Internal Medicine: Hem Onc

1) Increased CO
2) Increased extraction ratio
3) Rightward shift of oxyhemoglobin curve (Increased 2,3-DPG)
4) Expansion of plasma volume

1) Hb concentration less than 7g/dL
2) Pt requires increased oxygen-carrying capacity

1) Pallor (conjunctiva)
2) HYPOtension & Tachycardia
3) Nonspecific complaints - HA, fatigue, poor concentration, diarrhea, nausea
4) Signs of underlying cause - jaundice (hemolytic anemia), melena (GI bleed)

Hb increases by 1 point
Hct increases by 3 points

Decrease in H/H secondary to dilution of blood (i.e., volume infusion)

Reticulocyte index

*Index > 2% --> excessive RBC destruction or loss
*Index < 2% --> inadequate RBC production

Contains all clotting factors
Given for high PT/PTT, coagulopathy, and deficiency of clotting factors

Contains factor VIII and fibrinogen
Given for hemophilia A, decreased fibrinogen (DIC) and vWD

*Also has vWF and Factor XIII

1 unit raises count by 10,000

ABO-mismatched blood transfusion

*Symptoms: Fever/chills, n/v, flank/back pain, dyspnea

1) Iron-deficient anemia
2) Thalessemia
3) Anemia of chronic disease
4) Ringed sideroblastic anemia

1) Vitamin B12 deficiency
2) Folate deficiency
3) Liver disease (altered shape of RBCs due to altered metabolism of plasma lipoproteins)
4) Stimulated erythropoiesis (reticulocytes larger than mature RBCs)

1) Aplastic anemia
2) Anemia of chronic disease (chronic inflammation, malignancy)
3) Tumor
4) BM fibrosis
5) Renal failure (decreased erythropoietin)

Iron-deficiency anemia

*Chronic blood loss (menstruation or GI bleeding)
*Dietary deficiency/increased iron requirements (infancy, adolescence, pregnancy)

Serum ferritin (will be decreased)

*BM biopsy (gold standard) and Guaiac stool test also done

1) Decreased serum ferritin
2) Increased TIBC
3) Elevated transferrin
4) Decreased serum iron
5) Microcytic, hypochromic RBCs

1) Oral iron replacement (ferrous sulfate)
2) Parenteral iron replacement (IV or IM)
3) Blood transfusion not recommended unless anemia is severe or pt has cardiopulmonary dz

1) CONSTIPATION
2) Nausea
3) Dyspepsia

Inherited disorders characterized by inadequate production of either alpha or beta globin chains of hemoglobin

Homozygous beta-chain thalassemia

*Mediterranean populations

1) Severe anemia (microcytic hypochromic)
2) Massive hepatosplenomegaly
3) Expansion of BM space --> DEFORMITY OF BONES
4) Growth retardation/failure to thrive
5) Death from CHF (if untreated)

1) Hb electrophoresis --> HbF elevated
2) Peripheral blood smear --> microcytic hypochromic anemia

Frequent PRBC transfusions

No treatment necessary

*Pts usually asymptomatic

Colon cancer

Iron deficiency anemia

Deferoxamine

*These pts can develop CHF

Alpha thalassemia minor (mutation/deletion of 2 alpha loci)

*mild microcytic hypochromic anemia --> no treatment necessary

Mutation/deletion of 3 alpha loci
1) Hemolytic anemia
2) Splenomegaly
3) Electrophoresis shows HbH

Hemoglobin Barts - usually fatal at birth (Hydrops Fetalis) or shortly after birth

Abnormality in RBC iron metabolism

*Can be caused by drugs, lead exposure, collagen vascular disease, and neoplasms

1) Increased serum iron
2) Increased ferritin
3) Normal TIBC
4) Ringed sideroblasts in BM

*PYRIDOXINE for treatment

The release of inflammatory cytokines has suppressive effect on erythropoiesis

*No treatment necessary

BM failure leading to pancytopenia

*BM biopsy for definitive diagnosis

1) Idiopathic
2) Radiation exposure
3) Medications
4) Viral infections
5) Chemicals

1) Chloramphenicol
2) Sulfonamides
3) Gold
4) Carbamazepine

1) Anemia - fatigue, dyspnea
2) Thrombocytopenia - petechiae, easy bruising
3) Neutropenia - increased incidence of infections
4) Can become acute leukemia

