PANCE Blueprint Hematology (5%)

Lessons

1. 2020 PANCE Hematologic System Content Blueprint

2. 2019 PANRE and Pilot Alternative to PANRE Hematologic System Content Blueprint
3. Hematology Comprehensive Exam
4. Hematology Flashcards (Members Only)

5. Hematologic System With Joe Gilboy PA-C (Video Lecture)

   45 mins

6. Autoimmune hematologic disorders (PEARLS)
7. Coagulation Disorders (PEARLS)
   1. Clotting factor disorders (Lecture)

      9 mins

      Von Willebrand Disease (vWD)

      • Most common genetic bleeding disorder, autosomal dominant
      • ↑ PTT, prolonged bleeding time, ↓ Willebrand factor
      • Patients may present with excessive bleeding after a cut, or increased menstrual bleeding. 
      • Treat with DDAVP (desmopressin)

      Hemophilia is a hereditary bleeding disorder caused by a deficiency in one of two blood clotting factors: VIII or IX.  Presents with spontaneous hemarthrosis, ↑ aPTT and normal platelet count and function

      • Hemophilia A, which accounts for about 80% of all cases, is a deficiency in clotting factor VIII
      • Hemophilia B is a deficiency in clotting factor IX (Christmas disease)
   2. Hypercoagulable states

      • Factor V Leiden (the most common)
        • Mutated factor V resistant to breakdown by activated Protein C - results in hypercoagulability.
        • Increased DVT and PE especially in young patients.
        • Diagnosis with activated protein C resistance assay (factor V Leiden specific functional assay) - if positive, confirm with DNA testing. Normal PT/PTT.
        • Long-term antithrombotic therapy not recommended.
      • Protein C/S Deficiency
        • Protein C (with cofactor protein S) inactivates factors V and VIII. Deficiency of either protein C or S leads to active factors V and VIII, which leads to thrombosis.
        • DVT or PE at a young age. After warfarin initiation - skin necrosis. 
        • Diagnose with Protein C or S functional assay (preferred) - ↓ protein C or S activity levels.
        • Requires Heparin and oral anticoagulation for life.
      • Antithrombin III Deficiency
        • Antithrombin is a natural anticoagulant. It inhibits thrombin, factor Xa, and other serine proteases in the coagulation cascade such as factor IXa.
        • Antithrombin III activity is potentiated by Heparin.
        • Deficiency associated with DVT and PE.
        • Patients with thrombotic events require high-dose IV heparin then oral anticoagulation indefinitely. 
      • Antiphospholipid Syndrome
        • Autoimmune disorder, often associated with systemic lupus erythematosus (SLE), characterized by thromboses and recurrent spontaneous abortions.
        • Autoantibodies (lupus anticoagulant, anticardiolipin, and anti-β₂ glycoprotein antibodies) react against platelet membranes or prothrombin-platelet membrane complex, activating endothelial cells and platelets - this activates complement-mediated thrombosis.
        • Diagnose with lupus anticoagulant, prolonged dilute Russell viper venom time (DRVVT) test, prolonged (PTT), anti-β2 glycoprotein, and anticardiolipin antibody.
        • Patients with thrombotic events require high-dose IV heparin then oral anticoagulation indefinitely. 

       
   3. Thrombocytopenia (Pearls)
      1. Idiopathic thrombocytopenic purpura (ReelDx + Lecture)

         Autoimmune reaction to platelets usually after a viral illness (ITP is insidious and chronic)

         • Diagnosis of exclusion
           • Associated with HIV, HCV, SLE, CLL
           • CBC normal except low platelets.  (+ Direct Coombs Test)
      2. Thrombotic thrombocytopenic purpura (Lecture)

         Thrombotic Thrombocytopenia (TTP):↓ Platelets + anemia + schistocytes (RBC fragments) on smear and (-) Coombs test

         • After drugs: Quinidine, cyclosporine & pregnancy
           • Inhibition of ADAMTS13
         • Presentation: Adults
           • Purpura and “FAT RN”- Fever, Anemia, Thrombocytopenia, Renal failure, Neurological symptoms
         • Diagnostic studies: CBC normal except ↓ Platelets. Schistocytes (RBC fragments) on smear

         Hemolytic Uremic Syndrome (HUS): ↓ Platelets + anemia + renal failure (associated with E.coli O157: H7 and diarrheal illness in child)

