Blood

BLOOD

CIRCULATORY SYSTEM
* BLOOD
* HEART
* BLOOD VESSELS

FUNCTIONS OF BLOOD
* TRANSPORT
* PROTECTION
* REGULATION

TRANSPORT
* OXYGEN (O2)
* CARBON DIOXIDE (CO2)
* NUTRIENTS
* WASTES
* HORMONES
PROTECTION
* IMMUNE SYSTEM
o WHITE BLOOD CELLS
o ANTIBODIES
* CLOTTING SYSTEM
o PLATELETS
o FIBRINOGEN / FIBRIN

REGULATION
* BODY TEMPERATURE
* pH
* WATER BALANCE
* ELECTROLYTE BALANCE

BLOOD COMPOSITION
BLOOD IS COMPRISED OF TWO MAIN COMPONENTS:
* PLASMA
* FORMED ELEMENTS
THESE COMPONENTS CAN BE SEPARATED BY CENTRIFUGATION
THE FRACTION OF THE BLOOD VOLUME COMPRISED OF RED BLOOD CELLS IS TERMED THE HEMATOCRIT

PLASMA COMPOSITION
* WATER (~90%)
* SOLUTES (~10%)
o PROTEINS (~8%)
o OTHER COMPOUNDS (~2%)
+ NUTRIENTS
+ GASES
+ WASTES
+ HORMONES
+ ELECTROLYTES

PLASMA PROTEINS
* MOST ABUNDANT PLASMA SOLUTE
* LIVER CAN PRODUCE 4 GRAMS OF PLASMA PROTEINS PER HOUR
* THREE MAJOR CATEGORIES
o ALBUMINS
o GLOBULINS
o FIBRINOGEN
ALBUMINS
* ~60% OF PLASMA PROTEINS
* SMALL
* TRANSPORT LIPIDS, HORMONES, CALCIUM, ETC.
* BUFFER BLOOD pH
* CONTRIBUTE TO VISCOSITY & OSMOLARITY
* INFLUENCE BLOOD PRESSURE, BLOOD FLOW, AND FLUID BALANCE

GLOBULINS
* ~36% OF PLASMA PROTEINS
* THREE SUBCLASSES
o ALPHA (a)
o BETA (b)
o GAMMA (g)
* ALPHA (a)
o VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT
* BETA (b)
o VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT
* GAMMA (g)
o COMPONENTS OF IMMUNE SYSTEM
o PRODUCED BY PLASMA CELLS, WHICH ARE DESCENDED FROM WHITE BLOOD CELLS

FIBRINOGEN
* ~4% OF PLASMA PROTEINS
* PRECURSOR OF FIBRIN
* INVOLVED IN BLOOD CLOTTING

PLASMA: NUTRIENTS
* SUGARS
* AMINO ACIDS
* FATS
* CHOLESTEROL
* PHOSPHOLIPIDS
* VITAMINS
* MINERALS

PLASMA: GASES
* OXYGEN (O2)
o REQUIRED FOR CELLULAR RESPIRATION
* CARBON DIOXIDE (CO2)
o PRODUCT OF CELLULAR RESPIRATION
* NITROGEN (N2)
o USUALLY PHYSIOLOGICALLY UNIMPORTANT
o WHY DO YOU THINK IT IS THERE?

PLASMA: WASTES
NITROGENOUS WASTES
* PRODUCTS OF CATABOLISM
o (ESP: AMINO ACID CATABOLISM)
* MOST ABUNDANT IS UREA
* REMOVED FROM BLOOD BY KIDNEYS
* EXCRETED THROUGH URINE
* RATE OF REMOVAL BALANCES RATE OF PRODUCTION

PLASMA: ELECTROLYTES
* SODIUM (Na+)
* CALCIUM (Ca2+)
* POTASSIUM (K+)
* MAGNESIUM (Mg2+)
* CHLORIDE (Cl-)
* BICARBONATE (HCO3-)
* PHOSPHATE (HPO42-)
* SULFATE (SO42-)
* VARIOUS IONS
* SODIUM IS THE MOST PREVALENT
* INCREASE BLOOD OSMOLARITY
o AFFECT BLOOD VOLUME
o AFFECT BLOOD PRESSURE

FORMED ELEMENTS
* ERYTHROCYTES (RED BLOOD CELLS)
* LEUKOCYTES (WHITE BLOOD CELLS)
* PLATELETS (CELL FRAGMENTS)

ERYTHROCYTE FUNCTIONS
* CARRY O2 FROM LUNGS TO CELLS
* CARRY CO2 FROM CELLS TO LUNGS
* HOW DO O2 AND CO2 RELATE TO THE FUNCTIONS OF A CELL?

