Based on the limited information provided: - Diagnosis: Thrombotic thrombocytopenic purpura (TTP) - Management: Plasma exchange to remove ADAMTS13 inhibitor More information is needed to confirm the diagnosis and guide appropriate treatment. Some key questions include: - Is there evidence of schistocytes on the peripheral smear? - What is the patient's coagulation profile and haptoglobin level? - Is ADAMTS13 activity level reduced? - What is the patient's medical history and any potential triggers? - Are there any neurologic deficits on exam beyond altered mental status? Without confirming the presence of schistocytes and reduced ADAMTS13

1. Hemolytic Anemia:
A Comparison of Two Cases
JP Flores, MD with thanks to Meaghan O’Malley, MD
Division of Hematology-Oncology
Virginia Mason Noon Conference
March 26, 2019

2. Case #1: Patient JA
• HPI – 49 yo M w/ history of ETOH cirrhosis admitted with AKI, anemia,
thrombocytopenia, & hyperbilirubinemia
• Reason for consult: Hgb 6.7, hapto <10, weakly positive DAT
• Transfusion of 3 units PRBCs: Hgb 6.9  7.9
• PMHx:
• EtOH cirrhosis c/b ascites. No known varices. Recently on liver txp list, but put
on hold due to recent bacteremia
• HTN
• Rheumatic fever
• Obesity
• Anemia - thought to be secondary to Zieve’s syndrome
• FamHx – M, F, bro with EtOH abuse. Mother died of cirrhosis from EtOH and breast
cancer
• SocHx – Lives with sister and nephew. Prior heavy EtOH for 25 years, stopped in
7/09. Denies IVDA.
• Home Meds – Propanolol, Aldactone, Lasix, folic acid, Cefuroxime, lactulose,
sertraline
• ROS - +fatigue, abdominal discomfort

3. Case #1: Patient JA
• Physical Exam:
VS: T 36.4, AF, BP 105/53, HR 56, RR 18, 100% RA
GEN: Caucasian man lying in bed in no apparent distress.
HEENT: Icteric sclera. MMM. +Subglossal jaundice.
NECK: Supple, no LAD
LUNGS: CTA b/l
CHEST: Brady, nml S1/S2. III/VI SEM in RUSB.
ABDOMEN: Soft, distended, +fluid wave, +splenomegaly. Nontender.
SKIN/EXT: 3+ pitting edema in bilateral lower extremities up to knees.
Ecchymotic patches in flexor surface of forearms b/l, scattered
petechiae on extensor surfaces of arms.
NEURO: A&Ox3. Asterixis present.

4. Case #1: Patient JA
• Labs
• WBC 11.4, Hgb 7.1, plts 20
• MCV 93.7, RDW 21.2
• INR 2.1, PT 20.6, PTT 52.9
• AST 61, ALT 46, alk phos 98, tbili 21.9, direct bili 14.8
• BUN 100, Cr 2.9
• fibrinogen 171, LDH 231
• DAT: IgG weakly positive, C3 direct negative
• Haptoglobin <10
• Differential diagnosis for anemia?
• Hemolysis
• Anemia of chronic disease
• Blood loss
• Splenic sequestration
What is the next step?

5. Differential diagnosis: Coombs negative
hemolytic anemia
• G6PD Deficiency
• Paroxsymal Nocturnal Hemoglobinuria (PNH)
• Hemoglobinopathies
• Thalassemia
• Sickle cell disorders
• Hereditary spherocytosis and elliptocytosis
• Mechanical destruction
• Aortic stenosis or prosthetic valve
• March hemoglobinuria
• Thrombotic Microangiopathies
• TTP
• HUS and atypical HUS
• Drug induced TTP

6. My read: No obvious blasts or platelet clumps. Frequent spur cells
(acanthocytes) in evidence, +targets, few spherocytes. Few pencil
cells. Overall appearance microcytic and hypochromic.
Lazarchick, J. ASH Image Bank 2004;2004:101137
Diagnosis: Spur cell anemia secondary to
underlying liver disease