         • Post-infection: E.coli or Shigella
         • Children, severe kidney problems
8. Cytopenias (PEARLS)
   1. Anemias (PEARLS)
      1. Anemia of chronic disease (Lecture)

         6 mins

         Normal or ↓ MCV, ↓  TIBC, ↑ Ferritin (high iron stores) ↓ serum erythropoietin

         • Normochromic/microcytic (normocytic initially)
         • Diagnosis generally requires the presence of chronic infection
         • ↓ serum erythropoietin levels in anemia of renal failure
      2. Aplastic Anemia

         The only anemia where all three cell lines are decreased ↓ WBC, ↓ RBC, ↓ Platelets - will have normal MCV and ↓ Retic

         • Diagnostic studies: Pancytopenia
      3. Folate deficiency

         ↓ Folate, ↑ MCV (macrocytic anemia) looks like B12 but no neurologic symptoms

         • Population: Alcoholics
         • Megaloblastic anemia, elevated homocysteine
      4. Hemolytic anemia (Lecture)

         • Autoimmune Hemolytic Anemia (+ Direct Coombs Test) -  ↑ Retic, ↑ LDH, ↓ Haptoglobin, and ↑ Bilirubin (indirect) 
         • Hereditary Spherocytosis (+) osmotic fragility test. ↑ Retic, ↑ LDH, ↓ Haptoglobin, and ↑ Bilirubin (indirect) and presence of spherocytes
         1. G6PD deficiency

            After infection or medication (oxidative stress) in an African American male (x-linked) + Heinz Bodies and Bite Cells on smear (damaged hemoglobin - G6PD protects RBC membrane) 

      5. Iron deficiency (Lecture)

         13 mins

         ↓ MCV (microcytic), ↓ MCH (hypochromic), ↑ TIBC, ↓ Ferritin (best test, low iron stores), Target cells, pica and nail spooning
      6. Vitamin B12 deficiency (Lecture)

         ↑ MCV (macrocytic anemia), Hypersegmented Neutrophils and normal folate, decreased vibratory and position sense

         • Etiology: Pernicious anemia (antibody to intrinsic factor), gastrectomy, vegans
         • Smooth beefy, sore tongue and neurologic symptoms (poor balance, low proprioception)
         • Schilling test (pernicious anemia) less than 10% radiolabeled vitamin B12 in urine. Normal results when repeated with administration of intrinsic factor.

   2. Leukopenia

      Leukopenia is a decrease in the number of white blood cells (leukocytes) found in the blood, which places individuals at increased risk for infection

      • Low white cell count may be due to acute viral infections, such as a cold or influenza
      • Associated with chemotherapy, radiation therapy, myelofibrosis, aplastic anemia, stem cell transplant, bone marrow transplant, HIV, AIDS, and steroid use
      • Medical conditions such as systemic lupus erythematosus, Hodgkin's lymphoma, some types of cancer, etc.
      • Medications such as clozapine, bupropion, minocycline, valproic acid, lamotrigine, metronidazole, immunosuppressive drugs, and interferons used to treat MS
      • Often asymptomatic or associated with fatigue, malaise, and subjective fever
      • Leukopenia can be identified with a complete blood count 
        • In adults leukopenia is a total WBC count <3.7 K/ μL (normal WBC count 4.5– 11.0 K/ μL)
        • Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1.5 K/ μL
      • Treat by identifying and treating the cause or eliminating the causative agent
9. Cytoses (PEARLS)
   1. Polycythemia

      Polycythemia vera is a malignancy of the bone marrow that results in the overproduction of red blood cells (primarily) but also can affect platelets, and white blood cells

      • Classic symptoms include pruritus after hot baths, as well as swelling, burning pain, and rubor of the hands and feet (erythromelalgia)
      • Patients may also have gout due to increased cell turnover leading to hyperuricemia

      The 4 H's: H ypervolemia (↑ RBC), H istaminemia (↑ histamine due to release from mast cells), H yperviscosity (↑ hematocrit = ↑ viscosity), and H yperuricemia (↑uric acid)

      • Elevated RBC count, hemoglobin, hematocrit (usually >50)
      • Thrombocytosis, leukocytosis may be present
      • Serum erythropoietin levels are reduced
      • Elevated vitamin B12 level
      • Hyperuricemia is common
      • ↑ Histamine - proposed mechanism for intense pruritus associated with this disorder
      • Positive Jak2 tyrosine kinase mutation
      • Bone marrow biopsy confirms the diagnosis