1) Conversion of homocysteine to methionine
2) Conversion of methylmalonyl CoA to succinyl CoA (catabolism of branched-chain amino acids and odd-chain fatty acids)

Plentiful; can sustain a person for 3 years

*Dietary sources: meat & fish
*Absorbed in terminal ileum attached to intrinsic factor

1) Pernicious anemia - deficiency of intrinsic factor
2) Gastrectomy
3) Poor diet or alcoholism
4) Crohn's disease, ileal resection
5) Organisms competing for B12 (tapeworm, bacteria)

1) Megaloblastic anemia
2) SORE TONGUE (stomatitis & glossitis)
3) Neuropathy

Demyelination of posterior columns, lateral corticospinal tracts, and spinocerebellar tracts --> LOSS OF POSITION/VIBRATORY SENSE, ATAXIA, UPN signs

*URINARY INCONTINENCE, IMPOTENCE, DEMENTIA

1) Megaloblastic anemia (MCV > 100)
2) Hypersegmented neutrophils

1) Methylmalonic acid
2) Homocysteine

Autoimmune

*Inadequate production of intrinsic factor

Determines the cause of B12 deficiency
1) Give IM dose of unlabeled B12 to saturate binding sites
2) Give radioactive B12; measure urine & plasma levels to determine absorption
3) Repeat radioactive B12 with addition of intrinsic factor

*Malabsorption --> no improvement in serum levels
*Pernicious anemia --> improved absorption, increased serum levels

Parenteral B12 therapy q monthly (Cyanocobalamin)

Green vegetables

*Inadequate intake over 3 months can cause deficiency

1) Pregnancy
2) Seizure medications (phenytoin)
3) Inadequate dietary intake / alcoholism
4) Long-term oral antibiotics
5) Increased demand
6) Hemolysis
7) Folate antagonists (MTX)
8) Hemodialysis

where the heart murmur is auscultated best on the anterior chest to listen for heart murmurs

Premature destruction of RBCs
Congenital or acquired
Low Haptoglobin levels
Elevated LDH
Elevated indirect bilirubin

*HAPTOGLOBIN binds to Hb, so it is low when Hb is destroyed

Autosomal recessive --> Valine replaced by glutamic acid at 6th position of beta chain
Hb polymerizes under low oxygen conditions --> Sickled RBCs obstruct small vessels --> Ischemia

Life expectancy reduced by 25-30 yrs
Survival depends on frequency of vaso-occulsive crises

1) Severe, lifelong hemolytic anemia
2) Jaundice, pallor
3) Gallstones (pigmented)
4) High-output CHF (due to anemia)
5) Aplastic crisis (Parvovirus B19)

Blood transfusion

1) Painful crisis in bone
2) Hand-foot syndrome (dactylitis)
3) Acute chest syndrome (similar to pneumonia)
4) Splenic infarction (autosplenectomy)
5) Avascular necrosis of joints
6) Priaprism
7) CVAs
8) Ophthalmologic complications
9) Renal papillary necrosis
10) Infections - encapsulated bacteria, Salmonella osteomyelitis

Enhances HbF levels
Accelerates healing of leg ulcers and reduces recurrence

AUTOSOMAL DOMINANT
Defect in Spectrin
Loss in RBC membrane surface area -->
Spherical shaped RBCs destroyed in spleen (extravascular hemolysis)

1) Hemolytic anemia
2) Jaundice
3) Splenomegaly
4) Gallstones (pigment stones)
5) Hemolytic crises

1) Osmotic fragility test (hypotonic saline)
2) Elevated reticulocyte count
3) Sphere-shaped RBCs (spherocytes)
4) Negative Direct Coombs test

Splenectomy

1) X-linked recessive (mostly men)
2) Precipitated by sulfas, fava beans, malaria drugs, infection

*Mild form - African Americans --> only old RBCs affected
*Severe form - Mediterranean people --> old and new RBCs affected

Denatured Hb, resulting from unneutralized H2O2 in RBCs

*Seen in G6PD deficiency

RBCs after the removal of Heinz bodies by splenic macrophages

*Seen in peripheral smear of G6PD

1) Peripheral blood smear: Heinz bodies & Bite cells
2) Deficient NADPH formation
3) Measurement of G6PD

