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
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
Kaite Kammers
Ann-Chee Cheng
For AHIA, ITP, and TTP/HUS: 1. Recognize the presenting signs and symptoms of each
with each therapy
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)
hematologic diseases
○ A bit of a misnomer since they are often quite fatal!
autoimmune
followed by chronic management
○ Hematology referral
○ Warm (60-70%) ○ Cold agglutinin (10-20%) ○ Mixed (7-8%)
medications (especially antibiotics)
○ Reticulocytes & spherocytes ○ Only RBC line affected ○ (Usually) positive Coombs test
↔PLT ↓HGB/HCT
https://www.youtube.com/watch?v=wxzf_rg_Wd4
RBC’s destroyed in spleen or circulation by auto-antibodies
RBC
hemoglobin Heme globin Amino Acids Iron Bilirubin
Warm
Cold
normal body temp (~32 - 37 deg C)
appear overnight or with each cold exposure
Spherocyte in warm AIHA RBC agglutination in cold AIHA
https://doi.org/10.1182/asheducation-2018.1.382
○ ↓HGB/HCT, ↑bilirubin (⇒ jaundice), ↑reticulocytes, ↓haptoglobin ○ Spherocytes on peripheral smear
&/or Jaundice
○ Direct antiglobulin test (DAT)
induced immune hemolysis
Warm
equivalent)
fostamatinib, obinutuzumab Dramatic lysis: may consider plasmapheresis
Cold
Generally only severe cases are treated
*depletes B-cells
https://doi.org/10.1182/asheducation-2018.1.382
○ Kills CD20 positive cells → ○ Decreased production of antibodies & immunoglobulins
○ 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)
○ Effect may linger for 6 - 12 months after stopping treatment
AIHA Path: Immune mediated RBC destruction Labs: ↔PLT, ↓HGB/HCT, 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)
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 Coombs +
destruction of platelets”
○ 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 Manifestation Acute (triggered by viral infection) Self limiting (~80% achieve spontaneous remission) Chronic (~70%)
↓PLT ↔HGB/HCT
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
Feldman, 15 April 2016 Volume 2016:8 Pages 39—50 De Graaf, (2011). Cell Cycle 10:10, 1582-1589
ITP secondary to viral infection Viral antigen similar to plt antigen ↑ cross reactive IgG anti- plt autoantibodies TPO can’t normalize the plt count due to auto-antibody binding on the stem cells
https://doi.org/10.1182/asheducation-2013.1.276
↓PLT ↓ or ↔ TPO levels
Megakaryocyte Platelets
Primary
Secondary
(malignancy)
○ 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
○ Petechiae, purpura, epistaxis ○ Hematuria
○ Intracranial hemorrhage (1.4%) ○ Gastrointestinal bleed
disseminated intravascular coagulation, drug induced thrombocytopenia
Neunurt, Blood Adv (2019) 3 (23): 3829–3866; Newton JL et al. Eur J Haematol 2011; 86:420. .
American Society of Hematology (ASH) guidelines recommends moving AWAY from treatment based on platelet count Children
○ If steroids are not-prefered → IVIG or anti-D immunoglobulin Adults
Neunurt, Blood Adv (2019) 3 (23): 3829–3866.
Saturation of Fc receptor on macrophages will temporarily decrease platelet clearance
RPH Pearls
Adverse Events
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
Goal Restore durable platelet count allowing for sufficient hemostasis Acute
○ Pulse dose Dexamethasone is the favored steroid in adults
○ AFTER IVIG has been given Chronic
Gamunex-CⓇ Gammagard liquid Ⓡ Gammagard S/D Ⓡ
(Lyophilized powder)
Privigen Ⓡ Hizentra Ⓡ FDA indication Age > 2 y/o Age > 2 y/o Age > 2 y/o Age > 15 y/o Adult only C/I IgA deficiency w/ antibody to IgA IgA deficiency w/ antibody to IgA IgA deficiency w/ antibody to IgA hyperprolinemia IgA deficiency w/ antibody to IgA Route IV/SQ IV/SQ IV IV SQ Conc. 10% (do not dilute with NS) 10% 5%, 10% 10% 20% Sodium & sugar content No sugar & trace sodium No added sugar
Glucose 20 mg/mL (5%) No sugar & trace sodium No sugar & trace 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
Neunurt, Blood Adv (2019) 3 (23): 3829–3866.