ERYTHROCYTE QUANTITIES
* MEN: 4.6 – 6.2 MILLION/mL IN
o HEMATOCRIT 42 – 52 (% RBCs)
* WOMEN: 4.2 – 5.4 MILLION/mL
o HEMATOCRIT 37 – 48 (% RBCs)
* GENDER DIFFERENCES BASED ON:
o ANDROGENS INCREASE NUMBER
o MENSTRUAL LOSS DECREASES NUMBER
o BODY FAT (INVERSE RELATIONSHIP)
o FASTER CLOTTING IN MEN

ERYTHROCYTE STRUCTURE
* DISC SHAPED
* BICONCAVE
* 7.5 MICROMETER (mm) DIAMETER
* 2 MICROMETERS (mm) THICK

ERYTHROCYTE STRUCTURE
PLASMA MEMBRANE
* PHOSPHOLIPID BILAYER
* GLYCOPROTEINS, GLYCOLIPIDS
o DETERMINE BLOOD TYPE
* ACTIN AND SPECTRIN ON INNER SURFACE
o RESILIENCE / DURABILITY / PLIABILITY
* HIGH SURFACE AREA:VOLUME RATIO
o RESULT OF BICONCAVE SHAPE
o INCREASES RATE OF GAS DIFFUSION INTO AND OUT OF CELLS

ERYTHROCYTE STRUCTURE
CYTOPLASM
* LACKS ORGANELLES
o ESP: LACKS MITOCHONDRIA, NUCLEUS
o WHY IS THIS IMPORTANT?
o CANNOT REPAIR
o LIMITED LIFESPAN (~120 DAYS)
o CANNOT DIVIDE
o NEW CELLS FORMED IN BONE MARROW
* HEMOGLOBIN
o RED PIGMENT
o HIGH CONCENTRATION (33%)
o 280 MILLION MOLECULES PER CELL
o CARRIES MOST OF THE O2
o CARRIES SOME OF THE CO2
o PROTEIN & NON-PROTEIN COMPONENTS

HEMOGLOBIN
PROTEIN COMPONENT
* 4 POLYPEPTIDES (HETEROTETRAMER)
o 2 a-GLOBIN PROTEINS
o 2 b-GLOBIN PROTEINS
NON-PROTEIN COMPONENT
* 4 HEME GROUPS
o PORPHYRIN RING AND IRON ION
o IRON ION WITHIN HEME BINDS TO O2

ABO BLOOD TYPES
* DETERMINED BY SURFACE ANTIGENS
o GLYCOLIPIDS AND GLCOPROTEINS
+ (SUGARS ON CELL SURFACE)
o GENETICALLY DETERMINED
o RECOGNIZED BY ANTIBODIES
o INDIVIDUALS POSSESS ANTIBODIES TO ANTIGENS THEY THEMSELVES DO NOT POSSESS
o RECOGNITION OF THESE ANTIGENS BY ANTIBODIES CAUSES CELL CLUMPING
* DETERMINED BY GENE “I”
* THREE ALLELES
o IA
o IB
o i
* IA AND IB ARE CODOMINANT
* i IS RECESSIVE TO IA AND IB
* THREE ALLELES OF “I” GENE
* INDIVIDUALS POSSESS TWO COPIES
* FOUR BLOOD TYPES
o A GENOTYPE IAIA OR IAi
o B GENOTYPE IBIB OR IBi
o AB GENOTYPE IAIB
o O GENOTYPE ii

ANTIBODIES TO A AND B ANTIGENS
* APPEAR SHORTLY AFTER BIRTH
* PRESENT FOR ENTIRE LIFE
* PRODUCED IN RESPONSE TO SIMILAR ANTIGENS ON INTESTINAL BACTERIA
* CROSS-REACT WITH A AND B ANTIGENS
* TERMED “ANTI-A” AND “ANTI-B”
* CAUSE OF TRANSFUSION REACTIONS

Rh BLOOD TYPES
* DETERMINED BY SURFACE ANTIGENS
* UNRELATED TO ABO BLOOD TYPE
* GENETICALLY DETERMINED
* ALLELES OF THREE GENES
o C, c, D, d, E, e
o DD, Dd ARE Rh+
o dd MAY BE Rh-, DEPENDING ON ALLELES OF OTHER GENES
* ANTI-D ANTIBODIES NOT NORMALLY PRESENT
o PRESENT ONLY IN Rh- EXPOSED TO Rh+
o FIRST EXPOSURE NOT PROBLEMATIC
o SECOND EXPOSURE PROBLEMATIC
o TRANSFUSION / PREGNANCY
* IMMUNE RESPONSE PREVENTABLE
o RhoGAM (Rh IMMUNE GLOBULIN)