1) Avoid drugs that cause hemolysis
2) Maintain hydration
3) RBC transfusion when necessary

Production of autoantibodies against RBC membrane antigens --> leads to destruction of RBCs

*Antibodies bind at particular temperatures

1) IgG antibody binds at 37 degrees Celsius
2) EXTRAVASCULAR HEMOLYSIS --> SPLENOMEGALY
3) Idiopathic, or 2/2 to malignancies or collagen vascular diseases or drugs

*More common than cold AIHA

1) IgM antibody binds at 4 degrees Celsius
2) COMPLEMENT ACTIVATION and intravascular hemolysis --> Liver sequestration
3) Idiopathic or 2/2 infection (MYCOPLASMA PNEUMONIAE)

1) Si/Sx of anemia
2) Jaundice
3) Features of underlying disease

1) Direct Coombs test
2) Cold agglutinin titer

Warm AIHA: glucocorticoids (Prednisone), splenectomy, immunosuppression, RBC transfusion, folic acid supplements

Cold AIHA: avoid cold, RBC transfusion, chemotherapy *steroids NOT helpful

*Usually no treatment necessary for AIHA

Acquired deficiency of anchor proteins that link complement-inactivated proteins to blood cell membranes --> increased susceptibility of RBCs, WBCs, and platelets to complement-mediated lysis

1) Chronic intravascular hemolysis
2) Normochromic normocytic anemia
3) Pancytopenia
4) Venous thrombosis (Budd-Chiari)
5) Musculoskeletal pain

1) Ham's test
2) Sugar water test
3) Flow cytometry for CD55 and CD59

*CD55 and CD59 are anchoring proteins that also protect WBCs and RBCs from destruction by complement; when absent due to mutation, cells are attacked

Patient's cells incubated with acidified serum --> alternative complement pathway leads to lysis of PNH cells but not normal cells

1) Glucocorticoids (most pts don't respond)
2) Bone marrow transplant

Platelet count less than 150,000

Normal is 150,000 - 450,000

*Can occur in splenomegaly via sequestration

1) Bone marrow failure (aplastic anemia, FANCONI SYNDROME)
2) Bone marrow invasion (tumors, fibrosis)
3) Bone marrow injury (drugs, chemicals, radiation, infection)

1) Immune (infection, drug-induced, ITP, SLE, HIT-2, HIV)
2) Nonimmune (DIC, TTP, HIT-1)

1) CBC
2) Bleeding time, PT, PTT

HIT-1: Heparin directly causes platelet aggregation >48 hrs
HIT-2: Heparin induces antibody-mediated injury to platelet 3-12 days after administration

1) Cutaneous bleeding (petechiae, ecchymoses
2) Mucosal bleeding (epistaxis, menorrhagia, hemoptysis, GI bleeds)
3) Excessive bleeding after surgery
4) Intracranial hemorrhage and heavy GI bleeds

*NO hemarthroses or hematomas

1) Treat underlying cause
2) Platelet transfusion
3) Discontinue NSAIDS, antiplatelets, and anticoagulants

Autoimmune antibody (IgG) formation against platelets --> damaged platelets are removed by splenic macrophages

Seen in children after viral infection
Self-limited - 80% resolves in 6 months

Usually seen in women 20-40 yrs old
Spontaneous remission rare

1) Petechiae and ecchymoses of skin
2) Bleeding of mucous membranes
3) *NO Splenomegaly

1) Platelet count : usually <20,000
2) Peripheral smear
3) Bone marrow aspiration - increased megakaryocytes
4) Increased platelet-associated IgG

1) Adrenal corticosteroids
2) IV immune globulin (saturates RES system)
3) Splenectomy
4) Platelet transfusions

Disorder of unknown platelet consumption
Microthrombi occlude small vessels and cause mechanical damage to RBCs
Life-threatening

1) Hemolytic anemia
2) Thrombocytopenia
3) ACUTE RENAL FAILURE
4) Fever
5) Neurologic signs (AMS to hemiplegia)

1) Plasmaphoresis
2) Corticosteroids and splenectomy

**Platelet transfusion contraindicated

Autosomal recessive disorder of PLATELET ADHESION TO ENDOTHELIUM
Deficiency of GPIb-IX
Platelets abnormally large
Platelet count mildly low