Splenectomy removes of the primary site of platelet destruction and site for activation of platelet-reactive T & B cells
○ Penicillin or amoxicillin daily ○ Timing patient specific
Rituximab anti-CD20 antibody targeting B cells
1. PCV13, followed by PPSV23 > 8 weeks later 2. Hib 3. Meningococcal group ACWY 4. Meningococcal group B* *Menveo and PCV13 can be given at the same time. Menactra must be separated by 4 weeks from PCV13
https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html
Indication Dose Pearls Romiplostim (Nplate Ⓡ) inj
Chronic refractory ITP Age > 1 1 mcg/kg SC weekly Weekly dose adj based on plt count to reach goal of plt > 50 x 10⁹/L (MAX 10 mcg/kg) High cost drug (3 vials sizes available leads to lots of waste) do not use in pt w/ MDS Dispense in insulin syringes
Eltrombopag (PromactaⓇ) tab & oral susp
Chronic ITP HCV aplastic anemia 50 mg PO daily & dose adj for hepatic insufficiency and some of asian descent to maintain plt > 50 x 10⁹/L (MAX 75 mg) Box warning: hepatotoxicity Separate from meals (dairy 4 hrs) AE: HA, GI s/sx, DDI with polyvalent cations
Avotrombopag (DopteletⓇ) tab
Chronic ITP 20 mg PO daily Bi-weekly dose adj based on plt count to reach goal of plt > 50 x 10⁹/L (MAX 40 mg/day) No hepatotoxicity issues Administer with food AE: HA, GI s/sx, VTE
Binds to c-Mpl receptor in progenitor cells leading to ↑ plt production via proliferation / differentiation megakaryocytes
https://doi.org/10.1182/asheducation-2013.1.276
Spleen tyrosine kinase inhibitor; the major metabolite R406 inhibits signalling between the Fc activating receptor and B-cell receptors to reduce antibody mediated destruction of platelets Dose: 100 mg twice daily; may ↑ to 150 mg BID if plt < 50x10⁹/L after 1 month Dose Adjustment:
Drug Interactions:
Tavalisse, Prescribing Information. Rigel Pharmaceuticals, Inc. updated April 2018.
In children, ITP can look like leukemia
○ Prednisone (2-4 mg/kg/day; maximum, 120 mg daily, for 5-7 days) ○ Dexamethasone (0.6 mg/kg/day; maximum, 40 mg/kg/day, for 4 days)
■ Reserved for children < 10 years old due osteonecrosis risk
If ITP persists > 3 months AND non-life threatening bleeding: (Recommended order)
A 6-year-old girl is brought to the ED with persistent epistaxis, a 1 week history of easy bruising and recent resolution of chicken pox. Mother reports reports that she has been fatigued and this was the 4th episode of epistaxis this week. She has not taken any medications recently. Which of the following treatments would be the most appropropriate at this time?