7. Case #1: Spur Cell Anemia
• Spur cell anemia: extrinsic non-immune hemolytic anemia w/ presence of
acanthocytes, usually associated with cirrhosis
• Pathophysiology – Large RBCs w/ irregular prominent protrusions
• Abnormal surface area-to-volume ratio (Cooper et al, Semin Hematol 1980)
• Increase in cell membrane cholesterol
• Inability to remove and repair damaged fatty acids
• Changes in lipid composition render RBC susceptible to splenic destruction
• Removal of fatty acids leaves a lytic lyso-derivative in its place
• Lysophosphocholine acyl transferase (LAT) normally inserts replacement fatty
acid
• LAT is inhibited in spur cells (Allen et al, Blood 1996)
• Two important steps:
• Excess RBC cholesterol
• Extensive remodeling in the spleen

8. Case #1: Spur Cell Anemia
Vassiladis et al, Hepatology Research 2010:
• 54 pts w/ advanced cirrhosis
• 26 pts had spur cells on smear
• Presence of spur cells
• More advanced liver disease (P < 0.0001)
• Lower hemoglobin (P < 0.0001)
• Incr hyperbili (P < 0.0001)
• High retic ct (P < 0.0001)

9. Case #1: Spur Cell Anemia
•What do you want to do?
A) Prednisone 1mg/kg/day
B) Plasmapheresis
C) Liver transplant
D) Rituximab
E) Splenectomy
F) None of the above
 Treat the underlying issue

10. Case #2: Patient LS
Reason for consult: “abnormal labs”
• HPI – 54 yo M w/ h/o HTN admitted w/ “abnormal labs”. Anemia w/u underway
as outpt due to intermitt melena. Hgb down to 7.4 over past yr, GI w/u
negative. Contacted by PCP following lab draw, reported to ER.
•Hgb 7.4, MCV 106, LDH 480, hapt<10
• PMHx: HTN, anemia
• FamHx: Sis w/ rectal ca in her 50s
• SocHx: 40 py tobacco, former heavy ETOH use. Married, retired police officer
• Meds: Lisinopril, “Tension Tamer” tea nightly
• ALL: NKDA
• ROS: +fatigue

11. Case #2: Patient LS
• Physical Exam:
VS: T 36.9, HR 74, BP 128/68, HR 74, RR 18, 93% RA
Gen: well-appearing, pale, NAD
HEENT: PERRLA, EOMI, MMM. Pale conjunctiva. No icterus.
Neck: supple, no LAD
CV: RRR, no m/r/g
Resp: CTA b/l
Abd: soft, NT/ND, +BS, no HSM
Extr: no c/c/e
Skin: WWP, no lesions or rashes

12. Case #2: Patient LS
• Labs:
- WBC 4.5, Hgb 6.4, plts 99, MCV 106
- LDH 434, hapto < 10, total bili 1.2, dbili 0.5
- retic ct 9.79%
- iron 64, B12 296, fol 8.6
- DAT: IgG pos 4+, C3 pos 3+
• Differential diagnosis
• Autoimmune hemolytic anemia
• ? Tension Tamer tea
• Occult GI blood loss
• Iron deficiency anemia
What do you do next?

13. My read: Many microspherocytes indicated of hemolytic anemia, no
clumping. Normal WBC morphology with some atypical
lymphocytes, occasional large plts indicative of peripheral
destruction. No schistocytes or microangiopathic cells.
+Polychromatophilic cells present.
Maslak, P. et al. ASH Image Bank 2009;2009:9-00085
Diagnosis: Warm autoimmune hemolytic anemia

14. Case #2: Warm autoimmune
hemolytic anemia (AIHA)
• Definition – increased RBC destruction in the presence of anti-RBC autoantibodies.
+Anemia, indirect bili, LDH, ↓hapto, +spherocytes
• Incidence & Types – 1-3 per 100,000 individuals (Barros et al, Transf Med Reviews, 2010)
Warm AIHA (80%) Cold agglutinin AIHA Mixed-type PNH
• Mechanism
• Immunoadherence – IgG binds to RBC and Fc receptor on cytotoxic cell
• Phagocytosis engulfs RBC  partial ingestion  spherocyte
• Spherocytes then destroyed in the spleen
• Complement mediated – causes direct lysis of RBCs
• Causes
• Idiopathic
• Viral causes
• SLE – up to 10% of SLE pts in cohort studies (Jeffries et al, Lupus 2008)
• Malignancies (estimated at 11% in CLL) (Diehl et al, Semin Oncol 1998)
• Drugs
• Antibody detection – the direct Coombs test