      Treatment consists of repeated phlebotomy to lower hematocrit to ≤ 42%

      • Older patients (> 60 years old) and those with prior thrombosis should be treated with a myelosuppressive agent, most commonly hydroxyurea with or without aspirin
      • Anagrelide may be used to decrease the platelet count
   2. Thrombocytosis

      Thrombocytosis is the presence of high platelet (thrombocyte) counts in the blood and can be either primary or secondary

      • Primary (essential) thrombocythemia is defined as platelet count > 600,000/mm3 and is a diagnosis of exclusion
      • Secondary (reactive) thrombocytosis (due to infection, inflammation, bleeding, and so on) and other myeloproliferative disorders
      • It is primarily manifested by thrombosis (e.g., CVA), or paradoxically and less frequently, bleeding (due to defective platelet function). It is a disease with high morbidity but low mortality
      • Findings may include splenomegaly, pseudohyperkalemia, and elevated bleeding time
      • Erythromelalgia is burning pain and erythema of the extremities due to microvascular occlusions
      • Peripheral smear shows hypogranular, abnormally shaped platelets
      • Bone marrow biopsy to differentiate whether the high platelet count is reactive or essential shows an increased number of megakaryocytes
      • JAK2 tyrosine kinase mutation seen in 40% to 50% of cases
      • Treatment usually involves antiplatelet agents such as anagrelide and low-dose aspirin. Hydroxyurea is sometimes used for severe thrombocytosis
10. Hemoglobinopathies (PEARLS)
    1. Hemochromatosis

       Autosomal recessive disease causing excess iron absorption

       • Affect the liver (primary organ), pancreas, heart, joints, skin, thyroid, gonads and hypothalamus
       • High levels of serum iron
         • ↑ Elevated fasting serum transferrin saturation (>50%–55%)
         • ↑ Elevated ferritin (may be >1,000 ng/mL)
         • ↓ Decreased total iron binding capacity
         • Liver biopsy is no longer required for diagnosis but is helpful in determining the degree of fibrosis. Iron can be seen as brown spots inside hepatocytes and it becomes blue with a Prussian blue stain
         • HFE gene testing
       • Treat with phlebotomy—usually weekly at first
         • Once excess iron stores are removed, most patients can be managed with lifelong maintenance phlebotomies every 2–4 months
         • Deferoxamine (medication) chelation of iron— difficult to achieve negative iron balance; use if the patient is unable to undergo phlebotomy
    2. Sickle cell anemia (ReelDx)

       8 mins

       Very High Retic count + Pain in African American male, +  Sickled cells on peripheral smear + Diagnosis requires (+) HgbS on hemoglobin electrophoresis is definitive, howell-Jolly bodies, target cells
    3. Thalassemia (Lecture)

       Very ↓ MCV (microcytic and hypochromic) with a normal TIBC, Ferritin and ↑ elevated iron, normal to ↓ Retic count and a (+) HB Electrophoresis. Family history of blood cell disorder
11. Immunologic disorders (PEARLS)
    1. Transfusion reaction

       Transfusions can cause complications and some are life-threatening. They can be divided into non-immune mediated complications and immune-mediated complications Non-immune mediated complications

       • Blood transfusions risk of transmitting infectious microorganisms: CMV, Hepatitis B, and Hepatitis C and HIV
       • Frequent blood transfusions may cause iron overload state (secondary hemochromatosis)
       • Anticoagulants in blood products may cause hypocalcemia
       • Bacteremia
       • Hypercalcemia from destroyed RBC's releasing intracellular potassium

       Immune-mediated complications

       • Allergic or anaphylactic transfusion reaction due to a type one hypersensitivity reaction against plasma proteins found in transfused blood
       • Acute hemolytic transfusion reaction due to ABO blood group incompatibility
       • Febrile non-hemolytic transfusion reaction - relatively common following packed RBC and platelet transfusion
       • Transfusion-related acute lung injury (TRALI) - donor antibodies attack recipient WBCs and pulmonary endothelial cells

       Treat by stopping the transfusion

       • Epinephrine for anaphylaxis
       • IV fluids for an acute hemolytic transfusion reaction
       • Prevent febrile non-hemolytic transfusion reaction by giving leukoreduced blood products and acetaminophen for fever
       • Mechanical ventilation for transfusion-related acute lung injury (TRALI)
       • Diuretics for transfusion-associated circulatory overload (TACO)
12. Neoplasms, premalignancies, and malignancies (PEARLS)

