Kell Alloimmunization Case File

Kell Alloimmunization Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 25

A 26-year-old primigravida at 12 weeks’ gestation is seen in your office for her second prenatal visit. In reviewing her labs, you note that her blood type is O+ and she has anti-Kell antibodies at a titer of 1:32. She reminds you that when she was 18 years of age, she was involved in a serious auto accident in which she suffered a splenic laceration. She requires 8 units of packed red blood cells transfusion and a splenectomy. She denies any prior pregnancies or other medical complications, and says she has received the Pneumovax vaccination. The remainder of her labs and her physical examination today are unremarkable.

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 25:

Kell Alloimmunization

Summary: This is a 26-year-old primigravida at 12 weeks’ gestation with a history of blood transfusion in the past, and antibodies to the Kell antigen at a 1:32 titer.

➤ Most likely diagnosis: Kell isoimmunization.

➤ Next step: Develop plan for monitoring pregnancy with Kell isoimmunization, starting with paternal zygosity, and if the fetus is at risk for anemia then ultrasound monitoring.

➤ Potential complications: Fetal anemia, hydrops, intrauterine demise, preeclampsia, preterm birth.

ANALYSIS

Objectives

1. Understand the risk of isoimmunization with blood transfusions.
2. Be able to describe the titer above which further monitoring should be done in pregnancy.
3. Develop a plan for monitoring a patient who is Rh isoimmunized.
4. Understand indications for preterm delivery with Rh isoimmunization.

Considerations

This is a 26-year-old primigravida at 12 weeks’ gestation with a history of blood transfusion and antibodies to the Kell antigen. The first step in the management of this case is to perform paternal zygosity testing for the Kell antigen in order to determine if the fetus is at risk for alloimmunization. The Kell blood group is the most common of the minor RBC antibodies and the K antigen is present in 9% of Caucasian blood donors. Genotype frequencies in Caucasians are: KK (0.2%), Kk (8.7%), kk (91.1%). If the father is homozygous for the K antigen (KK), the fetus will be at risk for alloimmunization since the only “allele” the father can pass to the fetus will be K. If the father of the fetus is genotype Kk, then an amniocentesis can be done (with an attempt to avoid the placenta) to determine the fetal genotype and whether or not the fetus is at risk. Chorionic villus sampling CVS should be avoided since this can result in fetomaternal hemorrhage and an amnestic response in maternal antibody titer, therefore potentially worsening the disease. If the father of the fetus has the genotype kk, then the fetus is not at risk and no further testing is needed. Paternal blood should be sent with the amniotic fluid so that paternal gene rearrangement or paternity is not a potential source of laboratory error.

Since the patient was sensitized after a transfusion, there is a 91% chance that the baby’s father is Kell-negative (kk), thus the fetus will be Kell-negative and will be unaffected by maternal antibodies. If the fetus is K+ then the fetus is at risk for anemia as a result of the maternal antibodies against the Kell antigen. These antibodies cross the placenta and cause hemolysis of the fetal red cells as they do in Rh (D) alloimmunization. However, unlike Rh alloimmunization, the Kell antibodies have a second mechanism by which they cause fetal anemia, anti-Kell antibody-mediated suppression of erythropoiesis at the progenitor cell level. The anemia by this mechanism is through decreased fetal red cell production. For this reason, the titer of anti-Kell antibody in maternal serum and the amniotic fluid bilirubin level do not correlate well with the degree of fetal anemia.

As in Rh (D) alloimmunization, there is a critical maternal antibody titer that, once reached, indicates the fetus could be affected. Most laboratories use a critical titer for anti-D antibodies of 1:16 as a cut off (each laboratory should establish their own critical titer). In cases of Kell sensitization, the critical titer is lower, usually 1:8, because severe fetal anemia can occur at lower antibody titers than in cases of Rh (D) alloimmunization. Once the critical titer is reached, antenatal testing should begin. Of importance, if the patient has had a prior child affected by alloimmunization, then titers do not need to be followed, but rather, antenatal testing is begun at 18 weeks. If the critical titer is not reached, then titers can be repeated monthly until 24 weeks and then every 2 weeks until delivery.

APPROACH TO

Kell Alloimmunization

nce it is established that the fetus is at risk for anemia, ultrasound becomes the primary screening tool for the majority of the pregnancy. An ultrasound should also be done early in the pregnancy in order to correctly assign the gestational age. This is of paramount importance since all of our normative values to screen for fetal anemia are in respect to the gestational age of the fetus. 

The Doppler assessment of the fetal middle cerebral artery (MCA) peak systolic velocity (PSV) has come forward as the best noninvasive tool for fetal anemia screening. This test is founded on the principle that the anemic fetus preserves oxygen delivery to the brain by increasing cerebral flow. The sensitivity of increased MCA-PSV (above 1.5 multiples of the median [MoMs]) for the prediction of moderate or severe anemia is approximately 100%, either in the presence or absence of hydrops, with a false-positive rate of 12%. The optimal screening interval has not yet been determined; however, cases have been missed when more than 2 weeks elapse between Doppler studies. Most physicians are screening for anemia in 1 to 2 weeks intervals.

