Heme

• Hematology & Oncology covers chemotherapy, monoclonal antibodies, mediastinal masses, immune thrombocytopenic purpura, and other conditions.
• Pharmacology (Heme/Onc) covers Rituximab, Thrombolytics / Fibrinolytics, Vinca Alkaloids, Thrombophlebitis, and Coagulation Cascade Pathway, leukemias, and other conditions.

Chemotherapy

• Cytotoxic chemotherapy, which includes 5-fluorouracil, irinotecan, and leucovorin, targets rapidly growing cells found in neoplasms and physiological cells, such as hair, bone marrow, and gut mucosa.
• 6-mercaptopurine (6-MP) & Azathioprine are immunosuppressants inactivated by xanthine oxidase and thiopurine methyltransferase.
• Administer 6-MP and Azathioprine with drugs that inhibit these enzymes for maximal efficacy.
• Topoisomerase I inhibitors include irinotecan and topotecan
• Topoisomerase II inhibitors include etoposide and teniposide
• Methotrexate, Trimethoprim, and Pyrimethamine inhibit dihydrofolate reductase.
• Anthracyclines (doxorubicin) generate free radicals to break DNA and lead to dilated cardiomyopathy, presenting as heart failure with dyspnea and orthopnea.
• Doxorubicin causes lipid peroxidation of myocyte membranes through free radicals.
• Pembrolizumab is a PD-1 (programmed-death receptor) inhibitor that acts as a checkpoint inhibitor, downregulating the cytotoxic T-cell response, therefore inhibiting it will restore the T cell response.

Chemotherapy Resistance

• Increased expression of P-glycoprotein, a transmembrane ATP-dependent efflux pump with broad specificity, contributes to chemotherapy resistance.

Monoclonal Antibody

• The Fc region of these antibodies binds with immune cells to remove cells and only NK cells with granzymes induce apoptosis.
• Macrophages and neutrophils engage in antibody-dependent cellular toxicity, however, their role in antitumor activity is unclear.

Mediastinal Masses

• Common causes (4 Ts): Thymoma, teratoma (and other germ cell tumors, "terrible" lymphoma, and thyroid neoplasm.
• Nonseminomatous germ cell tumors elevates AFP and Beta-hCG.
• Thymomas are associated with myasthenia gravis.

Immune Thrombocytopenic Purpura

• Presentation: Decreased platelets, epistaxis (recurrent), easy bruising, ecchymoses, and can follow an upper respiratory tract infection (viral illness).
• Autoantibody-mediated destruction of platelets (ONLY PLATELETS, THERE WILL NOT BE ANEMIA OR FEVER SEEN AS SEEN IN THROMBOTIC THROMBOCYTOPENIC PURPURA)

Lab Tests

• INR (International Normalized Ratio) measures how fast blood clots.

Polycythemia Vera

• A myeloproliferative neoplasm with increased production of all cell lineages (erythrocytes, leukocytes, and thrombocytes) secondary to a JAK2 mutation (which codes for a non-receptor tyrosine kinase)
• Presentation: Thrombotic event (this condition creates a hypercoagulable state) and pruritus, especially after hot showers (due to mast cell production and degranulation)
• Labs: Increased Erythrocytes (increased Hb and Hematocrit), Increased Platelets, and Increased WBCs.

Thrombotic Thrombocytopenic purpura

• A thrombotic microangiopathy caused by a clotting problem
• Pathophysiology: Decreased ADAMTS13 Enzyme (which breaks down von Willebrand factor) leads to excessive platelet clumping and low platelets.

Rituximab

• A monoclonal antibody directed against CD20 antigens.
• Infusion reaction: Occurs in nearly 50% of patients who receive rituximab for the first time
• It binds to the CD20 on B cells, this causes B cells to release cytokines which can attribute to myalgias, fever, and occasionally anaphylactic symptoms.

Thrombolytics / Fibrinolytics

• Name: End in "-plase" (alteplase, reteplase, tenecteplase).
• Act by converting plasminogen to plasmin to breakdown blood clots.
• Usage: Post-MI because of its role in reperfusion of the heart

Vinca Alkaloids

• Examples include vincristine and vinblastine
• MOA: Microtubule inhibitors
• Vincristine side effects: Neurotoxicity
• Vinblastine: Myelosuppression

Key Chemotoxicities

• Cisplatin, Carboplatin → ototoxicity
• Vincristine → peripheral neuropathy
• Bleomycin, Busulfan → pulmonary fibrosis
• Doxorubicin, Daunorubicin → cardiotoxicity
• Trastuzumab → cardiotoxicity
• Cisplatin, Carboplatin → nephrotoxicity
• CYclophosphamide → hemorrhagic cystitis
• Nonspecific common toxicities of nearly all cytotoxic chemotherapies include myelosuppression (neutropenia, anemia, thrombocytopenia), GI toxicity (nausea, vomiting, mucositis), and alopecia.

