Labs and smears and
bears oh my
bears oh my
Threshold below which one would treat an asymptomatic patient ITP
20,000
In the absence of bleeding or need for invasive procedure no need to treat plt count below 20,000.
Preferred treatment for ITP in pregnancy
Steroids, IVIG are considered safe.
Rituximab, TPO agonists, splenectomy are generally avoided due to concerns about maternal/fetal health.
Name 3 diagnoses associated with secondary ITP
CLL, SLE, APLS, HIV, hepatitis C, CMV infection
What is the mechanism of IVIG?
IVIG is an immunomodulator that has several effects including modulation of complement activation, suppression of idiotypic antibodies, saturation of Fc receptors on macrophages; suppression of inflammatory cytokines, chemokines, and metalloproteinases.
Name a contraindication to IVIG
Renal failure: proposed mechanism is believed to be hyperosmolality caused by large molecular sugar stabilizers (sucrose, maltose, glucose, and sorbitol)
Hypersensitivity to immune globulin or any other component (fructose, hyaluronidase, human albumin)
Accepted platelet threshold for epidural
> 50-80,000
32F with history of SLE presents to LMC with pneumonia. She is on antibiotics and improving. Her baseline Hb is 12; at present Hb 10.7. Ferritin, B12, folate normal. Hemolysis labs normal except slightly elevated retic. Coombs +.
What is recommended next? A) observation B) rituximab C) Splenectomy D) Repeat Coombs E) Prednisone 60mg daily with long taper
A) Observation
A positive Coombs can be found in 5-10% of hospitalized patients and does not necessarily indicate hemolysis.
Ms. Smith is a 67F with history of hypothyroidism who presents to your office with petechiae.
wbc 5 normal diff Hb 8.2 MCV 85 plt 18k. LDH 520 Tbili 3.5 retic 4. Coombs+. IPF 18. No nutritional deficiencies, DIC or endocrinopathy. Smear is normal and subsequent bone marrow biopsy shows erythroid hyperplasia and increased megakaryocytes.
What is the diagnosis?
Bonus: What conditions should be ruled out.
Evans Syndrome
Idiopathic presence of Coombs+ AIHA and ITP (or any 2 of 3 immune cytopenias)
If diagnosis of Evans syndrome is made should evaluate for lymphoproliferative disorder, SLE.
Mechanism of steroids in AIHA
Reduces IgG production
Not effective for reducing IgM, hence not effective for IgM mediated hemolytic anemias
Name 2 risks associated with splenectomy
Pneumococcal sepsis
Risk of VTE
51M with no pmhx sees his PCP with fatigue for 4 months. CBC shows Hb 8.2 (6 months ago Hb 12). Hemolysis labs+. Smear shows frequent clumping of rbc.
What is the minimum cold agglutinin titer you would expect to see?
Clinically significant titers are generally > 1:32 - 1:64.
In active disease titer can be > 1:1000 at 4 degrees C
70M with history of CVA and chronic ITP s/p IVIG/steroids, splenectomy 20 years ago and in remission since presents with petechiae.
CBC shows plt 12k. He received IVIG and pulse steroids without response. You decide to proceed with rituximab but his HBV core Ab is positive.
How do you proceed? A) Decide to use TPO agonist instead B) Treat for full course of HBV and then start rituximab C) Prophylax for HBV and proceed with rituximab D) Recommend hospice
C) Prophylaxis for HBV and proceed with rituximab
HBV core Ab may represent prior infection or false positive. Proceed with tenofivir prophylaxis. Monitor weekly HBV DNA PCR for evidence of reactivation. If occurs would need to treat for HBV.
Name 3 causes of positive direct coombs test
Warm antibody immune hemolytic anemia (IgG)
Cold antibody immune hemolytic anemia
Alloimmune hemolytic transfusion reactions
Hemolytic disease of the newborn
Drug induced hemolytic anemia
NB: up to 10% of people with AIHA are Coombs negative!
What is the average onset of rituximab effect?
A) 5 hours B) 5 days C) 5 weeks D) 5 months
Initial response: 1 - 8 weeks; Peak response: 2 - 25 weeks
Mr. Jones is a 47M who was recently diagnosed with IGHV mutated CLL. He saw his oncologist who recommended treatment with Fludarabine, cyclophosphamide and rituximab (FCR). He is also started on allopurinol and acyclovir for prophylaxis. He got 2 cycles and seemed to tolerate well though when he presents for follow up he complains of severe fatigue and dyspnea. On exam he has scleral icterus.
