Setting: ED
CC: “I feel very weak and my skin has turned yellow.”
VS: R: 26 breaths/minute; BP: 102/64 mm Hg; P: 118 beats/minute; T: 99.8°F
HPI: A 43-year-old woman recently treated for a dental abscess with amoxicillin presents to the ED with 2 days of progressively worsening weakness, fatigue, and yellow skin. She says that her friends told her that her eyes have turned yellow.
PMHX:
Dental abscess
Root canal performed 4 days ago
Medications:
Amoxicillin for last 4 days
PE:
Skin: jaundiced
Head, ears, eyes, nose, throat (HEENT): scleral icterus
Abdomen: soft, nontender, no spleen felt
Initial Orders:
LFTs
CBC
UA
LDH
Move the clock forward only enough time to obtain test results. There is no way to tell from the jaundice and icterus whether this is from a biliary source or is hepatic or hemolytic in nature. You can only tell once you know whether it is direct bilirubin or indirect bilirubin.
Which form of hemolysis produces bilirubin in the urine?
a. None
b. Spherocytosis
c. Hemolytic uremic syndrome (HUS)
d. Autoimmune
e. Paroxysmal nocturnal hemoglobinuria (PNH)
Answer a. None
Only direct bilirubin goes into the urine. Indirect bilirubin does not go into urine. Hemolysis produces indirect bilirubin, which is not water soluble. There are two ways to get tests. One is: “Hey, I will order a bunch of tests because I do not know what is there!” The other is: “Direct bilirubin from hepatitis or obstructive jaundice goes into the urine. Indirect bilirubin from hemolysis does not go into the urine. I am getting the UA to prove or disprove, whether there is bilirubin in the urine, so I can establish a diagnosis.”
Move the clock forward 30 to 50 minutes.
Laboratory Test Results:
LFTs: normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT); total bilirubin 8 mg/dL, direct bilirubin 0.8 μmol/L
CBC: hematocrit 26%; MCV 105 fL; platelets normal; WBCs 7400/μL
UA: no urobilinogen; no RBCs
LDH: elevated
These results exclude a liver source of jaundice. Drug-induced hepatitis elevates AST, and viral hepatitis elevates ALT.
Why is MCV elevated?
a. Reticulocytes are larger than mature cells.
b. Lipids stick to RBCs making them look larger.
c. Myelodysplasia has developed.
d. Folic acid deficiency developed.
Answer a. Reticulocytes are larger than mature cells.
New cells or reticulocytes are slightly larger than mature RBCs. You should expect a slightly elevated MCV with hemolysis. Although lipids do sometimes stick to cells making them larger, this has nothing to do with this case. It is unlikely folic acid deficiency can develop in 1 to 2 days and change MCV like this.
LDH level increases with any form of cell destruction.
Orders:
Repeat CBC
Haptoglobin
Reticulocyte count
Coombs test
Peripheral smear
Which of the following is most likely to give spherocytes on smear?
a. Autoimmune hemolysis
b. Glucose-6-phosphate dehydrogenase (G6PD) deficiency
c. PNH
d. Cold agglutinin disease
Answer a. Autoimmune hemolysis
Immunoglobulin G (IgG) antibodies grab onto a piece of the RBC membrane. Macrophages and the spleen remove pieces of the membrane. This produces a tighter, smaller cell with less membrane but the same amount of hemoglobin. This produces a cell that is small and round—a spherocyte.
Move the clock forward 1 hour.
CBC: hematocrit 24%
Haptoglobin: decreased
Reticulocyte count: 8%
Coombs test: positive IgG warm antibody
Smear: no schistocytes; no fragmented cells; spherocytes are seen
Hereditary spherocytosis is most likely to enlarge the spleen.
What is the difference between a direct and indirect Coombs test?
a. There is no difference in vitro.
b. A direct Coombs test detects IgG attached to RBCs; an indirect Coombs test detects antibodies in circulation.
c. A direct Coombs test leads to cell destruction; an indirect Coombs test does not.
Answer b. A direct Coombs test detects IgG attached to RBCs; an indirect Coombs test detects antibodies in circulation.
In a direct Coombs test, antibodies attach to RBCs. The antibodies are used against Fc receptors to detect clumping. In an indirect Coombs test, neutral sheep RBCs are introduced into patient serum. Antibodies then attach to the RBCs. Although an indirect Coombs test implies a higher level of antibody than a direct Coombs test, the clinical implications are negligible.
Splenic enlargement needs time. Autoimmune hemolysis is too acute to enlarge the spleen.
When the Coombs test result is positive and you see a clear decrease in haptoglobin and elevation in reticulocyte count and jaundice, you know this is autoimmune hemolysis. You should add glucocorticoids, such as prednisone or methylprednisolone, and repeat the CBC in 4 to 6 hours.
Penicillins destroy RBCs with a hapten mechanism. Antibodies are made to both the RBC membrane and penicillin.
Where are the RBCs being destroyed?
a. Spleen
b. Liver
c. Intravascular
Answer a. Spleen
Warm IgG antibodies lead to destruction of RBCs in the spleen. Cold immunoglobulin M (IgM) antibodies destroy RBCs in the liver. IgG antibodies can be treated with steroids. IgM antibodies do not respond to steroids.
IgM cold agglutinins originate from mycoplasma and Epstein-Barr virus.
IgM-induced hemolysis does not respond to steroids or splenectomy.
Methylprednisolone and folic acid are started. You move the clock forward 8 hours and then 24 hours. The repeat CBC shows a dropping hematocrit from 24% to 22% to 20%, and a transfusion of two units of packed RBCs is given. The hematocrit stays at 20%. Two more units raise the hematocrit concentration from 20% to 21%.
Each unit of packed red blood cells should increase the hematocrit concentration by 3 points.
What should you do to increase the hematocrit concentration?
a. Remove the spleen today.
b. Start IVIG.
c. Add dexamethasone to methylprednisolone.
d. Perform plasmapheresis.
Answer b. Start IVIG.
IVIG can help rapidly interrupt immune-mediated hemolysis if it is from a drug such as penicillin or on an autoimmune basis. There is no benefit to using multiple glucocorticoids. Plasmapheresis only removes circulating antibodies and does not work in hemolysis from a hapten mechanism. It will work with HUS or thrombotic thrombocytopenic purpura (TTP).
Removing the spleen is effective in preventing recurrences of immune-mediated cell destruction, but should not be done first.
IVIG saturates Fc receptors on macrophages.
IVIG prevents the macrophage from “grabbing” the IgG on the RBC and dragging it off to be destroyed in the spleen.
Azathioprine and cyclophosphamide are effective, but take a month to work.
Rituximab works for both cold agglutinins (IgM) and warm (IgG) by inhibiting CD20 cells.
Death from autoimmune or warm IgG hemolysis is very rare. If steroids do not control the disease and transfusions do not increase the cell count, IVIG can work acutely. Azathioprine, cyclophosphamide, and rituximab are immunosuppressives but take several weeks to work. Splenectomy prevents recurrences in 70% of patients.