Thrombophlebitis

• Condition where blood clots form in veins, leading to inflammation and swelling.
• Multiple thrombi: Trousseau syndrome (migratory superficial thrombophlebitis).
• Associated with cancer.

Coagulation Cascade Pathway

• A series of reactions leading to thrombus formation through an intrinsic and extrinsic pathway.

Coagulation Cascade Pathway: Extrinsic

• Initiated by trauma and involves factors VII and tissue factor.
• Test: PT

Coagulation Cascade Pathway: Intrinsic

• Initiated by damaged surface and involves factors: NOT VII (but has the rest of them up to X).
• Test: PTT

Tumor Lysis Syndrome

• Large amounts of dying tumor cells that release intracellular contents into the bloodstream causes this.
• Cardiac effects (from increased K+ and decreased Ca2+) can result in arrhythmias and ECG changes.
• Brain (from decreased Ca2+) can cause seizures and tetany.
• Skeletal Muscle (from increased K+).
• Kidneys (from increased uric acid and Phosphorous) can result in AKI from calcium phosphate crystals and uric acid crystals.
• Uric acid precipitates (solidifies) in the DCT and CD (more acidic environment of nephron).

Leukemias: Acute Lymphoblastic Leukemia (ALL)

• Presentation: Adolescent with large mediastinal mass, petechiae present on trunk.
• Diagnosis: Flow cytometry identifying population of T lymphoblasts (CD3 and TdT).

Leukemias: Chronic Lymphocytic Leukemia (CLL)

• Cancer of the blood, lymphocytes, but specifically mature B cells.
• Therefore will have a lot of CD20.
• Presentation: Asymptomatic for a long time but then develops anemia, leukocytosis (obviously lots of B cells), and thrombocytopenia.

Leukemias: Acute Myeloid Leukemia (AML)

• Neoplasm of myeloid cell line
• If blasts are over 20% = AML
• Auer rods helpful for diagnosis (down to either AML or CML) .
• In CML, there are more mature cells and fewer blasts.
• AML is related to a deficiency in neutrophils after treatment
• Risk factors: benzene, alkylating chemotherapy, radiation.

Leukemias: Acute promyelocytic Leukemia

• An M3 variant of AML is associated with t(15;17) and will still have auer rods.
• Genetic Translocation: Retinoic acid receptor alpha (RARA) gene on chromosome 17 and promyelocytic leukemia (PML) gene on chromosome 5
• t(15;17) = APML

Leukemias: Chronic Myelogenous Leukemia (CML)

• Defined by the presence of the Philadelphia chromosome (translocation of chromosome 9 and 22) or BCR-ABL fusion gene or neoplasm of myeloid cell line
• Philadelphia chromosome can also be in ALL and AML, but it is still needed for diagnosis of CML
• Active tyrosine kinase helps cause the malignancy.
• Pathophysiology: Constitutive activation of the ABL1 tyrosine kinase
• Labs: leukocytosis and increased myeloid cells.

Mastocytosis

• Abnormal proliferation of mast cells correlated with increased histamine secretion.
• Diagnosis: Skin biopsy with large clusters of mast cells that are positive for KIT (CD117).
• Additional findings: Gastric hypersecretion

Hemolytic Disease of the Newborn

• Caused by a blood type mismatch between mother and fetus leading to antibodies against fetal RBCs, resulting in hemolysis.
• Rh Hemolytic Disease: Rh- mother and Rh+ fetus with first pregnancy.
• During delivery, the mother is exposed to fetal blood, leading to anti-D IgG antibodies. Subsequent pregnancies with the Anti-D IgG Abs cross the placenta and attack the baby, causing hemolysis.
• Symptoms include Kernicterus (deposition of unconjugated bilirubin in the brain, mostly at the basal ganglia, pons, and cerebellum).
• Yellow discoloration indicates hyperbilirubinemia.

Reticulocytes

• Immature RBCs
• Wright-Giemsa staining will show them bluish due to ribosomal RNA

Burkitt Lymphoma

• Rare, aggressive type of non-Hodgkin's lymphoma affecting mature B cells
• Associated with EBV infection
• Presentation: Jaw mass, rapidly enlarging, lymphadenopathy, African person
• Cause: Translocation of the MYC gene on chromosome 8 to chromosome 14 [t(8;14)], caused by MYC overexpression
• Histologically numerous mitotic figures and apoptotic bodies. Can be characterized by a "starry sky" appearance.

