demystifying the hematology alphabet soup: aiha, itp, ttp/hus · affect plt or rbc, or both! when...

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

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

↔PLT ↓HGB/HCT

Hemolysis

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

https://www.youtube.com/watch?v=wxzf_rg_Wd4

AIHA: Pathophysiology Warm

● IgG mediated

● Occurs at body temp (~ 37 deg C)

● Slower process, symptoms occur

over time

Cold

● IgM mediated

● Occurs at room temp or less than

normal body temp (~32 - 37 deg C)

● Fast process, symptoms seem to

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

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

Warm

● Glucocorticoids (1 mg/kg prednisone

equivalent)

● Rituximab

● Splenectomy

● Hematopoietic stem cell transplantation

● Future prospects: Sirolimus, bortezomib, fostamatinib, obinutuzumab

Dramatic lysis: may consider plasmapheresis

Cold

Generally only severe cases are treated

● All IV fluids should be warmed

● Rituximab

● Bendamustine + Rituximab (BR)*

● Fludarabine + Rituximab*

● Bortezomib*

*depletes B-cells

● Treat underlying condition ( ie. Infection or malignancy) ● Anemia ⇒ ↑ Erythropoiesis (↑ folate demand) give folic acid supplement ● VTE prophylaxis with LMWH (during acute exacerbation)


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

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)

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.

A. Surgical consult for splenectomy 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

WBC 8 (normal) HGB 5 (low) HCT 17% (low) PLT 230 (normal) Smear RBC agglutination Coombs +

ITP Overview ● 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

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

● Megakaryocyte size/proliferation

● platelet production

Normal Thrombogenesis

Feldman, 15 April 2016 Volume 2016:8 Pages 39—50 De Graaf, (2011). Cell Cycle 10:10, 1582-1589

ITP Pathophysiology 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


↓PLT

↓ or ↔ TPO levels

Megakaryocyte

Platelets

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 10⁹/L AND asymptomatic or minor bleeding → Observation

● Plts < 30 x 10⁹/L AND asymptomatic or minor bleeding → Steroids

Neunurt, Blood Adv (2019) 3 (23): 3829–3866.

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

ITP: IVIG (First line)

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

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

or sodium

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

ITP Second Line Therapies

Neunurt, Blood Adv (2019) 3 (23): 3829–3866.

ITP: Second line Splenectomy removes of the primary site of platelet destruction and site for

activation of platelet-reactive T & B cells

● Gold standard for restoring physiological plt count in refractory ITP

● 60% achieve complete remission; 20% partial response

● Give immunizations at least 2 weeks before surgery

● Post splenectomy antibiotic prophylaxis

○ Penicillin or amoxicillin daily

○ Timing patient specific

Rituximab anti-CD20 antibody targeting B cells

● Provides short term solution lasting about 6+ months

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

ITP: TPO-Receptor Agonists

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


ITP: Fostamatinib (Tavalisse) 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:

● ↑ LFT (9%), hypertension, diarrhea (31%), neutropenia (6%)

Drug Interactions:

● Strong CYP3A4 inducers (avoid use) ● Strong CYP3A4 inhibitors (↑ risk of Tavalisse toxicity)

Tavalisse, Prescribing Information. Rigel Pharmaceuticals, Inc. updated April 2018.

ITP in Children In children, ITP can look like leukemia

● Steroids only AFTER bone marrow biopsy ○ 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

● +/- IVIG PRIOR to platelet transfusion

If ITP persists > 3 months AND non-life threatening bleeding: (Recommended order)

● Eltrombopag (only FDA approved oral agent; age > 1 y/o), THEN

● Rituximab (RR: 40-50%)

● Splenectomy (avoided as long as possible and deferred until older than 5 y/o)

Clinical Case #2 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?

A. High dose steroid therapy with prednisone B. Platelet & PRBC transfusion C. Observation then follow up with hematologist in 1 month D. Give IVIG until bone marrow biopsy is complete then steroids

WBC 4 (low normal) HCT 37% (normal) HGB 12 (normal) PLT 5 (low)

AHIA ITP


RBC destruction

Immune mediated PLT

destruction



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



Typically follows

infection

Dx of exclusion (rule out

malignancy in peds)

TTP/HUS Overview ● Thrombotic microangiopathy (TMA)

○ 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

● TTP/HUS are both part of the TMA syndrome spectrum

↓PLT ↓HGB/HCT

TTP Typical HUS aHUS

TTP: Overview ● TTP = Thrombotic Thrombocytopenic Purpura ● Incidence ~ 3 in 1 million adults in the US annually

○ Not very common in children ○ Median age of diagnosis = 41 years

● 90% mortality when untreated ● Deficiency in enzyme ADAMTS-13 due to autoantibodies or mutation

○ Von Willebrand factor (VWf) = clotting factor in endothelium ○ ADAMTS-13 breaks down VWf, preventing build-up in vasculature

● Characterized by: ○ Schistocytes on smear ○ Consumptive thrombocytopenia ○ “FATRN” symptoms

