Acquired: PNH, MAHA, Infections, Immune. Further categorization of Immune HA:
Autoimmune: Warm (ie SLE) or Cold (ie Mycoplasma)
Alloimmune (ABO incompatibility)
Drug-Induced: Many drugs but classically 3/4th general cephalosporins
Hemolysis labs include Reticulocyte Count, Indirect bilirubin levels, Haptoglobin, LDH, hemoglobinurea, hemosiderinuria (elevated Hb on urine dipstick is an indicator of intravascular rather than extravascular hemolysis)
PNH median age of onset is 30, life expectancy prior to Eculuzimab (see below) was about 10-15 years after diagnosis although this new drug may prolong life expectancy but it’s too early to know
Acute hemolytic events can occur after stress, infections, alcohol use
PNH is associated with venous and/or arterial thrombosis (venous more common) likely due to the hypercoagulable state from free hemoglobin in the bloodstream. The thrombi form in unusual areas – cerebral veins and abdominal veins.
Other clinical findings associated with PNH are cytopenias, smooth muscle dystonias (due to lack of NO, erectile dysfunction/dysphagia/abdominal pain)
Nocturnal hemolysis is thought to be due to intestinal absorption of LPS, a complement activator, at night
The pathophysiology of PNH is an acquired mutation causing lack of formation of phosphatidyllinositol (PGI) anchor on RBCS which present the CD59 and CD55 epitopes. Flow cytometry in PNH shows a lack of CD59 and CD55 cells. The lack of these markers causes the cells to be vulnerable to complement mediated lysis.
Eculuzimab blocks complement C5 thereby blocking destruction of RBCs. Patients on this medication are at risk for infections due to encapsulated organisms (ie Strep Pneumo, Neisseria meningitidis, Haemophilus influenza etc). Note this drug is 10,000 bucks a pop (infusion every 2 weeks)!
The natural history of Chronic Myeloid Leukemia is the chronic phase, accelerated phase, and the blast phase.
Chronic Phase: This is generally stable, chronic disease and patients can be asymptomatic. Often they are picked up on routine blood count showing leukocytosis. There is a 6% 5 year risk of progressing to blast phase when they are treated with Imatinib.
Accelerated Phase: This is when blasts are detected but they haven’t reached a high level of > 20%.
Blast Phase: This is conversion of CML to acute leukemia with > 20% blasts on peripheral smear or bone marrow. About 70% present with AML blast crisis and roughly 30% with ALL blast crisis. Treatment depends on whether flow cytometry/analysis shows AML or ALL.
Imatinib (Gleevec) is a first generation tyrosine kinase inhibitor. It is used for patients with chronic CML to help prevent progression to blast phase. Side effects include pulmonary edema, peripheral edema, muscle cramps, QTC prolongation, arrhythmias, among others.
Leukostasis which is defined as hyperleukocytosis (>50K WBC) with symptoms including CNS, respiratory, and cardiac. There are various thresholds for initiating leukapharesis depending on the type of leukemia, presence of symptoms, and level of WBC elevation. In general, AML is more likely than ALL to cause leukostasis. The acute leukemia’s are more likely to cause leukostasis than the chronic leukemias.
Leukopharesis can have serious side effects so only used when absolutely necessary.
Hydroxyurea blocks DNA synthesis and can be use in myeloproliferative disorders and CML. Of note also used in sickle cell disease as it increased Fetal Hemoglobin levels.
Clinical Pearl: ALL is more likely than AML to present with tumor lysis syndrome.