OTHER BLOOD GROUPS
* > 100 OTHER BLOOD GROUPS
* USEFUL IN GENETIC / BIOCHEMICAL TESTING
* RARELY CAUSE TRANSFUSION REACTIONS

ERYTHROCYTE DISORDERS
ANEMIA
* ERYTHROCYTE DEFICIENCY, OR
* HEMOGLOBIN DEFICIENCY
* THREE CLASSES
o INADEQUATE SYNTHESIS
o BLEEDING
o RBC DESTRUCTION
* CONSEQUENCES
o OXYGEN DEPRIVATION (HYPOXIA)
+ SHORTNESS OF BREATH
o REDUCED BLOOD OSMOLARITY
+ WATER RETENTION IN TISSUES (EDEMA)
o REDUCED BLOOD VISCOSITY
+ HEART BEATS FASTER
+ CARDIAC FAILURE
SICKLE-CELL ANEMIA
* ~0.25% OF AFRICAN AMERICANS
* GENETICALLY DETERMINED
* ABERRANT b-GLOBIN ALLELE (HbS)
o SINGLE AMINO ACID SUBSTITUTION
o GLUTAMIC ACID (HbA)  VALINE (HbS)
* CELLS SICKLE UNDER LOW OXYGEN
* MULTIPLE DELETERIOUS EFFECTS

* WHY IS THE FREQUENCY SO HIGH?
o MALARIA PREVALENT IN AFRICA
o Plasmodium PARASITE LIVES IN RBCs
o SURVIVES POORLY IN CELLS WITH HbS
o INDIVIDUALS WITH HbS LESS LIKELY TO DIE (HETEROZYGOTES MOST FIT)
o THUS, HbS PROVIDES PROTECTION

LEUKOCYTES
* 5,000 – 10,000 CELLS/mL
* FIVE TYPES:
o NEUTROPHILS 60 – 70 % 9 – 12 mM
o LYMPHOCYTES 25 – 33% 5 – 8 mM (most)
o MONOCYTES 3 – 8 % 12 – 15 mM
o EOSINOPHILS 2 – 4% 10 – 14 mM
o BASOPHILS <0.5 – 1% 8 – 10 mM
* GRANULOCYTES
o NEUTROPHILS
o EOSINOPHILS
o BASOPHILS
* AGRANULOCYTES
o LYMPHOCYTES
o MONOCYTES
LEUKOCYTES
NEUTROPHILS
* HIGHLY MOBILE
* INCREASE IN RESPONSE TO BACTERIAL INFECTIONS
* KILLS BACTERIA
o PHAGOCYTOSIS
o CHEMICALLY (BURST LYSOSOMES)

EOSINOPHILS
* INCREASE WITH ALLERGIES
* INCREASE WITH PARASITIC INFECTIONS
* PHAGOCYTOSIS
o ANTIGEN / ANTIBODY COMPLEXES
o ALLERGENS
* HYDROLYTIC ENZYME RELEASE
o RESPONSE TO HOOKWORM, TAPEWORM, ETC.
o TOO LARGE TO PHAGOCYTIZE
BASOPHILS
* GENERALLY NOT PHAGOCYTIC
* AID OTHER LEUKOCYTES
o RELEASE HISTAMINE
+ INCREASE BLOOD FLOW TO AREA
o RELEASE HEPARIN
+ INHIBIT CLOTTING
LYMPHOCYTES
* INCREASE IN IMMUNE RESPONSE
* SEVERAL SUBCLASSES
* VARIOUS IMMUNE FUNCTIONS
o ESP: SECRETE ANTIBODIES

MONOCYTES
* DIFFERENTIATE INTO MACROPHAGES
* PHAGOCYTOSIS OF PATHOGENS
* PHAGOCYTOSIS OF DEBRIS
* PRESENT ANTIGENS TO OTHER CELLS OF IMMUNE SYSTEM
PLATELETS
* 130,000 – 400,000 / mL
* NOT CELLS
o FRAGMENTS OF MEGAKARYOCYTES
o SMALL (2 – 4 mM DIAMETER)
* POSSESS VARIOUS ORGANELLES
* PSEUDOPODS
o AMOEBOID MOVEMENT
o PHAGOCYTOSIS
PLATELET FUNCTIONS
* SECRETE CLOTTING FACTORS
* SECRETE VASOCONSTRICTORS
* FORM TEMPORARY PLATELET PLUGS
* DISSOLVE OLD BLOOD CLOTS
* PHAGOCYTOSIS OF BACTERIA
* SECRETE CHEMICALS TO ATTRACT LEUKOCYTES TO SITES OF INFLAMMATION
* SECRETE GROWTH FACTORS

