Demystifying the Hematology Alphabet Soup: AIHA, ITP, TTP/HUS - PowerPoint PPT Presentation

Demystifying the Hematology Alphabet Soup: AIHA, ITP, TTP/HUS Kaite Kammers, PharmD, BCPS, BCOP Clinical Pharmacist - Oncology, Providence Alaska Medical Center Ann-Chee Cheng, PharmD, BCPS Clinical Pharmacist, Alaska Native Medical Center AKPhA Annual Convention February 8, 2020

Disclosures Kaite Kammers ● Nothing to disclose Ann-Chee Cheng ● Nothing to disclose

Objectives For AHIA, ITP, and TTP/HUS: 1. Recognize the presenting signs and symptoms of each 2. Describe the pathophysiology of each 3. Recognize treatments and describe pharmacy pearls associated with each therapy

Definitions AIHA = autoimmune hemolytic anemia ITP = idiopathic/ immune thrombocytopenic purpura TMA = thrombotic microangiopathy TTP = thrombotic thrombocytopenic purpura HUS = hemolytic uremic syndrome HGB = hemoglobin (protein in red blood cells that helps transports oxygen) HCT = hematocrit (% of red blood cells in total blood)

HGB vs HCT?

Overview of These Diseases ● All diseases in today’s lecture are benign hematologic diseases ○ A bit of a misnomer since they are often quite fatal! ● Affect PLT or RBC , or both! ● When in doubt… disease is usually autoimmune ● Require urgent treatment ( in ICU or ED ) followed by chronic management Hematology referral ○ ● May look similar at first glance of a CBC

↔ PLT ↓HGB/HCT AIHA: Overview ● Autoimmune premature destruction of RBCs ● Incidence ~ 1 in 80,000, rare but not unheard of in Alaska! ● Disease predominantly of adults ● TWO major groups: ○ Warm (60-70%) ○ Cold agglutinin (10-20%) ○ Mixed (7-8%) ● Associated with blood cancers, viral infections, and many medications (especially antibiotics) ● Characterized by: ○ Reticulocytes & spherocytes ○ Only RBC line affected (Usually) positive Coombs test ○

Hemolysis Iron RBC Heme Bilirubin hemoglobin Amino Acids globin RBC’s destroyed in spleen or circulation by auto-antibodies https://www.youtube.com/watch?v=wxzf_rg_Wd4

AIHA: Pathophysiology Warm Cold ● IgG mediated ● IgM mediated ● Occurs at body temp (~ 37 deg C) ● Occurs at room temp or less than ● Slower process, symptoms occur normal body temp (~32 - 37 deg C) over time ● Fast process, symptoms seem to appear overnight or with each cold exposure RBC agglutination in cold AIHA Spherocyte in warm AIHA https://doi.org/10.1182/asheducation-2018.1.382

AIHA: Signs & Symptoms ● Fatigue ● Anemia ( Hemolytic ) ↓HGB/HCT, ↑bilirubin ( ⇒ jaundice), ○ ↑reticulocytes, ↓haptoglobin ○ Spherocytes on peripheral smear ● Splenomegaly / Hepatomegaly ● Urine discoloration (“coca cola urine”) &/or Jaundice ● Direct Coombs test + (IgG + C3b) ○ Direct antiglobulin test (DAT) ● Rule out: delayed RBC transfusion reaction, drug induced immune hemolysis

AIHA: Treatment ● Treat underlying condition ( ie. Infection or malignancy) ● Anemia ⇒ ↑ Erythropoiesis (↑ folate demand) give folic acid supplement ● VTE prophylaxis with LMWH (during acute exacerbation) Warm Cold ● Glucocorticoids ( 1 mg/kg prednisone Generally only severe cases are treated equivalent) ● All IV fluids should be warmed ● Rituximab ● Rituximab ● Splenectomy ● Bendamustine + Rituximab (BR)* ● Hematopoietic stem cell transplantation ● Fludarabine + Rituximab* ● Future prospects: Sirolimus, bortezomib, ● Bortezomib* fostamatinib, obinutuzumab *depletes B-cells Dramatic lysis: may consider plasmapheresis https://doi.org/10.1182/asheducation-2018.1.382

Rituximab ● anti-CD20 targeting monoclonal antibody Kills CD20 positive cells → ○ Decreased production of antibodies & immunoglobulins ○ ● BLACK BOX WARNINGS ○ Mucocutaneous reactions ○ Progressive multifocal leukoencephalopathy (PML) High risk for infusion reactions ○ ○ Risk for HBV reactivation ■ Check vaccination/ HBV status prior to start therapy ■ HBV prophylaxis in patients who are positive (entecavir) ● Vaccines may not be as effective Effect may linger for 6 - 12 months after stopping treatment ○

AIHA Path: Immune mediated RBC destruction ↔PLT, ↓HGB/HCT, Labs: spherocytes on smear Coombs + S/S: Bleeding, bruising, fatigue Thpx: Steroids ( W ) Rituximab ( W or C ) Warmth ( C ) Other: Rule out malignancy Cold ( C ) vs Warm ( W )

Clinical Case #1 71 year old male presents to the ER with shortness of breath, fatigue, and painful blue-tinged extremities after shoveling his driveway from the recent snowfall. On physical exam, the physician notes mild splenomegaly, yellow scleral icterus, and a negative stool guaiac test. WBC 8 (normal) HGB 5 (low) HCT 17% (low) PLT 230 (normal) Smear RBC agglutination A. Surgical consult for splenectomy Coombs + B. High dose methylprednisolone C. Observation + folic acid, then follow up with hematologist in 1 month D. Give PRBC & warm fluids, counsel to avoid the cold