Hairy Cell Leukemia

• A mature B-cell tumor
• Presentation: Middle-aged men, massive splenomegaly, pancytopenia, dry bone marrow aspiration
• Blood smear: lymphocytes (B cells) with cytoplasmic projections

Langerhans Cell Histiocytosis

• Proliferation and accumulation of Langerhans cells
• Presentation: Child, lytic bone lesion (most commonly on the skull)
• Biopsy: langerhan cells and Eosinophils also present
• Markers: CD1, CD1a, S-100

Plasma Cell Dyscrasias: Multiple Myeloma

• Blood cancer affecting plasma cells (B cells)
• There are too many abnormal plasma cells
• Presentation: Bone pain, kidney issues/lesions, and hypercalcemia.
• Myeloma cells produce RANKL
• CRAB presentation is useful for this disease; hyperCalcemia, Renal insufficiency, Anemia, Bone lytic lesions.
• Pathophysiology: malignant Plasma cells secrete: IL-1, TNF-alpha, RANKL
• The light chains created by the plasma cells can misfold and form amyloid fibrils
• LAMBDA LIGHT CHAINS

• 10% plasma cells on bone marrow sample = multiple myeloma

• M Spike: Associated with overproduction of monoclonal immunoglobulins (use serum protein electrophoresis)

Monoclonal gammopathy of undetermined significance

• Overproduction of any Ig type (but the M spike < 3 g/dL)
• Presentation: Asymptomatic

Cells of the Blood: Thrombocytes

• ADP effect on platelets causes rapid and irreversible aggregation through action on P2Y1 and P2Y12 receptors.

Sickle Cell Disease

Complications

• Avascular necrosis can occur, presenting with gradual onset (2hrs) of localized pain.
• Sickle cells occluding vasculature lead to vaso-occlusive crisis and avascular necrosis.

Coagulopathies

Von Willebrand Factor (vWF)

• The hemostatic glycoprotein, synthesized by endothelial cells and megakaryocytes, mediates platelet adherence.
• It binds to subendothelial collagen.
• Deficiency can manifest as easy bruising and prolonged mucocutaneous bleeding like gingival bleeding and heavy menses.
• Testing: An abnormal ristocetin cofactor assay indicates deficiency.

Erythropoietin (EPO)

• A glycoprotein hormone secreted by kidneys, increases RBC differentiation by acting in bone marrow.
• It works on JAK2/STAT
• Deficiencies: Chronic Kidney Disease can cause a normocytic anemia with decreased EPO secretion and therefore decreased RBC count.
• Secretion occurs in the kidney by peritubular fibroblast cells in renal cortex

Leukocytosis

• Leukocytosis is defined as increased leukocytes in the blood.
• Demarginalization of neutrophils from endothelial attachments occurs in leukocyte adhesion deficiency therefore causing leukocytosis.
• Infection leads to cytokine release, triggering increased release of immune cells and leukocytes from the bone marrow, increasing Leukocytes.

Blood Transfusion

High Volume Blood Transfusion Side Effects

• Citrate anticoagulants chelate plasma calcium, can lead to hypocalcemia, causing peripheral neuromuscular excitability (paresthesia, muscle spasms).

• Delayed Hemolytic Transfusion Reaction (DHTR): Patient previously exposed to a minor RBC antigen (D antigen, from pregnancy or prior transfusion), develop antibodies which causes a response when reintroduced

Cystic Fibrosis

• Often causes decreased absorption of fat-soluble vitamins (ADEK).
• Decreased vitamin K will decrease the ability of vitamin K dependent coagulation factors.
• Look for prolonged PT (extrinsic pathway).

Anemias

Extravascular Autoimmune

• Autoimmune conditions like SLE are associated with autoimmune hemolytic anemia which is extravascular and IgG mediated (warm).
• Presentation: Chronic disease (inflammation), causing a high indirect bilirubin concentration.

Pyruvate Kinase Deficiency

• Decreased ATP production causes a decreased ability for RBCs to maintain their structure allowing them to be removed by the spleen.
• Causes hyperplasia of the spleen (red pulp hyperplasia).

Anemia Through O2 Content

Labs

• Arterial PO2 reflects the amount of oxygen getting into the blood from the lungs.
• Arterial O2 content reflects the amount of oxygen in the blood (bound and unbound).
• Mixed Venous PO2 is the amount of oxygen dissolved in the blood after the blood has passed through the body (not including oxygen that is bound to Hb).
• Mixed Venous O2 is the total amount of oxygen in the blood, including free and bound to Hb.

Concept

• Normal arterial PO2 and low arterial O2 content means there is enough oxygen in the blood but there is not a lot bound to Hb implying deficient Hb and ultimately anemia.

G6PD Deficiency

• X-linked recessive inheritance.

Thalassemia

• Results in microcytic anemia.

Types and Differentiation

• A patient with HBA2 most likely has a mutation in the Beta-globin gene, inheritance is dependent on severity

Bone Marrow Transplant

• Requires matching HLA subtypes.
• Should they have genomic defects, administer blood transfusions from an unrelated donor.

Autologous Transplantation

• Transplant is from self.

Risks

• Reactivation of latent diseases may happen due to transient immunosuppression.
• No risk of graft versus host disease or graft rejection

Relationship to Partial Pressure of Arterial Oxygen

• PaO2 reflects the amount of dissolved oxygen in the blood plasma, not the amount of blood bound to hemoglobin.
• Hemoglobin binding of oxygen and iron oxidation do not change throughout the condition.