*GPIb is the receptor for von Willebrand factor

Autosomal recessive
Disorder of PLATELET AGGREGATION - deficiency of GPIIb-IIIa
*Prolonged bleeding time, normal platelet count

*GPIIb-IIIa has the ability to bind fibrinogen

Autosomal dominant deficiency or defect in vWF

*MC inherited bleeding disorder
*vWF carries factor III in the blood and enhances platelet aggregation and adhesion

Type 1 - decreased levels of vWF (MC)
Type 2 - qualitative abnormalities of vWF
Type 3 - absent vWF (LC)

1) Cutaneous and mucosal bleeds
2) Menorrhagia
3) GI bleeding possible

Clinical & laboratory findings:
Prolonged bleeding time, decreased vWF, decrease factor VIII activity, reduced ristocetin-induced platelet aggregation

1) DDAVP (desmopressin)
2) Factor VIII concentrations (especially type 3 vWD)
*Avoid cryoprecipitate, aspirin/NSAIDs

Synthetic analog of Vasopressin
Used to treat vWD types 1 & 2 and hemophilia A
Induces endothelial release of vWF (with subsequent increase in Factor VIII) by binding to V1 receptors

*Increases water reabsorption in collecting ducts when bound to V2 receptors*

X-linked recessive (males) deficiency of factor VIII

1) Hemarthrosis
2) Intracranial bleeding
3) Intramuscular hematomas
4) Retroperitoneal hematomas
5) Hematuria or hemospermia

Knees

1) Prolonged PTT
2) Low factor VIII level and normal vWF levels

1) Analgesia - avoid aspirin/NSAIDs
2) Immobilization of joint, ice packs, rest

1) Factor VIII concentrate
2) Desmopressin (DDAVP) - mild disease

X-linked recessive
Deficiency of factor IX
Presents similar to hemophilia A

Factor IX concentrate

*DDAVP plays no role

Abnormal activation of coagulation --> Formation of microthombi --> Fibrolysis --> Hemorrhage

*most common in critically ill patients

1) Infection - gram-negative sepsis is MCC
2) Obstetric complications
3) Major tissue injury - trauma, burns
4) Malignancy
5) Shock, circulatory collapse
6) Rattlesnake venom

Bleeding & thrombosis

*End organ infarction, especially in CNS and kidney

1) PT, PTT, bleeding time, thrombin time
2) Fibrin split products
3) D-dimer

1) Fibrinogen level
2) Platelet count (thrombocytopenia)

1) FFP to replace clotting factors
2) Platelet transfusion
3) Cryoprecipitate (fibrinogen and clotting factors)
4) Low does of heparin (thrombosis-dominated picture)
5) Oxygen and IV fluids

Intracranial bleeding, stroke, pulmonary embolism, bowel infarction, ARF, arterial occlusion

2,7,9,10, proteins C&S

*post-translational gamma-carboxylation

1) Broad-spectrum antibiotics in combination with NPO status
2) TPN (unless it's added)
3) Malabsorption of fat-soluble vitamins
4) Warfarin - vitamin K antagonist

Factor VII

1) Hemorrhage
2) PT prolongation; PTT follows

1) Vitamin K replacement - takes several days
2) FFP if bleeding is severe

1) Decreased production of clotting factors
2) Cholestasis causes decreased vitamin K absorption (fat-soluble vitamins ADEK need bile)
3) Hypersplenism (splenomegaly due to portal HTN) causes thrombocytopenia

1) Abnormal bleeding - GI bleeding MC
2) Prolonged PT and PTT

1) FFP
2) Vitamin K (cholestasis)
3) Platelet transfusion
4) Cryoprecipitate (fibrinogen deficiency)

1) Antithrombin (AT) III deficiency
2) Antiphospholipid Antibody Syndrome
3) Protein C deficiency
4) Protein S deficiency
5) Factor V Leiden (activated protein C resistence)
6) Prothrombin gene mutation
7) Hyperhomocysteinemia

Autosomal dominant

*AT III inhibits thrombin, so deficiency leads to increased clotting

1) Hypercoagulability
2) Venous or arterial thrombosis

1) Factor V
2) Factor VIII

*Deficiency causes unregulated fibrin synthesis

Cofactor of Protein C

*Deficiency causes decreased protein C activity

Mutation in factor V gene
*Protein C can no longer inactivate factor V --> unregulated prothrombin activation --> increase in clotting