CONTROL OF BLEEDING
HEMOSTASIS
* VASCULAR SPASM
* PLATELET PLUG FORMATION
* COAGULATION
VASCULAR SPASM
* CONSTRICTION OF BROKEN VESSEL
* IMMEDIATE PROTECTION AGAINST BLEEDING
* MULTIPLE TRIGGERS
TRIGGERS OF VASCULAR SPASM
* PAIN RECEPTORS  NERVES  BLOOD VESSELS CONSTRICT
* SMOOTH MUSCLE OF BLOOD VESSELS CONSTRICT
* PLATELETS RELEASE SEROTONIN (CHEMICAL VASOCONSTRICTOR)
PLATELET PLUG FORMATION
* BLOOD VESSEL BROKEN
* COLLAGEN FIBERS EXPOSED
* PLATELETS BIND TO COLLAGE FIBERS
o FORM PSEUDOPODS
o ATTACH TO VESSEL AND OTHER PLATELETS
o CONTRACT AND PULL WALLS TOGETHER
o DEGRANULATION
PLATELET PLUG FORMATION
* DEGRANULATION
o RELEASE OF COMPOUNDS TO
+ VASOCONSTRICT
+ ATTRACT PLATELETS
+ STIMULATE DEGRANULATION
+ PROMOTE AGGREGATION
o POSITIVE FEEDBACK
CONTROL OF BLEEDING
* COAGULATION (CLOTTING)
* MOST EFFECTIVE DEFENSE
* FIBRINOGEN  FIBRIN  POLYMER
* TWO REACTION PATHWAYS
o EXTRINSIC MECHANISM
+ CLOTTING FACTORS FROM DAMAGED BLOOD VESSEL
o INTRINSIC MECHANISM
+ CLOTTING FACTORS FROM BLOOD
CLOTTING FACTORS
* PROCOAGULANTS
* PROTEINS PRODUCED IN LIVER
* INACTIVE  ACTIVE
o EACH ACTIVATES THE NEXT
o REACTION CASCADE
o AMPLIFICATION AT EACH STEP
o POSITIVE FEEDBACK INVOLVED
* CLOT RETRACTION
o CLOT FORMED
o PLATELETS ADHERE TO FIBRIN
o PLATELETS CONTRACT
o PULLS EDGES OF BROKEN VESSEL TOGETHER
* PLATELETS SECRETE PDGF
o PLATELET-DERIVED GROWTH FACTOR
o STIMULATES MITOSIS
* FIBROBLASTS INVADE AND PRODUCE CONNECTIVE TISSUE

CLOT DISSOLUTION
* FIBRINOLYSIS
* MULTIPLE STEPS
* POSITIVE FEEDBACK
* SIMILAR, IN REVERSE
PREVENTION OF COAGULATION
* PLATELET REPULSION
* DILUTION AND BLOOD MOVEMENT
* ANTICOAGULANTS
o ANTITHROMBIN (LIVER)
o HEPARIN (BASOPHILS)

COAGULATION DISORDERS
HEMOPHILIA

* DEFICIENCY IN A CLOTTING FACTOR
* CASCADE DISRUPTED
* CLOTTING DEFICIENCY
COAGULATION DISORDERS
HEMOPHILIA A
COAGULATION DISORDERS
HEMOPHILIA B
BLOOD CELL PRODUCTION
STEM CELLS
* PLURIPOTENT CELLS
o UNDIFFERENTIATED CELLS
o ABLE TO DIVIDE AND DIFFERENTIATE INTO MULTIPLE TYPES OF CELLS
o NOT ALL ARE “TOTIPOTENT”
o (NOT FULLY DIFFERENTIATED)
o E.G., HEMOCYTOBLASTS (BLOOD)
o E.G., EMBRYONIC STEM CELLS
* YOLK SAC
o EARLIEST HEMOPOIETIC TISSUE
o PRODUCES STEM CELLS
o COLONIZE OTHER ORGANS
+ BONE, LIVER, SPLEEN, THYMUS, ETC
o LIVER STOPS HEMOPOIESIS AT BIRTH
o SPLEEN STOPS ERYTHROPOIESIS SHORTLY AFTER BIRTH
* MYELOID HEMOPOIESIS
o OCCURS IN BONE MARROW
o FORMS ALL SEVEN FORMED ELEMENTS
* LYMPHOID HEMOPOIESIS
o OCCURS IN SEVERAL ORGANS
+ THYMUS, TONSILS, LYMPH NODES, SPLEEN, INTESTINES, ETC.
o PRODUCES LYMPHOCYTES
HEMOCYTOBLASTS
* STEM CELLS
* PLURIPOTENT
* DIFFERENTIATE INTO ALL FORMED ELEMENTS
o ERYTHROPOIESIS
o LEUKOPOIESIS
o THROMBOPOIESIS