Doppler assessment of the fetal MCA-PSV is the preferred tool for determination of fetal anemia in Kell sensitized pregnancies since the delta OD 450 value is less accurate in these cases. In Kell sensitized fetuses, suppression of erythropoiesis rather than hemolysis (which generates bilirubin) is the major cause of fetal anemia. 

If MCA-PSV is above 1.5 MoMs or delta OD 450 readings are in the lower portion of the Rh (D) affected zone (Queenan curve) or 65% or greater into zone 2 of the Liley curve, then cordocentesis for fetal hematocrit/hemoglobin and confirmation of blood type should be performed to make the diagnosis of fetal anemia. When a cordocentesis is planned, preparations should always be made for possible fetal transfusion.

Screening

Maternal blood type and antibody screen are sent at the first prenatal visit along with the other prenatal labs. If the patient screens positive for an RBC antibody, then the fetus may be at risk for hemolytic disease depending on the titer of antibody detected and whether or not the fetus has the offending antigen. Once the antibody titer reaches the critical value, then antepartum testing is begun.

Treatment

The treatment for fetal anemia is transfusion or delivery depending on the gestational age at which the anemia is detected. If the fetal MCA Dopplers remain below the 1.5 MoM, then delivery can be scheduled at 37 to 38 weeks after an amniocentesis result suggests lung maturity (lecithin-sphingomyelin ratio or lamellar body counts should be used since bilirubin can interfere with the fluorescence depolarization techniques, TDx-FLM). If the MCA Dopplers are found to be above 1.5 MoM, and the patient is not yet 35 weeks, then fetal cordocentesis is done with preparation for possible fetal transfusion. If the MCA Dopplers are greater than 1.5 MoM, and the patient is 35 weeks gestational age or more, then an amniocentesis is done for delta OD 450 and fetal lung maturity; MCA Dopplers can overestimate the possibility of fetal anemia after 35 weeks, therefore, a second test, delta OD 450, is done to screen further for anemia if the Dopplers are abnormal. Recently, administration of phenobarbital (30 mg po three times a day for 10 days) has been found to reduce the need for neonatal exchange transfusion in fetuses with hemolytic disease by enhancing hepatic maturation.

After fetal transfusion, the MCA Dopplers improve immediately. For the subsequent Doppler studies, a value over 1.69 has been used to predict the timing of the next transfusion. The increased peak systolic velocity is thought to be the result of the presence of adult hemoglobin as well as a change in the fetal cerebral circulation due to the differential oxygen binding capacity of these transfused red cells. Some physicians estimate that the hematocrit will drop by 1% per day. The final posttransfusion hematocrit will predict the time of the next transfusion to occur when the hematocrit is expected to be less

than 30%.

With all forms of Rh isoimmunization, careful monitoring for preeclampsia is important during the second and third trimesters of pregnancy because of its association with isoimmunization.

Comprehension Questions

25.1 A 29-year-old G3P2 with antibody titers of 1:4 which are stable and not increasing presents to your office at 22 weeks’ gestation. She states that in her last pregnancy, her baby was found to be jaundiced and anemic at birth. What is the next best step in the care of this patient?

A. Continue to follow serial antibody titers and if they are found to be increasing, then start screening with MCA Doppler studies every 2 weeks.

B. Start screening for anemia right away with MCA Dopplers every 2 weeks.

C. Reassure the mother that since the baby did not need a transfusion this fetus will not be at risk.

D. Start serial amniocentesis for delta OD 450 at 35 weeks.

25.2 Which of the following fetuses (A-D) is most likely to have a normal hemoglobin level?

A. A Caucasian patient who was transfused 10 units of packed RBCs after a car accident that was found to have anti-Kell antibodies of 1:16 at her first prenatal visit.

B. A patient with + Kell antibodies of 1:64 and a delta OD 450 in the “unaffected zone” of the Queenan curve.

C. A fetus with ascites and pleural effusions in a patient with RBC alloimmunization in a prior pregnancy.

D. Fetus with a MCA Doppler of over 1.5 MoM and an anti-D antibody titer of 1:32.

25.3 A 29-year-old G1P0 at 11 weeks’ gestation is being seen for her fist prenatal visit. Which of the following statements is most accurate regarding tests for isoimmunization?

A. If the antibody screen is positive, there is strong likelihood of isoimmunization.

B. If the patient is Rh positive, an antibody screen does not need to be performed.

C. Antibody screen on paternal blood is important in Rh negative women to determine likelihood of the fetus being affected.

D. In a patient with a positive antibody screen for Rh antibodies, RhoGAM is not needed.

25.4 In an Rh-isoimmunized patient, which of the following tests for fetal lung maturity is unreliable when performed on amniotic fluid?