1) Venous thromboembolism :DVT & PE

Warfarin

Potentiates the action of antithrombin III to inhibit clotting factors IIa and Xa
Prolongs PTT (intrinsic pathway)

*t1/2 is 1 hour

1) DVT/PE
2) Acute coronary symptoms
3) DVT prophylaxis (Low-dose)
4) Atrial fibrillation
5) After vascular bypass graft

1) Bleeding
2) Heparin-induced thrombocytopenia (HIT)
3) Possible osteoporosis
4) Transient alopecia
5) Rebound hypercoagulability after removal (depression of AT III)

1) Previous HIT
2) Active bleeding
3) Hemophilia, thrombocytopenia
4) Severe HTN
5) Recent surgery on eyes, spine, or brain

Protamine sulfate

*FFP given in emergency situation

Inhibits factor Xa
Less inhibition of factor IIa and platelet aggregation than heparin

*Does not affect PT or PTT

Subcutaneous injection

*No IV administration

Vitamin K antagonist --> Decreases factors 2,7,9,10, protein C, protein S
Prolongation of PT

*Takes 4-5 days for anticoagulation to begin

1) Hemorrhage
2) Skin necrosis
3) Teratogenic - avoid during pregnancy
4) Intracranial bleed

Vitamin K

*Corrects abnormal PT within 4-10 hours with normal liver function

Neoplastic proliferation of single plasma cell line
Produces monoclonal immunoglobulin
Anemia, leucopenia, thrombocytopenia present in advanced disease

1) Skeletal manifestations (osteolytic lesions)
2) Anemia (normocytic, normochromic)
3) Renal failure
4) Recurrent infections - MCC of death (2/2 to deprivation of normal immunoglobulins)
5) Amyloidosis

1) Serum and urine protein electrophoresis (monoclonal Ig spike - M protein)
2) X-rays (lytic lesions)
3) Bone marrow biopsy (10% abnormal plasma cells)
4) Other findings (hypercalcemia, increased serum protein [hyperglobinemia], rouleaux RBCs, elevated ESR, Bence Jones protein in urine)

1) Hypercalcemia
2) Bone pain
3) Spinal cord compression

1) Systemic chemotherapy (alkylating agents)
2) Radiation
3) Autologous peripheral blood stem cell transplantation

Secondary to activation of osteoclast-activating factor by neoplastic plasma cells

Median survival of 2-4 years with tx
10% 5-year survival

Malignant proliferation of PLASMACYTOID LYMPHOCYTES (Lymphoplasmacytic lymphoma)
IgM paraprotein causes HYPERviscosity of blood

*Uncontrolled clonal proliferation of terminally differentiated B lymphocytes

1) IgM > 5g.dL
2) Bence Jones proteinuria (10%)
3) Absence of bone lesions

1) Lymphadenopathy
2) Splenomegaly
3) Anemia
4) Abnormal bleeding
5) Hyperviscosity syndrome (IgM)

1) Chemotherapy
2) Plasmapheresis

Asymptomatic cousin of multiple myeloma
IgG spike <3.5 g
<10% plasma cells in BM
<1 g/day of Bence Jones proteinuria

*No tx necessary; close observation

1) 15 - 30
2) >50

*Bimodal distribution

1) Lymphocyte predominance (many B cells, few Reed Sternberg cells)
2) Nodular sclerosis (Reed Sternberg cells in collagen)
3) Mixed cellularity (Reed Sternberg cells in pleomorphic background)
4) Lymphocyte depleted (worst prognosis)

Stage I: single LN
Stage II: 2 or more LNs on same side of diaphragm
Stage III: both sides of diaphragm involved
Stage IV: disseminated disease

*Suffixes: A = no symptoms, B = fever, weight loss, night sweats

Painless LNPathy

*Supraclavicular, cervical, axillary, mediastinal nodes

1) LN biopsy - Reed Sternberg cells required
2) Presence of inflammatory cell infiltrates (plasma cells, eosinophils, fibroblasts, lymphocytes)
3) CXR, CT (chest & abdomen)
4) BM biopsy