WBC 4 (low normal) HCT 37% (normal) HGB 12 (normal) PLT 5 (low)
AHIA ITP Path: Immune mediated RBC destruction Immune mediated PLT destruction Labs: ↔PLT, ↓HGB/HCT, spherocytes on smear Coombs + ↓PLT, ↔ HGB/HCT, normal smear S/S: bleeding, bruising, fatigue bleeding, bruising Thpx: Steroids (W) Rituximab (W or C) Warmth (C) Steroids IVIG Rituximab Other: Rule out malignancy Cold (C) vs Warm (W) Typically follows infection Dx of exclusion (rule out malignancy in peds)
○ Microvascular occlusive disorder ○ Thrombus formation in small or larger blood vessels ○ Mechanical injury of erythrocytes leads to occlusions in vascular organs ○ Patients present with: thrombocytopenia and microangiopathic hemolytic anemia
↓PLT ↓HGB/HCT
TTP Typical HUS aHUS
○ Not very common in children ○ Median age of diagnosis = 41 years
○ Von Willebrand factor (VWf) = clotting factor in endothelium ○ ADAMTS-13 breaks down VWf, preventing build-up in vasculature
○ Schistocytes on smear ○ Consumptive thrombocytopenia ○ “FATRN” symptoms
↓PLT ↓HGB/HCT
↓ ADAMTS 13 ↑ vWF ↑ Platelet aggregation (↓ PLT) ↓ Blood flow Shearing of erythrocytes = schistocytes (↓HGB/HCT)
https://www.nejm.org/doi/full/10.1056/NEJMicm1813768
Bendapudi et al. Lancet Haematol 2017;4(4):e157
Factor Point Platelets < 30k 1 Hemolysis 1 No active cancer 1 No solid organ or stem cell transplant 1 MCV < 90 1 INR < 1.5 1 Creatinine < 2.0 1 PLASMIC Score Risk of severe ADAMTS deficiency 0 to 4 Low 5 Intermediate 6 to 7 High
plasmapheresis”)
○ Removes auto-antibodies against ADAMTS-13 ○ Often combined with immunosuppressive therapy to decrease production of ADAMTS-13 antibodies (rituximab, glucocorticoids, vincristine, etc.)
○ Replace plasma with plasma that has functional ADAMTS-13
○ For high-risk patients only
○ Apadamtase alfa (BAX 930) - currently in phase 3 trials
https://www.nhlbi.nih.gov/health-topics/thrombotic-thrombocytopenic-purpura Scully M. Recombinant ADAMTS-13. Blood. 2017;130(19):2055-2063.
Cheng CW. Am J Clin Pathol. 2017;148(3):190-198.
severe features:
○ Neurologic symptoms ○ High troponin levels
○ 11 mg kit for injection (SQ or IV) ○ Dosing (11 mg/dose): ■ First dose given IV prior to plasma exchange, followed by 1 dose SQ after plasma exchange on day 1 ■ Subsequent doses given SQ after plasma exchange for up to 28 days ○ Can typically wait to order drug and manage with plasmapheresis acutely
A 33-year-old female is brought to the ED with periodic episodes of confusion which quickly resolve. Her husband reports that she has been extremely fatigued over the past week. Temperature 102.2 deg F, BP 140/70, HR 103, RR 18. Exam shows jaundiced skin and mild scleral icterus. She has a systolic ejection murmur and 1+ edema of her lower extremities. Which of the following treatments would be the most appropropriate at this time?
HCT 29% (low) HGB 10.3 (low- ish) PLT 42k (low) BUN 26 (elevated) SCr 1.4 (elevated) Schistocytes present on peripheral blood smear.
AHIA ITP TTP Path: Immune mediated RBC destruction Immune mediated PLT destruction ADAMTS-13 deficiency → ↑vWF Labs: ↔PLT, ↓HGB/HCT, spherocytes on smear Coombs + ↓PLT, ↔ HGB/HCT, normal smear ↓PLT, ↓HGB/HCT, schistocytes on smear S/S: bleeding, bruising, fatigue bleeding, bruising FATRN sx Thpx: Steroids (W) Rituximab (W or C) Warmth (C) Steroids IVIG Rituximab Plasma exchange FFP Caplacizumab Other: Rule out malignancy Cold (C) vs Warm (W) Typically follows infection Dx of exclusion (rule out malignancy in peds) Congenital or acquired PLASMIC score
○ More common in children ○ Often associated with pregnancy in adults
○ Typical: toxin mediated hemolysis from infection ○ Atypical: complement mediated hemolysis
○ Schistocytes on smear ○ Consumptive thrombocytopenia ○ “FATRN” symptoms, especially renal dysfunction
↓PLT ↓HGB/HCT
Typical = toxin mediated (often from from E. Coli gastroenteritis) Atypical = complement mediated (dysregulation in endogenous system)
https://clinicalgate.com/hemolytic-uremic-syndromes/
Barbour T. 2006;176:1305-1310.