15. Case #2: Management of AIHA
• Steroids 1mg/kg daily – 1st
line therapy
• Decreases synthesis of anti-RBC antibodies (Packman et al, Blood Rev
2008)
• Suppresses sequestration of RBCs by splenic
macrophages
• Approx 80% of warm AIHA will respond to steroids
• Splenectomy - 2nd
line therapy
• Never been compared head-to-head
• Variable results; 38-70% response rate
• Removes the primary site of RBC sequestration
• Other Rx – danazol, IVIG, alemtuzumab, cytoxan,
azathioprine

16. AIHA – Use of Rituximab
Mechanism in AIHA
1) B cell depletion - produce anti-RBC antibodies
2) Immune complex decoy hypothesis
• Rituxan-opsonized B cells attract monocytes and macrophages away
from auto-Ab complexes (Taylor et al, Nature Clin Pract, 2007)
Dosing and Use
• Doses of 375 mg/m^2 x 4 wks  CR in 87-100% of pediatric patients
• In adults, rates of CR range from 25-100% (Barros et al, Transf Med
Reviews, 2010)
Rituxan used successfully in variety of AIHA
• Idiopathic AIHA
• Secondary AIHA (BMT, autoimmune d/o, CLL)
• Pts who had previously rec’d steroids or other treatments
• Has been used in relapsed patients as well

17. Rituxan – what’s the data?
Bussone et al, Am J Hematol 84:153-157, 2009
• Largest retrospective review of Rituxan in AIHA (27 patients)
• Patients – 27 cases
• 16 women and 11 men over a 4-yr period
• Median Hgb level was 5.9 g/dl
• Had rec’d 2.1 ± 1.4 lines of therapy
• Treatment – 4 wkly infusions of rituxan 375 mg/m^2
• PR = Hgb >10 w/ at least 2 g/dl increase
• CR = Hgb >11 g/dl or 12 g/dl in absence of hemolysis
• Response – Initial response in 25/27 (93%)
• Mean f/u of 20.9 mo: 18/25 (72%) were still in remission
• Prednisone withdrawn in 11 of 25 (44%) responders

18. Bussone et al retrospective review, 2009
Back to our cases…

19. Case #1: Patient JA – SCA
• Reactivated on liver transplant list
• Underwent uncomplicated OLT
• Trend of counts:
• Course c/b anastomatic stricture s/p stenting, o/w doing great!
Date Hemoglobin
3/14/16 8.7 g/dl
4/26/16 9.4 g/dl
5/24/16 9.7 g/dl
6/28/16 10.3 g/dl
8/2/16 11.6 g/dl

20. Case #2: Patient LS – wAIHA
• Started prednisone 1mg/kg for Hgb 6.4
• 2 days later, discharged with Hgb 7.9, plts 127, pred 80
• 7/1/16 – prednisone completely stopped
• 8/9/16 – Hgb 13.7, plts 97K
• Fairly neg rheum w/u  role of MDS
• Refused bone marrow biopsy at last clinic visit
Date Hgb & plts Plan
3/19/16 9.2 g/dl, 150K No change
3/26/16 11.0 g/dl, 126K Decr prednisone to 70 mg
4/1/16 11.7 g/dl, 103K Clinic visit, start slow taper
4/27/16 13.5 g/dl, 99K
6/8/16 14.5 g/dl, 100K Alternating 10 mg & 20 mg

21. Questions?

22. Bonus Case #1 – 35 yo F with AMS

23. Questions
• Diagnosis?
• Management?
• Need more information?

24. More Information
• 35 year old woman presents to the ER with altered mental status
• T: 39.2 HR: 103, BP 100/60, RR: 16
• Exam shows petechial rash
• WBC: 10 Hgb 8, Plt 12, Cr 2.5, LDH 495
• Diagnosis?
• Management?

25. Bonus Case #2 23 yo M with back pain