Hb 6.4 LDH 570 retic 6. Coombs IgG+
What drug is most likely implicated?
Fludarabine
Purine analogues are known to cause immune hemolytic anemia, though it is thought that in combination with CR it may be less frequent. Recommended to discontinue permanently if occurs.
60M with history of HTN presents to your office with fatigue. He was recently on a skiing trip and following his last run down a double black diamond noted yellowing of his eye and dark urine.
Hb 7.1 TBili 6.5 LDH 500 retic 5. Coombs C3+ only. Cold agglutinin titer is negative.
What is the name of the next test to confirm the diagnosis?
Bonus point: Identify the antibody
Donath-Landsteiner test - confirmatory test for Paroxysmal Cold Hemoglobinuria
Cools serum to 4 degrees to allow absorption of the anti-P autoAb into rbc and then re-warms to 37 degrees at which point complement mediated hemolysis occurs.
Antibody is cold IgG against P antigen
First line treatment for cold agglutinin disease.
Bonus: What treatments are not indicated?
Rituximab +/- bendamustine, fludarabine, interferon
Steroids, splenectomy, IVIG are not indicated due to lack of proven benefit.
Name infections associated with cold agglutinin disease.
Bonus point: Name the antigen in each
Mycoplasma (I antigen)
EBV (i antigen)
22M presents with history of poorly controlled HIV presents with painless loss of vision in his right eye. He is diagnosed with posterior uveitis due to ocular syphilis. He received 20 million units/day of penicillin in a continuous infusion over 10 days.
Upon being seen by his PCP one week later he is fatigued, jaundiced. CBC shows Hb 8.1, hemolysis labs+, Coombs IgG+ C3-
What is the mechanism of his drug induced AIHA? A) Autoantibody B) Hapten-induced C) Complement mediated D) Innocent bystander
B) Hapten-induced
Large doses of PCN or cephalosporins can cause hapten-induced AIHA. The drug binds to the rbc membrane. An anti-drug Ab attaches to the membrane bound drug, leading to opsonization. This resembles warm AIHA. Resolves weeks after discontinuation.
57M with history of chronic ITP s/p IVIG/steroids, splenectomy and rituxan. Most recently on N-plate but now with refractory disease.
You decide to proceed with second course of rituximab. He tolerates very well and goes into remission.
6 months later at his follow up visit he reports several weeks of progressive confusion, vision changes and gait disturbance. On exam he has dysmetria. MRI brain shows T1 hypointense lesions in the L parieto-occipital region and cerebellum concerning for demyelination.
What is the diagnosis?
Progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus infection has been reported with rituximab. Onset is delayed but usually within 1 year of therapy. Presents with progressive confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months.
In cold agglutinin disease name the antibody and antigen pairing.
Cold agglutinin disease involves production of IgM that fixes complement on RBC most commonly against I antigen
34F with known cold agglutinin disease presents with chest pain. Troponin is elevated. Hb 6. hemolysis labs+. Coombs IgG- C3+.
She receives several units of warmed PRBC transfuion but has persistent chest pain.
What is reasonable therapy to offer at this time? A) Splenectomy B) IVIG C) Plasmapheresis D) cyclosporine E) Fludarabine + rituximab
C) Plasmapheresis
Though there is not a lot of data to support, this may be used as a temporizing measure in severe cases. It rapidly removes IgM but does not reduce production.
First line therapy would likely be bendamustine + rituximab.
32F with history of SLE presents to the hospital with ear pain. She is found to have otitis media.
Hb 6.5 (baseline 12), hemolysis labs+, Coombs+
What is the most likely antibody pattern? A) IgG+ C3+ B) IgG+ C3- C) IgG- C3+ D) IgG- C3-
A) IgG+ C3+
SLE is associated with warm AIHA. 95% with AIHA will have IgG+ and/or C3+. This is the most common pattern.
Mechanism of fostamatinib
Oral inhibitor of the spleen tyrosine kinase (Syk) which is thought to be associated with macrophage platelet clearance.
Approved for patients with chronic ITP refractory to other second line therapies.
DAILY DOUBLE - s/o to Dr. Hong
Name an adverse effect of Emicizumab (hemlibra)
Black box warning when used in combination with aPCC (FEIBA) for thrombosis and thrombotic microangiopathy
FEIBA contains factors IX/IXa and X/Xa, which are the substrates for Emicizumab. Because emicizumab does not require activation to exert its cofactor function, an excess of factor IXa may lead to uncontrolled thrombin generation and the resulting thrombotic complications.