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The Big RhIg. Colt McClain, MD 4/4/14. The Outline. What, How, When, and Why of RhIg Role in D-incompatible platelet transfusions Summary. RhIg. What is it? Passive anti-D IgG antibodies Half-life of RhIG IV is 31 days and RhIG IM is 19 days.
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The Big RhIg Colt McClain, MD 4/4/14
The Outline • What, How, When, and Why of RhIg • Role in D-incompatible platelet transfusions • Summary
RhIg • What is it? • Passive anti-D IgG antibodies • Half-life of RhIG IV is 31 days and RhIG IM is 19 days. • Able to detect low titer (1:4) of anti-D antibody for months. • How does it work? • The anti-D antibody in RhIg coats any D+ RBCs, disallowing production of anti-D antibodies.
RhIg • How is it made? • Made from the pooled plasma of healthy RhD-negative individuals who have IgG anti-D antibodies. • Product is tested for HCV, HBV, parvovirus B19, and HIV. • Processed either by cold ethanol fractionation or by ion exchange chromatography isolation procedure. • Passes through a viral clearance filter before being packaged for use. • When did it become available? • 1968: Available for the prevention of RhD alloimmunization in RhD-negative women only after delivery of RhD-positive newborns. • 1981: FDA approved for routine postpartum and antenatal administration by the US Food and Drug Administration in 1981.
RhIg • Current Use in OB? • All women who are RhD-negative and who are not alloimmunized receive an injection of RhIG at the beginning of the third trimester and after the birth of an RhD-positive infant. • Also includes other situations where feto-maternal hemorrhage occurs. • What doses are available? • Mini-RhIG contains 50 mcg of anti-D antibody. Used to prevent alloimmunization from exposure to ≤2.5 mL of RhD-positive fetal RBCs or 5 mL of fetal blood. • Used for pregnancy losses that occur at ≤13 weeks' EGA. • Full-dose RhIG contains 300 mcg of anti-D antibody. Used to prevent alloimmunization from exposure to ≤15 mL of RhD-positive fetal RBCs or 30 mL of fetal blood. • Given in pregnancies that end after the first trimester when a possible feto-maternal hemorrhage is suspected (vaginal bleeding, amniocentesis, or abruption), prophylactically at 28 weeks' gestation, and after the birth of a term RhD-positive newborn.
RhIg How much is given? • Determined by the number of fetal RBCs in maternal circulation. • Rosette test is the screening test. If negative, then 1 vial of full dose RhIg is given. If positive, then quantification of the number of fetal RBCs needs to be performed. • If rosette test is positive, then quantify the number of fetal RBCs by Kleihauer-Betke test or flow cytometry. • (KB% x maternal blood volume)/30 = # of Vials (if decimal <5 round up 1; if decimal >5 then round up 2) • Up to 5 vials of 300 mcg of RhIG can be given in one 24-hour period.
RhIg • Is it helpful? • From 1970 to 1979, the incidence of RhD alloimmunization decreased by 90% with routine postpartum administration of RhIG. • With prophylactic antenatal administration of RhIG at 28 weeks' gestation, the incidence decreased to 0.2%. • What are the drawbacks? • RhIG crosses the placenta, but no reported cases of HDFN. • Infectious risk from exposure to plasma from multiple donors. • Not uncommon: site reactions, allergic reaction, body aches. • Rare: acute renal insufficiency and DIC. • Cost ($60-80 per vial) • So the benefits >>>>> risks.
RhIg • Is it used in other scenarios? • FDA approved for immune thrombocytopenic purpura in 1995. • In ITP, the patient’s platelets are coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. Usually self-limited. • Corticosteroids are the first-line therapy for acute ITP. • IVIG and RhIg are second line options. • RhIg coats RhD positive RBCs, which causes the spleen to clear the coated RBCs instead of the platelets.
RhIg • Can only use in RhD positive patients who have not undergone splenectomy • Recommended IV dose for treatment of ITP is 50 mcg/kg given as a single dose or in two divided doses on separate days • Significant increases in platelet count occur within 1-3 days with peak counts observed a mean of 8 days after infusion • Hemolysis is expected, peaking approximately 6 days after treatment with a mean hemoglobin decrease of 1.7 gm/dl (range 0.6 to 6.1 g/dl) after a full dose • Primary advantages of RhIg-IV over standard IVIG preparations are lower cost (IVIG dose 1 g/kg; $75 per g) and less donor exposure • Disadvantages of RhIg are hemolysis and rare reports of DIC and acute renal failure
RhIg • Is it used in other scenarios? • Hard to always match up RhD negative status given short shelf life of platelets. • Given to RhD negative patients that receive RhD positive platelets. • Apheresis platelets contain less than 0.001 mL of RBCs. • Whole blood derived platelets contain a few tenths of a mL of RBCs. • AABB Standards: “transfusion service must establish a policy for RhIg prophylaxis for D- patients exposed to D+ RBCs.”
