9, neuronal degeneration, progressive gait & limb ataxia, arreflexia, hypertrophic cardiomyopathy, axonal sensory neuropathy, kyphoscoliosis, dysarthria, hand clumsiness, loss of sense of position, impaired vibratory sensation.
   
 Gaucher’s disease: glucocerebrosidase deficiency, glucocerebroside accumulation, femur necrosis, crumpled paper inclusions in macrophages.
   
Ganzman’s thromboasthenia: gpIIbIIIa deficiency, deficient platelet aggregation.
   
Hartnup Disease: tryptophan deficiency, leads to niacin deficiency, pellagra-like dermatosis
   
Hemochromatosis: HFE gene, C282Y MC mutation, chromosome 6, unrestricted reabsorption of Fe+ in SI, iron deposits in organs, bronze diabetes, DM1, malabsorption, cardiomyopathy, joint degeneration, increased iron, ferritin, TIBC. Complications: liver cirrhosis, hepatocelullar carcinoma
 
Homocystinuria: due to B6 deficiency (defective Cystathionine synthase) or due to B9,B12 deficiency (defective Homocysteine Methyltrasnferase), dislocated lenses (in & down), DVT, stroke, atherosclerosis, MR.
 
Krabbe's Disease: Galactocerebrosidase deficiency, galactocerebroside accumulation, gobloid cells, optic atrophy, peripheral neuropathy.
 
Leukocyte Adhesion Defect (LAD): CD-18+ deficiency, omphalitis in newborns, chronic recurrent bacterial infxs, increase WBC count, no abscess or pus formation.
 
  Metachromic Leukodystrophy: Aryl-sulfatase A deficiency, sulfatides accumulation, Demyelination (central & peripheral), Ataxia, Demantia (DAD)
 
  Niemann-Pick Disease: sphingomyelinase deficiency, sphingomyelin accumulation, HSM, cherry-red macula, foam cells.
   
Phenylketonuria (PKU): phenylalanine hydroxylase deficiency, Phe accumulation, MR, microcephaly, diet low in Phe!!! also in pregnancy, avoid aspartame, musty odor.
 
Polycystic Kidney Disease (children): ARPKD, rogressive & fatal renal failure, multiple enlarged cysts perpendicualr to renal capsule, association with liver cysts. Bilateral palpable mass.
 
  Rotor Sd: direct hyperBbnemia, cMOAT deficiency, no black liver
 
Shwaman Diamond Sd: exocrine pancreatic insufficiency (2°MCC in children after CF), bone marrow dysfunction, skeletal abnormalities, short stature.
 
Situs inversus: assoc w/ Kartagener sd
 
Sicke Cell Disease and Trait: Hb S, beta globin chain, chromosome 11, position 6, nucleotide codon change (glutamic acid --> valine), vaso-occlusive crisis (pain), autosplenectomy, acute chest pain sd, priapism, hand-foot sd, leg ulcers, aplastic crisis, drepanocytes & Howell-Jolly bodies, hemolytic anemia, jaundice, bone marrow hyperplasia
 
 Tay-Sachs Disease: Hexoaminidase A deficiency, GM2 accumulation, cherry-red macula, onion skin lysosomes.
 
Thalasemia: alpha (chromosome 16, gene deletion), beta (chromosome 11, point mutation)
 
Werner Disease: adult progeria
 
  Wilson’s Disease: Chromosome 13, WD gene, ATP7B gene (encondes for Copper transporting ATPase), copper accumulation in liver, brain (putamen), eyes (Descemet membrane - Kayser-Fleischer ring), decreased ceruloplasmin.
 
  Xeroderma Pigmentosa: defective excision endonuclease, no repair of thymine dymers caused by UV radiation, excessive freckling, multiple skin cancers.

Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia

Thalassemia provides partial resistance against malaria.