A. Lecithin-sphingomyelin ratio (L/S)

B. TDx or surfactant albumin ratio

C. Lamellar body count

D. Phosphatidylglycerol (PG)

ANSWERS

25.1 B. This patient has a prior child who was affected by red cell alloimmunization; therefore, there is no need to follow antibody titers during this pregnancy. The best next step is to start screening every 2 weeks with MCA Dopplers for evidence of fetal anemia. When performing MCA Dopplers, other ultrasound signs of anemia can be assessed, such as signs of cardiac failure (tachycardia, ascites/effusions, skin edema), abnormal fetal growth, and polyhydramnios. Amniocentesis for delta OD 450 can be done serially if MCA Doppler studies are not available. This would replace the MCA Dopplers every 2 weeks for fetal anemia screening. In this patient, screening should not be delayed until 35 weeks. In patients followed by MCA Dopplers, after 35 weeks there is an increase in the false-positive rate so that a positive test should be followed by an amniocentesis for delta OD 450, while a negative test would rule out the possibility of fetal anemia.

25.2 A. All of the above scenarios represent patients with pregnancies at risk for possible fetal anemia. The patient “A” is at the lowest risk for fetal anemia because she developed antibodies after a trauma which resulted in the transfusion of multiple blood products. The chance that the father of the baby has the Kell antigen is less than 10% and the chance that the father is KK+ is less than 1%. The father, if he has the Kell antigen, is more likely to be heterozygous and therefore, there is a 50% chance he will not transmit the gene to his offspring, so the possibility of fetal anemia is even lower. 

The fetus with the Kell antibodies and “unaffected” zone of the Queenan curve is still at risk since the Kell antibody also suppresses red blood cell production and does not only cause anemia by hemolysis. The bilirubin level in the amniotic fluid can be falsely reassuring in these cases because the amniotic fluid will not reflect the decrease in red cell production. The fetus in case “C” has other ultrasound evidence of anemia and a strong clinical history which together would prompt the need for a diagnostic test such as a cordocentesis. The final scenario in case “D” is the most typical. The patient is followed carefully after her antibody titers increase above the critical level and then she has MCA Doppler results which suggest that the fetus is anemic. This patient will need a cordocentesis to confirm the diagnosis and possible transfusion if the fetal hemoglobin is under 30.

25.3 D. If a pregnant woman has a positive antibody screen for Rh, and already has been sensitized, RhoGAM is not indicated, since RhoGAM is used to prevent isoimmunization. The antibody screen only indicates that antibodies against common red blood cell antigens are present in the patient’s serum. The titer strength and identification of the antibody help to determine the likelihood of isoimmunization. An antibody screen needs to be performed regardless of the Rh status, since other antigens can cause sensitization such as Kell or Duffy.

25.4 B. TDx is performed by light polarization. Bilirubin in the amniotic fluid can falsely elevate the TDx value and give the impression of lung “maturity.” The PG and L/S ratios are performed by thin-layer chromatography and are not affected by the presence of bilirubin. The lamellar body count is unaffected by the presence of bilirubin since it is a direct count of lamellar bodies.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ Phenobarbital (30 mg po three times a day for 10 days) has been found to reduce the need for neonatal exchange transfusion in fetuses with hemolytic disease by enhancing hepatic maturation (Level II-2).

➤ In cases of Kell sensitization, the critical titer is lower, usually 8, because severe fetal anemia can occur at lower antibody titers than in cases of Rh alloimmunization (Level III).

➤ The sensitivity of increased MCA-PSV (above 1.5 multiples of the median [MoMs]) for the prediction of moderate or severe anemia is approximately 100%, either in the presence or absence of hydrops, with a false-positive rate of 12% (Level II-2).

REFERENCES

1. Ashwood, ER. Standards of laboratory practice: evaluation of fetal lung maturity. National Academy of Clinical Biochemistry. Clin Chem. 1997;43:211. 

2. Daniels G, Hadley A, Green CA. Causes of fetal anemia in hemolytic disease due to anti-K. Transfusion. 2003;43:115. 

3. Detti L, Oz U, Guney I, et al. Doppler ultrasound velocimetry for timing the second intrauterine transfusion in fetuses with anemia from red cell alloimmunization. Am J Obstet Gynecol. 2001;185:1048. 

4. Mari G. Middle cerebral artery peak systolic velocity: is it the standard of care for the diagnosis of fetal anemia? J Ultrasound Med. 2005;24:697. 

5. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative group for Doppler assessment of the blood velocity in anemic fetuses. N Engl J Med. 2000;342:9. 

6. Moise KJ Jr., Carpenter RJ Jr., Chorionic villus sampling for Rh typing: clinical implications [Letter]. Am J Obstet Gynecol. 1993;168:108-113. 

7. Neerhof MG, Dohnal JC, Ashwood ER, et al. Lamellar body counts: a consensus on protocol. Obstet Gynecol. 2001;97:318. 

8. van Dongen H, Klumper FJ, Sikkel E, et al. Non-invasive tests to predict fetal anemia in Kell-alloimmunized pregnancies. Ultrasound Obstet Gynecol. 2005;25:341. 

9. Vaughan JI, Manning M, Warwick RM, et al. Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia. N Engl J Med. 1998;338:798. 

10. Weinstein L. Irregular antibodies causing hemolytic disease of the newborn: a continuing problem. Clin Obstet Gynecol. 1982 Jun;25(2):321-332.

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