Barcelona, Spain • Study from 1999 to 2009 • Inclusion criteria: D negative, no anti-D, and no prior exposure to D positive blood products • Patients characterized as immunosuppressed-hematologic disease (33.7%), immunosuppressed-solid tumor (14.5%), and immunocompetent (51.8%). • 1014 patients (615 M, 399 F) with mean age of 60 • 88% of platelets were pooled • 12% of platelets were apheresis
Barcelona, Spain • Poor follow up • No patients that just received apheresis platelets formed an anti-D. • In total, 12 of 315 patients (3.8%) developed an anti-D. • Conclusion: only give RhIg to women with childbearing potential
Beth Israel Deaconess • Historically, gave RhIg to women of child-bearing potential and patients who were future liver transplant recipients. • Other cases were up to discretion of TM attending. • Looked at cases from 1997 to 2011. Only included patients who received apheresis D-incompatible platelets and had an antibody screen at least 4 weeks after the transfusion (excluded 354 patients).
Beth Israel Deaconess • 130 patients met criteria and received 565 platelet units (52% M and 48% F). • 56 (43%) were immunosuppressed and 74 (57%) were immunocompetent. • 68 patients (52%) received more than one D incompatible platelet unit with 13 patients (10%) receiving more than 10 units. • None of the patients developed an anti-D antibody.
Tucson, AZ • 67 D- patients received a total of 866 D+ platelet apheresis transfusions from 2004 to 2007. • 30 patients were female and 37 were male and the mean age was 46.5 years (included 13 pediatric patients). • The mean number of transfused platelet units per patient was 12.9. • Clinical diagnosis at the time of transfusion varied, including hematologic disorders or malignancies (n = 31), trauma (n = 10), heart conditions (n = 15), organ failure or transplant (n = 9), and other malignancies (n = 2). • No patients made an anti-D (length of follow up not provided).
St. Jude • 0 of 42 D- pediatric oncology patients receiving D+ apheresis platelets (745 units) over a 1.5 year period developed an anti-D antibody.
Putting It All Together • Meta: 0 of 239 D- patients developed an anti-D antibody when exposed to D+ apheresis platelets. • Meta: 12 of 554 (2.2%) D- patients developed an anti-D antibody when exposed to D+ platelets (apheresis and pooled).
Summary • RhIg has been an amazing advancement for OB and preventing HDFN. • Also, not too shabby at treating ITP. • Accumulating evidence that the RBC volume is insufficient in apheresis platelets for high levels of anti-D formation. • Maybe just give RhIg to women of child-bearing age for D-incompatible platelets.
Discussion • To Give Or Not To Give? That is the question. • 27 y/o female with SLE • 15 y/o male receiving chemotherapy for neuroblastoma • 43 y/o female in a MVC • 65 y/o male POD#2 colon resection for IBD • 38 y/o male s/p SCT for ALL • 30 y/o female s/p tubal ligation
References • Roback JD, Combs MR, Grossman BJ, Hillyer CD editor. Technical manual. 16th ed. Bethesda, MD: American Association of Blood Banks; 2008. • Moise KJ. Red cell alloimmunization. In: Gabbe SG, Niebyl JR, Simpson JL editor. Obstetrics: Normal and problem pregnancies. 5th ed. Philadelphia: Livingston-Churchill/Elsevier; 2005. • Kumpel BM. On the immunologic basis of Rh immune globulin (anti-D) prophlaxis. Transfus 2006;46:1652-1656. • Chavez GF, Mulinare J, Edmonds LD. Epidemiology of Rh hemolytic disease of the newborn in the United States. JAMA 1991;265:3270-3274. • Cid J, Carbasse G, Pereira A, Sanz C, Mazzara R, Escolar G, Lozano M. Platelet transfusions from D+ donors to D- patients: a 10 year follow-up study of 1014 patients. Transfusion 2011;51:1163-9. • OBrien KL, Haspel RL, Uhl L. Anti-D alloimmunization after D-incompatible platelet transfusions: a 14 year single institution retrospective review. Transfusion 2014;54:650-4. • Bartley AN, Carpenter JB, Berg MP. D+ platelet transfusions in D- patients: cause for concern? Immunohematology 2009;25:5-8. • Molnar R, Johnson R, Sweat LT, Geiger TL. Absence of D alloimmunization in D- pediatric oncology patients receiving D-incompatible single donor platelets. Transfusion 2002;42:177-82.