ERYTHROCYTE PRODUCTION
ERYTHROPOIESIS
ERYTHROCYTE PRODUCTION
ERYTHROPOIESIS
ERYTHROCYTE HOMEOSTASIS
IRON METABOLISM
ERYTHROCYTE DEATH
HEMOLYSIS
* IRON
* PORPHYRIN RING
LEUKOCYTE PRODUCTION
LEUKOPOIESIS
PLATELET PRODUCTION
THROMBOPOIESIS
PLATELET PRODUCTION

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Venous Thromboembolic Disease

VENOUS THROMBOEMBOLIC DISEASE
by:R. Duncan Hite, MD
Section on Pulmonary and Critical Care Medicine

Venous Thromboembolic Disease

* Venous thrombosis - ~ 5 million pts yearly
+ Most caused by inadequate prophylaxis in hospitalized pts
* 10 % suffer pulmonary embolism ~ 500,000
* ~ 1% of all hospitalized pts have PE
* Contributes to 6 % of all hospital deaths
* ~ 125,000 deaths annually from PE
+ 3rd most common cardiovascular cause of death (MI, CVA)
+ Most deaths occur early – PREVENTION IS KEY!!
* Diagnosis of PE made in < 30% when contributes to death; < 10% if incidental

Case studies
Venous Thromboembolic Disease
Epidemiology

* 85 - 90% of PE pts have DVT risk factors
* 90-95% of PEs arise from lower ext. DVT
* Defined DVT Risk Factors: (Virchow’s Triad)
o Venous stasis - CHF, Immobility, Age > 70, Travel, Obesity, Recent surgery (4 weeks) or hospitalization (6 mos)
o Venous Injury - Prior DVT/PE, LE Trauma/Surgery
# LE trauma or surgery - Very high (50+%)
# Major surgery - (5 - 8%)
o Hypercoaguability - Cancer, Pregnancy, Nephrotic Syndrome, Hyperhomocysteinemia, Factor V Leyden mutation, Deficiency of Protein C/S or ATIII, Anti Phospholipid Ab, HITTS, Smoking

Pulmonary Hypertension Hemodynamic Effects
Deep Venous Thrombosis
Diagnosis
* Venography - remains the “gold standard”
+ Pitfalls: Difficult to perform, expensive, contrast load, DVT
* Compression Ultrasound (Sonography, Duplex and Color Doppler)
+ Criteria: echogenicity, noncompressibility, distension, free floating thrombus, absence of Doppler waveform, Abnormal color image
+ Accuracy:
# Symptomatic Patients: Sensitivity = 90-100%, Specificity = 95-100%
# High Risk Asymptomatic: Sensitivity = 50-80%, Specificity = 95-100%
* Impedance Plethysmography
* Radionuclide Venography (Indium-111)
* MRI - increasing popularity and utilization, includes deep pelvic veins

Deep Venous Thrombosis Prevention
* Orthopedic Surgery
o LMWH or Coumadin (INR 2.0 - 3.0) beginning preoperatively or immediately postoperatively. Adjusted dose SQ Heparin is an acceptable alternative but more complex.
o Adjuvant use of mechanical devices may add additional benefit. May be sufficient as primary prophylaxis for TKR if used optimally.
o Low dose SQ Hep, Aspirin, IPC alone are not recommended (less effective).
o Duration:
+ minimum of 7-10 days
+ Post Discharge Prophylaxis: 4-6 weeks for high risk patients
* General Surgery (including Urologic)
o Prophylaxis with SQHep, LMWH, ES or IPC
+ Moderate Risk - minor procedure with a risk factor or 40-60 yo, major procedures and <40
+ High Risk - minor procedure with risk factors or >60, major procedures with risk factors or age >40.
+ Increased Risk of Bleeding - use ES or IPC
o Combination therapy: very high risk - multiple risk factors
o Postdischarge Prophylaxis: selected very high risk pts
* Gynecologic Surgery
o Major surgery for benign disease
# SQ Hep BID, LMWH, IPC, continue for several days post op
o Major surgery for malignancy
# SQ Hep TID, Combination AC/Mech, high dose LMWH
* Neurosurgery
o Intracranial Surgery
# IPC or ES, Low dose SQHep or LMWH may be acceptable
# Combination IPC or ES with SQHep or LMWH in high risk