ITP Overview ↓PLT ↔ HGB/HCT Isolated thrombocytopenia caused by autoantibodies ⇨ “self ● destruction of platelets” ● Clinically distinct manifestation in children vs. adults ● Characterized by: Normal smear ○ ○ Only platelets affected ○ No other obvious explanation for low platelets Children Adult Annual Incidence 8 in 100,000 12 in 100,000 Peak Incidence 2-4 years old; girls : boys (1:1) Women:Men (2.5:1) Common Acute (triggered by viral infection) Chronic (~70%) Manifestation Self limiting (~80% achieve spontaneous remission)

Normal Thrombogenesis Thrombopoietin (TPO) is one of the hematopoietic growth factors (ie. EPO, GCSF) mainly produced by the liver that regulates platelet production. Binds to c-MPL receptors on platelets and megakaryocytes to induce ● Megakaryocyte size/proliferation ● platelet production Feldman, 15 April 2016 Volume 2016:8 Pages 39 — 50 De Graaf, (2011). Cell Cycle 10:10, 1582-1589

ITP Pathophysiology Megakaryocyte ITP secondary to viral infection Viral antigen similar to plt antigen Platelets ↑ cross reactive IgG anti - plt autoantibodies ↓PLT TPO can’t normalize the plt count due to auto-antibody ↓ or ↔ TPO levels binding on the stem cells https://doi.org/10.1182/asheducation-2013.1.276

ITP Pathophysiology Primary ● Isolated thrombocytopenia without other apparent causes Secondary ● Lymphoproliferative disorders (malignancy) ● Systemic lupus erythematosus ● Antiphospholipid syndrome ● Infections like HIV, HCV and H. pylori ● Drug-induced

ITP Signs & Symptoms ● Relevant Labs ISOLATED thrombocytopenia (platelet count < 100 x 100⁹/L) ○ ○ ↓ PLTS, ↔ HGB/HCT , normal bone marrow biopsy ○ Spontaneous bleeding typically doesn’t occur until platelets < 30 x 10⁹/L ● Fatigue ● Bleeds / bruises easily ○ Petechiae, purpura, epistaxis Hematuria ○ ● Severe bleeding Intracranial hemorrhage (1.4%) ○ Gastrointestinal bleed ○ ● Rule out TTP, infection, bone marrow disorders, malignancy (pediatric ALL) disseminated intravascular coagulation, drug induced thrombocytopenia Neunurt, Blood Adv (2019) 3 (23): 3829 – 3866; Newton JL et al. Eur J Haematol 2011; 86:420. .

Treatment Initiation for New Diagnosis American Society of Hematology (ASH) guidelines recommends moving AWAY from treatment based on platelet count Children ● No or minor bleeding → Observation ● Non- life threatening bleeding and/or ↓ QOL → Steroids ○ If steroids are not- prefered → IVIG or anti -D immunoglobulin Adults ● Plts > 30 x 10 ⁹ /L AND asymptomatic or minor bleeding → Observation ● Plts < 30 x 10 ⁹ /L AND asymptomatic or minor bleeding → Steroids Neunurt, Blood Adv (2019) 3 (23): 3829 – 3866.

ITP: IVIG (First line) Saturation of Fc receptor on macrophages will temporarily decrease platelet clearance RPH Pearls ● Obtain IgA testing ● Choose SQ vs. IV ● Assess glucose content Adverse Events ● headache, fever, nausea ● infusion reactions, fluid overload anti-D immunoglobulin (WinRho Ⓡ ) : an option for those who are RhoD + with a spleen https://www.slideshare.net/irheum/when-to-use-ivig-in-rheumatic-diseases

ITP: Treatment Overview Goal Restore durable platelet count allowing for sufficient hemostasis Acute ● Steroids +/- IVIG or anti-D immunoglobulin (when applicable) ○ Pulse dose Dexamethasone is the favored steroid in adults ● Platelet transfusion (ONLY in major bleeding) ○ AFTER IVIG has been given Chronic ● Splenectomy ● Rituximab, TPO-receptor agonists, spleen tyrosine kinase inhibitor

IVIG Product Comparison Gamunex-C Ⓡ Gammagard S/D Ⓡ Privigen Ⓡ Hizentra Ⓡ Gammagard liquid Ⓡ (Lyophilized powder) FDA indication Age > 2 y/o Age > 2 y/o Age > 2 y/o Age > 15 y/o Adult only C/I IgA deficiency IgA deficiency w/ IgA deficiency w/ IgA deficiency w/ w/ antibody to antibody to IgA antibody to IgA antibody to IgA IgA hyperprolinemia Route IV/SQ IV/SQ IV IV SQ Conc. 10% (do not 10% 5%, 10% 10% 20% dilute with NS) Sodium & sugar No sugar & No added sugar Glucose 20 mg/mL No sugar & trace No sugar & trace content trace sodium or sodium (5%) sodium sodium IgA content 46 mcg/ml 37 mcg/mL < 1 mcg/mL < 25 mcg/mL < 50 mcg/mL https:// www.fffenterprises.com/assets/downloads/FFF_ReferenceChart-ImmuneGlobulin-IG.pdf

ITP Second Line Therapies Neunurt, Blood Adv (2019) 3 (23): 3829 – 3866.