Chemotherapy and radiation to involved field

*Stages 1, 2, & 3a: Radiotherapy alone
*Stages 3b, 4: Chemotherapy

1) HIV/AIDS
2) Immunosuppression
3) Viral infections (EBV, HTLV-1)
4) H. pylori gastritis
5) Autoimmune disease (Hashimoto's thyroiditis, Sjogren's syndrome)

1) LNPathy (rapid enlargement)
2) Hepatosplenomegaly, abdominal pain, fullness
3) Recurrent infections, anemia, thrombocytopenia (BM involvement)

1) LN biopsy (any LN >1cm present for more than 1 month)
2) Other tests: CXR (hilar or mediastinal adenopathy), CT, LDH and Beta-2 microglobulin, LFTs, CBC, CMP, BM biopsy)

C: Cyclophosphamide
H: Hydroxydaunomycin
O: Oncovin (Vincristine)
P: Prednisone

*Used in Tx of NHL

t(14:18)

*Bcl-2 on chromosome 18 gives fusion protein anti-apoptotic abilities

t(8:14)

T-cell lymphoma of skin and bloodstream

Neoplastic proliferation of abnormal WBCs
--> Interfere w/ production of normal WBCs, RBCs, and platelets

Depends on type of WBC affected:
Granulocytes or monocytes: Myelogenous leukemia
Lymphocytes: Lymphocytic leukemia

1) Anemia
2) Increased bacterial infections (neutropenia)
3) Mucosal or cutaneous bleeding (thrombocytopenia)
4) Splenomegaly, hepatomegaly, LNPathy
5) Bone & joint pain
6) Neurologic dysfunction (CNS involvement)

1) Hyperuricemia
2) Hyperkalemia
3) Hyperphosphatemia

Potential complication of chemo seen in acute leukemia and high-grade NHL
Rapid cell death releases intracellular contents -->
HYPERkalemia, HYPERuricemia, HYPERphosphatemia

*Medical emergency

Malignant proliferation of hematopoietic stem cells --> excessive RBC production

*Median survival = 9-14 years

1) Hyperviscosity symptoms - HA, dizziness, weakness, pruritus, dyspnea
2) Thrombotic phenomena - DVT, CVA, MI, portal vein thrombosis
3) Bleeding
4) Splenomegaly, hepatomegaly
5) HTN

ALL

*This is the leukemia most responsive to therapy

Chronic lymphocytic leukemia

Acute myelogenous leukemia

Monoclonal proliferation of lymphocytes that are morphologically mature but FUNCTIONALLY DEFECTIVE --> Do not become plasma cells

*Least aggressive leukemia
*WBCs: 50 - 200

1) Absolute lymphocytosis - mature WBCs
2) Smudge cells (cells "beaten up" in blood)

1) Fludarabine
2) Chlorambucil

Neoplastic proliferation of myeloid stem cells
Indolent course becomes acute --> Blast Crisis
Translocation: t(9,22) Philadelphia Chromosome
*Average survival - 3 years

1) Granulocytes
2) Erythrocytes
3) Platelets

Chemotherapy (antimetabolites or alkylating agents) may control chronic phase
*Blast crisis usually terminal

Usually above 50

1) Repeated phlebotomy
2) Hydroxyurea or Recombinant Interferon Alpha (Myelosuppression)

1) Elevated RBC mass (men >36, women >32)
2) Arterial oxygen saturation >92%
3) Splenomegaly

1) Thrombocytosis (>400)
2) Leukocytosis (>12)
3) Leukocyte alkaline phosphatase >100 (w/o fever or infection)
4) Serum vitamin B12 >900 pg/ml

Acquired clonal blood disorders
Ineffective hematopoiesis
Apoptosis of myeloid precursors
Pancytopenia despite normal BM
*Poor prognosis - progresses to acute leukemia

Dysplastic marrow cells with blasts or ringed sideroblasts

*Can progress from sideroblastic anemia

RBC and platelet transfusions
Vitamin supplementation - B6, B12, folate

*BM transplant is only cure

Platelet count > 600,000/mm^3
Manifested by thrombosis
HYPOgranular, abnormally-shaped platelets

1) Anti-platelet agents (Anagrelide, low-dose aspirin)
2) Hydroxyurea

Fibrosis of BM --> Pancytopenia and extramedullar hematopoiesis

*Teardrop cells on peripheral smear are hallmark feature