In the case of atypical HUS… your endothelium!
Typical HUS:
agents not recommended
○ Fluid balance ○ Electrolyte management
Atypical HUS:
○ Eculizumab (Soliris(R)) ○ Ravulizumab (Ultomiris(R))
○ Eculizumab (Soliris) ■ Dosed Q2W ○ Ravulizumab (Ultomiris) ■ Dosed Q8W, 2 weeks after loading dose
○ High risk for meningococcal infections ○ Meningococcal immunization >/= 2 weeks prior to first dose
○ If vaccinated < 2 weeks prior to first dose, recommend 2 weeks antibiotic prophylaxis ■ Penicillin or azithromycin ○ Dose adjustments for plasma exchange or FFP infusion (see package insert) ○ Patient specific drug, can be urgently acquired overnight from Alexion representative
https://alexion.com/Documents/Soliris_USPI.pdf
Meningococcal vaccines:
1. Serogroup ACYW a. Menactra b. Menveo 2. Serogroup B a. Bexero b. Trumenba
A 6 year old boy presents to the ED with abdominal pain, nausea, and fatigue. His mother states the boy developed abdominal pain and profound diarrhea about 5 days ago. Since then, his diarrhea has improved, but his diffuse abdominal pain and nausea have worsened. The boy has not urinated in the past ~24 hours. Mom notes that several other family members were sick with similar symptoms earlier this week after they all attended the same family cookout. Physical exam shows diffuse edema, abdominal tenderness, and temperature of 100.8 deg F. Which of the following is most appropriate at this time?
WBC 10 (high normal) HCT 35% (low) HGB 7.5 (low) PLT 53k (low) BUN 32 (elevated) SCr 1.9 (elevated)
AHIA ITP TTP Typical HUS aHUS
Path:
Immune mediated RBC destruction Immune mediated PLT destruction ADAMTS-13 deficiency → ↑vWF Toxin mediated microangiopathy Complement mediated microangiopathy
Labs:
↔PLT, ↓HGB/HCT, spherocytes on smear Coombs + ↓PLT, ↔ HGB/HCT, normal smear ↓PLT, ↓HGB/HCT, schistocytes on smear ↓PLT, ↓HGB/HCT, schistocytes on smear ↓PLT, ↓HGB/HCT, schistocytes on smear
S/S:
Bleeding, bruising, fatigue bleeding, bruising FATRN sx FATRN sx Diarrhea FATRN sx
Thpx:
Steroids (W) Rituximab (W or C) Warmth (C) Steroids IVIG Rituximab Plasma exchange FFP Caplacizumab Supportive care Dialysis Eculizumab Ravulizumab Plasma exchange Dialysis
Other:
Rule out malignancy Cold (C) vs Warm (W) Typically follows infection Dx of exclusion (rule out malignancy in peds) Congenital or acquired PLASMIC score Most common in children Renal dysfunction
Q1) Which of the following IVIG products is considered IgA poor?
A. Gammagard S/D B. Gamunex-C C. Hizentra D. Privigen
Q2) Which of the following drugs are MOST affected by plasmapheresis when treating a TTP patient?
A. Large Vd & highly protein bound B. Large Vd & poorly protein bound C. Small Vd & highly protein bound D. Small Vd & poorly protein bound
Q3) When a patient is to be initiated on eculizumab, which of the following vaccines should be administered prior to starting therapy?
A. Hepatitis B B. Meningococcal C. Influenza D. Pneumococcal