Beta thalassemia

- most commonly seen in people of Mediterranean descent

Etiology

usually due to point mutations in promoter sequences or splicing sites

β-globin locus - short arm of chromosome 11

In a normal cell, the β-globin chains are coded by a total of two alleles . Thus, there are two forms of the disease.

Beta thalassemia minor (trait): one defective allele

Beta thalassemia major (Cooley's anemia): two defective alleles

Pathophysiology

Inefficient erythropoiesis → anemia

Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF  and ↑ HbA2

 

Alpha thalassemia

most commonly seen in people of Asian and African descent

Etiology

usually due to deletion of at least one out of the four existing alleles

Inheritance pattern: autosomal recessive

In a normal cell, the α-globin chains are coded by a total of four alleles. 

Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.

- Silent carrier (minima form): one defective allele (-α/αα)

- Alpha thalassemia trait (minor form) -Two defective alleles ,Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations

- Hemoglobin H disease: three defective alleles

- Hemoglobin Bart disease (major form): four defective alleles

Pathophysiology

Alpha thalassemia major (HbH disease) and Bart disease: faulty α-globin chain synthesis → ↓ α-chains → ↑ β-, γ-chains → ↑ HbH, ↑ Hb-Bart's

ENDOMETRIOSIS

The proliferation and functioning of endometrial tissue outside of the uterine cavity

Incidence: - 15-30% of all premenopausal women, -mean age at presentation: 25-30 years
 
Etiology - unknown

theories

- retrograde menstruation theory of Sampson
- Mullerian metaplasia theory of Meyer
- endometriosis results from the metaplastic transformation of peritoneal mesothelium under the influence of certain unidentified stimuli
- lymphatic spread theory of Halban
- surgical transplantation
- deficiency of immune surveillance


Predisposing Factors

- nulliparity
- age > 25 years
- family history
- obstructive anomalies of genital tract

Sites of Occurrence

ovaries  most common location, 60% of patients have ovarian involvement
broad ligament
peritoneal surface of the cul-de-sac (uterosacral ligaments)
rectosigmoid colon
appendix


Symptoms

there may be little correlation between the extent of disease and symptomatology

pelvic pain - due to swelling and bleeding of ectopic endometrium, unilateral if due to endometrioma

dysmenorrhea (secondary) - worsens with age, suprapubic and back pain often precede menstrual flow (24-48 hours) and continue throughout and after flow

infertility - 30-40% of patients with endometriosis will be infertile, 15-30% of those who are infertile will have endometriosis

dyspareunia  on deep penetration

premenstrual and postmenstrual spotting
bladder symptoms - frequency, dysuria, hematuria

bowel symptoms - direct and indirect involvement diarrhea, constipation, pain and hematochezia

Diagnosis

truly a surgical diagnosis

history - cyclic symptoms - pelvic pain, dysmenorrhea, dyschezia

physical examination

- tender nodularity of uterine ligaments and cul-de-sac
- fixed retroversion of uterus
- firm, fixed adnexal mass (endometrioma)

laparoscopy

- dark blue or brownish-black implants (mulberry spots) on the uterosacral ligaments, cul-de-sac, or anywhere in the pelvis
- chocolate cysts in the ovaries (endometrioma)
- powder-burn lesions
- early white lesions and blebs


Treatment

pseudopregnancy - cyclic estrogen-progesterone (OCP) or medroxyprogesterone (Provera)

pseudomenopause - danazol (Danocrine) = weak androgen, s/e:  weight gain, fluid retention, acne, or hirsutism, leuprolide (Lupron) = GnRH agonist (suppresses pituitary GnRH)

s/e: hot flashes, vaginal dryness, reduced libido, and osteoporosis with prolonged use .these can only be used short term because of osteoporotic potential

surgical

- laparoscopic resection and lasering of implants
- lysis of adhesions
- use of electrocautery
- unilateral salpingo-oophorectomy
- uterine suspension
- rarely total pelvic clean-out
- follow-up with 3 months of medical treatment