↓PLT ↓HGB/HCT

TTP: Pathophysiology ↓ ADAMTS 13

↑ vWF

↑ Platelet aggregation (↓ PLT)

↓ Blood flow

Shearing of erythrocytes = schistocytes (↓HGB/HCT)

Schistocytes

https://www.nejm.org/doi/full/10.1056/NEJMicm1813768

https://www.nejm.org/doi/full/10.1056/NEJMicm1813768

TTP: Signs and Symptoms

F = fever

A = anemia (hemolytic, look for schistocytes)

T = thrombocytopenia (consumptive)

R = renal dysfunction (usually mild)

N = neurocognitive dysfunction (can be rather pronounced)

PLASMIC Score ● Used to quantify the likelihood of TTP and make presumptive diagnosis

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

TTP: Treatment ● Plasma exchange (or “large volume

plasmapheresis”) ○ Removes auto-antibodies against ADAMTS-13

○ Often combined with immunosuppressive therapy to decrease

production of ADAMTS-13 antibodies (rituximab,

glucocorticoids, vincristine, etc.)

● Fresh Frozen Plasma (FFP) ○ Replace plasma with plasma that has functional ADAMTS-13

● High dose steroids (1 mg/kg daily)

● Caplacizumab ○ For high-risk patients only

● Recombinant ADAMTS-13 ○ 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.








Plasmapheresis & the RPH

Cheng CW. Am J Clin Pathol. 2017;148(3):190-198.

Caplacizumab (Cablivi) ● Inhibits A1-domain of vWF → decreases vWF-mediated PLT adhesion and consumption

● Typically reserved for patients with high-risk disease (PLASMIC score = 5-7) and with

severe features:

○ Neurologic symptoms

○ High troponin levels

● RPH Pearls ○ 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

Clinical Case # 3 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?

A. Surgical consult for splenectomy

B. Caplacizumab

C. Large volume plasmapheresis

D. Platelet & PRBC transfusion

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


RBC destruction

Immune mediated PLT

destruction

ADAMTS-13 deficiency

→ ↑vWF



Coombs +


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



Typically follows

infection


malignancy in peds)

Congenital or acquired

PLASMIC score

HUS: Overview ● HUS = Hemolytic Uremic Syndrome ● Incidence ~ 2-3 in 100,000 people in the US annually

○ More common in children ○ Often associated with pregnancy in adults

● 3-5% mortality (typical), ~25% mortality (atypical) ● TWO distinct causes of HUS:

○ Typical: toxin mediated hemolysis from infection ○ Atypical: complement mediated hemolysis

● Characterized by: ○ Schistocytes on smear ○ Consumptive thrombocytopenia ○ “FATRN” symptoms, especially renal dysfunction

↓PLT ↓HGB/HCT

HUS: Pathophysiology Typical = toxin mediated (often from from E. Coli gastroenteritis) Atypical = complement mediated (dysregulation in endogenous system)

https://clinicalgate.com/hemolytic-uremic-syndromes/






Alternative Complement Pathway

Barbour T. 2006;176:1305-1310.

In the case of atypical HUS… your endothelium!

HUS: Signs & Symptoms

F = fever

A = anemia (hemolytic, look for schistocytes)

T = thrombocytopenia (consumptive)

R = renal dysfunction (SEVERE!)

N = neurocognitive dysfunction (can be more mild)

HUS: Treatment Typical HUS:

● Antibiotics & antimotility

agents not recommended

● Supportive care!!! ○ Fluid balance

○ Electrolyte management

● Dialysis

Atypical HUS:

● Anti-complement therapy ○ Eculizumab (Soliris(R))

○ Ravulizumab (Ultomiris(R))

● Plasma exchange

● Dialysis

● Kidney transplant

Anti-Complement Therapy ● Inhibition of membrane attack complex (MAC) by binding to complement C5

○ Eculizumab (Soliris)

■ Dosed Q2W

○ Ravulizumab (Ultomiris)

■ Dosed Q8W, 2 weeks after loading dose

● BLACK BOX WARNING + REMS program ○ High risk for meningococcal infections

○ Meningococcal immunization >/= 2 weeks prior to first dose

● RPH Pearls ○ 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

https://alexion.com/Documents/Soliris_USPI.pdf

Clinical Case #4 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?

A. Eculizumab

B. Eculizumab + penicillin, after meningococcal vaccination

C. Large volume plasmapheresis

D. Hydration + supportive care

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


RBC destruction

Immune mediated PLT

destruction

ADAMTS-13 deficiency

→ ↑vWF

Toxin mediated

microangiopathy

Complement mediated

microangiopathy



Coombs +


normal smear

↓PLT, ↓HGB/HCT,


↓PLT, ↓HGB/HCT,


↓PLT, ↓HGB/HCT,


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



Typically follows

infection


malignancy in peds)

Congenital or acquired

PLASMIC score

Most common in

children

Renal dysfunction

Review Questions 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