Deep Venous Thrombosis Prevention
* Trauma
o LMWH as soon as possible
o IPC or ES until LMWH started
* Acute Spinal Cord Injury
o LMWH recommended
o Low dose SQHep, ES or IPC are less effective
o Combination Mechanical/anticoagulant may be acceptable
o Continue throughout rehabilatation
* Medical (Cancer, CHF, Bedrest, MI, CVA…)
o Low dose SQ Hep or LMWH
o IPC if anticoagulation contraindicated

PE SIGNS AND SYMPTOMS
Symptoms
* Dyspnea - 80%
* Chest pain - 70%
* Cough - 50%
* Apprehension - 50%
* Hemoptysis - 30%

Signs
* Tachycardia - 60%
* Tachypnea - 70%
* Fever - 60%
* Clinical DVT - 30%

Pulmonary Embolism Diagnosis
* Chest x-ray - nonspecific abnormalities in most; normal early
+ Westermark's sign and Hampton's hump uncommon
* Arterial blood gas – hypoxemia is common
+ 15 - 20% will not manifest hypoxemia (i.e. normal A-a gradient)
* ECG – nonspecific changes typically
+ S1Q3T3 pattern in massive PE with RV strain
+ helpful in evaluating other causes of chest pain

PE – V/Q LUNG SCAN
* Radiolabeled Xenon inhaled for ventilation and radiolabeled Technetium for perfusion
* Safe
* Not very specific
* Not very useful if pre-existing lung disease

Pulmonary Embolism Diagnosis - V/Q Scan
Pulmonary Embolism
Diagnosis - Pulmonary Arteriogram
* Remains “gold standard” for Dx of PE
* Expensive
* Low morbidity and mortality
o Mortality < 0.1%
o Major morbidity < 0.5%
o Pulmonary Hypertension not a contraindication
Pulmonary Embolism
Diagnosis - Pulmonary Arteriogram
Lobar Defect
Segmental Defect
Pulmonary Embolism
Diagnosis - Chest CT
* Accurate for segmental or larger PE
+ Sensitivity 85 - 95% (Overall 50-60%)
+ Specificity 90 - 100%
* Accuracy depends on interpreter
+ Large Inter-interpreter variability
+ Reduced accuracy with less experience
* Significant contrast load ~ 65% of PA gram
* Similar expense to Pulmonary Arteriogram
* Can identify other pulmonary etiologies
Pulmonary Emboli Diagnosis - MRA
Venous Thromboembolism Treatment
Continuous IV Heparin:
Heparin-Induced Antibodies
Venous Thromboembolism Treatment
Low Molecular Weight Heparins:
Venous Thromboembolism Outpatient LMWH
Enoxaparin sodium
Unfractionated heparin
Venous Thromboembolism
Treatment
Synthetic Heparins:
Fondaparinux (Arixtra)
Oral anticoagulation (Coumadin)
Inferior Vena Cava Filter

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Approach to the Jaundiced Patient

Approach to the Jaundiced Patient
Internal Medicine Survivor Series
By:Joel Bruggen, MD

New Onset Jaundice
* Viral hepatitis
* Alcoholic liver disease
* Autoimmune hepatitis
* Medication-induced liver disease
* Common bile duct stones
* Pancreatic cancer
* Primary Biliary Cirrhosis (PBC)
* Primary Sclerosing Cholangitis (PSC)

Jaundiced Emergencies
* Acetaminophen Toxicity
* Fulminant Hepatic Failure
* Ascending Cholangitis

Jaundice Unrelated to Intrinsic Liver Disease
* Hemolysis (usually T. bili < 4)
* Massive Transfusion
* Resorption of Hematoma
* Ineffective Erythropoesis
* Disorders of Conjugation
o Gilbert’s syndrome
* Intrahepatic Cholestasis
o Sepsis, TPN, Post-operation

New Onset Jaundice
* Viral hepatitis
* Alcoholic liver disease
* Autoimmune hepatitis
* Medication-induced liver disease
* Common bile duct stones
* Pancreatic cancer
* Primary Biliary Cirrhosis (PBC)
* Primary Sclerosing Cholangitis (PSC)