    6 mins

    1. Acute and chronic lymphocytic leukemia (Lecture)

       Acute lymphocytic leukemia (ALL): CHILD + Lymphadenopathy + bone pain + bleeding + fever in a CHILD, bone marrow > 20% blasts in bone marrow

       • Population: Children - most common childhood malignancy peak age 3-7
       • Highly responsive to chemotherapy (remission > 90%)

       Chronic Lymphocytic Leukemia (CLL): Middle age patient, often asymptomatic (seen on blood tests), fatigue, lymphadenopathy, splenomegaly

       • Population: Adults - most common form of leukemia in adults - peak age 50 y/o
       • Diagnostic studies: SMUDGE CELLS on peripheral smear, mature lymphocytes
       • Treatment with observation, if lymphocytes are > 100,000 or symptomatic treat with chemo
    2. Acute and chronic myelogenous leukemia (Lecture)

       9 mins

       Acute Myeloid Leukemia (AML): BLASTS + AUER RODS  in ADULT PATIENT

       • Population: Adults (80%) majority of patients > 50 y/o
       • Anemia, thrombocytopenia, neutropenia. Splenomegaly, gingival hyperplasia and Leukostasis (WBC > 100,000)
       • Auer Rods and > 20% blasts seen in bone marrow

       Chronic Myeloid Leukemia (CML): Strikingly Increased WBC count > 100,000 + hyperuricemia + Adult patient (usually > 50 years old)

       • Population: Adults - patient usually > 50 y/o
       • 70% asymptomatic until patient has blastic crisis (acute leukemia) 
       • Diagnostic studies: Philadelphia chromosome (translocation of chromosome 9 and 22) - "Philadelphia CreaM cheese", splenomega
    3. Lymphoma (ReelDx + Lecture)

       Hodgkin's Lymphoma: painless lymphadenopathy + bimodal age distribution (15-35) and (>60)

       • Fever, chills, and night sweats for > 1 month
       • Painless enlarged posterior cervical and supraclavicular lymph nodes
       • CXR - mediastinal adenopathy
       • Excisional biopsy of lymph node shows Reed-Sternberg cells
       • Combination chemotherapy cures most patients, even those with advanced-stage disease
       • Radiation therapy is the initial treatment of choice for patients with low-risk stage IA and IIA disease; the 10-year survival rate exceeds 80%

       Non-Hodgkin Lymphoma

       • Look for an immunocompromised (HIV) Patient with GI symptoms and painless peripheral lymphadenopathy
       • Patients with indolent lymphoma with one or two involved nodes may be treated with radiation alone
       • Intermediate or high-grade lymphomas are treated with chemotherapy, immunotherapy, and autologous stem cell transplantation
    4. Multiple myeloma (Lecture)

       Cancer of monoclonal plasma cells - produces large amounts of IgG (55% of cases) or IgA (25% of cases)

       • An older patient with bone and back pain refractory to treatments
       • “CRAB”- C alcium elevation, r enal failure, a nemia, and b one lesions
       • Urinalysis: monoclonal proteinuria (Bence Jones Protein)
       • Blood smear: Rouleaux formation (stacked RBCs)
       • Radiograph: X-ray showing lytic "punched-out" bone lesions of skull, spine, long bones
       • Serum/Urine electrophoresis: Monoclonal (M protein) Spike (IgG or IgA)
       • Bone marrow biopsy: > 10% clonal plasma cells
       • Bone marrow transplant is definitive therapy, preferable in young patients
    5. Myelodysplasia

       Myelodysplastic Syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells

       • MDS is often referred to as a “bone marrow failure disorder”
       • MDS is primarily a disease of the elderly (most patients are older than age 65)
       • Can be idiopathic/secondary to exposure - Toxins, genotoxic drugs, immunosuppressive agents, chemotherapy, radiation therapy (t-MDS, therapy-related MDS)
       • Symptoms may include shortness of breath, fatigue, easy bruising, and paleness.
       • Low RBCs, WBCs, platelets, normal/mildly elevated mean corpuscular volume (MCV), increased red cell distribution width (RDW)
       • Low reticulocyte count, dysplastic RBCs, WBCs, normal platelets
       • Increased blasts - 1–20% blasts

       Treatment: Myelodysplastic syndrome may progress to leukemia

       • Stem cell transplant is the only curative option for young individuals