HBV Serology
Resolved HBV
HBV vaccinated
Chronic HBV
Acute HBV
HBSAb
HBcAb
IgG
HBcAb
IgM
Acute Hepatitis C
HCV RNA
Anti-HCV
Infection Day 0
HCV RNA Day 12
HCV Antibody Day 70
Plateau phase = 57 days

Alcoholic Liver Disease
* The history is the key – 60 grams/day
* Gynecomastia, parotids, Dupuytren’s
* Lab clues: AST/ALT > 2, MCV > 94

AST < 300
* Alcoholic hepatitis:
o Anorexia, fever, jaundice, hepatomegaly
o Treatment:
+ Abstinence
+ Nutrition
+ Consider prednisolone or pentoxifylline

Alcoholic Liver Disease
Discriminant Function Formula:
DF = [4.6 x (PT – control)] + bilirubin
Consider treatment for DF > 32
* Prednisolone 40 mg/day x 28 days
o contraindications: infection, renal failure, GIB
* Pentoxifylline 400 mg PO tid x 28 days

Autoimmune Hepatitis
* Widely variable clinical presentations
o Asymptomatic LFT abnormality (ALT and AST)
o Severe hepatitis with jaundice
o Cirrhosis and complications of portal HTN
* Often associated with other autoimmune dz
* Diagnosis:
o Compatible clinical presentation
o ANA or ASMA with titer 1:80 or greater
o IgG > 1.5 upper limits of normal
o Liver biopsy: portal lymphocytes + plasma cells

Drug-induced Liver Disease
* Hepatocellular
o acetaminophen, INH, methyldopa, MTX
* Cholestatic
o chlorpromazine, estradiol, antibiotics
* Chronic Hepatitis
o methyldopa, phenytoin, macrodantin, PTU
* Hypersensitivity Reaction
o Phenytoin, Augmentin, allopurinol
* Microvesicular Steatosis
o amiodarone, IV tetracycline, AZT, ddI, stavudine

Acetaminophen Toxicity
* Danger dosages (70 kg patient)
o Toxicity possible > 10 gm
o Severe toxicity certain > 25 gm
o Lower doses potentially hepatotoxic in:
+ Chronic alcoholics
+ Malnutrition or fasting
+ Dilantin, Tegretol, phenobarbital, INH, rifampin
+ NOT in acute EtOH ingestion
+ NOT in non-alcoholic chronic liver disease

Acetaminophen Toxicity
* Day 1:
o Nausea, vomiting, malaise, or asymptomatic
* Day 2 – 3:
o Initial symptoms resolve
o AST and ALT begin to rise by 36 hours
o RUQ pain, tender enlarged liver on exam
* Day 4
o AST and ALT peak > 3000
o Liver dysfunction: PT, encephalopathy, jaundice
o Acute renal failure (ATN)

Acetaminophen Toxicity Treatment
Indications for NAC therapy:
Fulminant Hepatic Failure
* Definition:
o Rapid development of hepatic dysfunction
o Hepatic encephalopathy
o No prior history of liver disease
* Most common causes:
o Acetaminophen
o Unknown
o Idiosyncratic drug reaction
o Acute HAV or HBV (or HDV or HEV)

Fulminant Hepatic Failure
* Close glucose monitoring IV glucose
* Avoid sedatives - give PO lactulose
* Avoid nephrotoxins and hypovolemia
* Vitamin K SQ
o Do not give FFP unless active bleeding, since INR is an important prognostic factor
* GI bleed prophylaxis with PPI
* Transfer all patients with FHF who are candidates to a liver transplant center

Indications:
* Hepatitis C 29%
* Alcoholic Liver Disease 15%
* Cirrhosis of unknown etiology 8%
* Hepatocellular Carcinoma 7%
* Fulminant Hepatic Failure 6%
* Primary Sclerosing Cholangitis 5%
* Primary Biliary Cirrhosis 4%
* Metabolic Liver Disease 4%
* Autoimmune Hepatitis 3%
* Hepatitis B 3%

Liver Transplantation:
Contraindications
* ABSOLUTE
o active alcohol or drug abuse
o HIV positivity
o extrahepatic malignancy
o uncontrolled extrahepatic infection
o advanced cardiopulmonary disease
* RELATIVE
o Age over 65
o poor social support
o poorly controlled mental illness

Obstructive Jaundice
CBD stones (choledocholithiasis) vs. tumor
* Clinical features favoring CBD stones:
o Age < 45
o Biliary colic
o Fever
o Transient spike in AST or amylase
* Clinical features favoring cancer:
o Painless jaundice
o Weight loss
o Palpable gallbladder
o Bilirubin > 10

Ascending Cholangitis
* Pus under pressure
* Charcot’s triad: fever, jaundice, RUQ pain
o All 3 present in 70% of patients, but fever > 95%
o May also present as confusion or hypotension
* Most frequent causative organisms:
o E. Coli, Klebsiella, Enterobacter, Enterococcus
o anaerobes are rare and usually post-surgical
* Treatment:
o Antibiotics: Levaquin, Zosyn, meropenem
o ERCP with biliary drainage

Ascending Cholangitis
Indications for Urgent ERCP
* Persistent abdominal pain
* Hypotension despite adequate IVF
* Fever > 102
* Mental confusion
* Failure to improve after 12 hours of antibiotics and supportive care

Obstructive Jaundice Malignant Causes
* Cancer of the Pancreas
* Cancer of the Bile Ducts (Cholangiocarcinoma)
* Ampullary Tumors
* Portal Lymphadenopathy

Primary Biliary Cirrhosis
* Cholestatic liver disease (ALP)
o Most common symptoms: pruritus and fatigue
o Many patients asx, and dx by abnormal LFT
* Female:male ratio 9:1
* Diagnosis:
o Compatible clinical presentation
o AMA titer 1:80 or greater (95% sens/spec)
o IgM > 1.5 upper limits of normal
o Liver biopsy: bile duct destruction
* Treatment: Ursodeoxycholic acid 15 mg/kg

Primary Sclerosing Cholangitis
* Cholestatic liver disease (ALP)
* Inflammation of large bile ducts
* 90% associated with IBD
o but only 5% of IBD patients get PSC
* Diagnosis: ERCP (now MRCP)
o No autoantibodies, no elevated globulins
o Biopsy: concentric fibrosis around bile ducts
* Cholangiocarcinoma: 10-15% lifetime risk
* Treatment: Liver Transplantation

Diagnosis of Immune-Mediated Liver Disease
Periductal concentric fibrosis
Unusual Causes of Jaundice
* Ischemic hepatitis
* Congestive hepatopathy
* Wilson’s disease
* AIDS cholangiopathy
* Amanita phalloides (mushrooms)
* Jamaican bush tea
* Infiltrative diseases of the liver
o Amyloidosis
o Sarcoidosis
o Malignancy: lymphoma, metastatic dz

Wilson’s Disease
* Autosomal recessive – copper metabolism
* Chronic hepatitis or fulminant hepatitis
* Associated clinical features:
o Neuropsychiatric disease
o Hemolytic anemia
* Physical exam: Kayser-Fleischer rings
* Diagnosis: ceruloplasmin, urinary Cu
* Treatment: d-penicillamine

Critical Questions in the Evaluation of the Jaundiced Patient
* Acute vs. Chronic Liver Disease
* Hepatocellular vs. Cholestatic
o Biliary Obstruction vs. Intrahepatic Cholestasis
* Fever
o Could the patient have ascending cholangitis?
* Encephalopathy
o Could the patient have fulminant hepatic failure?

Evaluation of the Jaundiced Patient HISTORY

* Pain
* Fever
* Confusion
* Weight loss
* Sex, drugs, R&R
* Alcohol
* Medications
* pruritus
* malaise, myalgias
* dark urine
* abdominal girth
* edema
* other autoimmune dz
* HIV status
* prior biliary surgery
* family history liver dz

Evaluation of the Jaundiced Patient PHYSICAL EXAM
* BP/HR/Temp
* Mental status
* Asterixis
* Abd tenderness
* Liver size
* Splenomegaly
* Ascites
* Edema
* Spider angiomata
* Hyperpigmentation
* Kayser-Fleischer rings
* Xanthomas
* Gynecomastia
* Left supraclavicular adenopathy (Virchow’s node)

Evaluation of the Jaundiced Patient LAB EVALUATION
* AST-ALT-ALP
* Bilirubin – total/indirect
* Albumin
* INR
* Glucose
* Na-K-PO4, acid-base
* Acetaminophen level
* CBC/plt
* Ammonia
* Viral serologies
* ANA-ASMA-AMA
* Quantitative Ig
* Ceruloplasmin
* Iron profile
* Blood cultures

Evaluation of the Jaundiced Patient
* Ultrasound:
o More sensitive than CT for gallbladder stones
o Equally sensitive for dilated ducts
o Portable, cheap, no radiation, no IV contrast
* CT:
o Better imaging of the pancreas and abdomen
* MRCP:
o Imaging of biliary tree comparable to ERCP
* ERCP:
o Therapeutic intervention for stones
o Brushing and biopsy for malignancy

Case studies

Approach to the Jaundiced Patient.ppt

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