PLATELETS AND PLASMA TRANSFUSION IN NEONATES.pptx

Protocol for platelets and plasma transfusion in infants and neonates

1. PLASMA AND PLATELETS TRANSFUSION PROTOCOL IN NEONATES AND INFANTS Dr.Dolat Jr -1,IHTM SMS MEDICAL COLLAGE,JAIPUR

2. C ontents:- Introduction Pathophysiology of thrombocytopenia in infants Platelets transfusion in infants Platelet product selection for infants Plasma transfusion in infants Plasma product selection for infants

3. INTRODUCTION Physiologically speaking , infants and children are not simply “small adults” when considering causes and treatments of anemia, thrombocytopenia, and coagulopathy. Several factors such as gestational age, congenital diseases, immature liver, maternal factors, and transplacental antibody transfer must all be considered when evaluating and treating neonates with anemia, thrombocytopenia, bleeding, or coagulopathy. Bleeding tendencies and diseases prevalent in childhood must be understood for optimal transfusion support.

4. Additionally, special consideration must be given to the product(s) transfused to infants and children, whether the transfusion be for prophylactic reasons or otherwise. These considerations include ABO compatibility, total blood volume, immaturity, immunosuppression, immunodeficiencies , and blood donor exposure. Pathophysiology of thrombocytopenia in infants Platelet counts in developing fetuses are typically higher than 150,000/ μL by the end of the first trimester,97,98 and most healthy newborns have counts above this level at term. However, 1–5% of all neonates are affected by thrombocytopenia, with platelet counts

5. Preterm infants and those born small for gestational age are more likely to be affected by thrombocytopenia than term infants. U p to 25% of all neonates admitted to neonatal intensive care units (NICUs) having mild, moderate, or severe thrombocytopenia at some point during their hospital stay. Babies in the NICU with extremely low birth weights are quite likely to have low platelet counts, with 73% of infants weighing under 1000 g reported to have platelet counts lower than 150,000/ μL . Neonatal thrombocytopenia can be caused by decreased platelet production, increased platelet destruction, or a combination of These.

6. The pathophysiology of neonatal thrombocytopenia noted at or soon after birth may also be due in part to maternal hypertension,placental insufficiency, and/or perinatal hypoxemia , such conditions are more likely to be present in preterm than term infants. Perinatal infections such as Group B Streptococcus or Escherichiacoli may also be associated with early neonatal thrombocytopenia as may congenital infections such as toxoplasmosis, rubella, CMV. Thrombocytopenia that develops after the first few days of life may be due to postnatally acquired sepsis, disseminated intravascular coagulopathy (DIC), or necrotizing enterocolitis (NEC). Unique to neonates, transplacental transfer of maternal alloantibodies may contribute to thrombocytopenia in otherwise “ wellappearing ” infants.

7. Maternal antibodies against human leukocyte antigens (HLA) as well as human platelet-specific glycoprotein antigens (HPA) are capable of crossing the placenta, binding to the platelets of fetuses, and producing neonatal alloimmune thrombocytopenic purpura (NAITP). Antibodies against HPA-1a are the most well- known causes of NAITP in Caucasians, with women lacking the HPA-1a antigen and expressing the HLA DBR3*0101 being at particularly high risk of developing these antibodies during pregnancy with HPA-1a expressing fetuses. Antibodies againstHPA-5b, HPA-15a, or other HPA proteins may also lead to NAITP. Rarely, maternal autoantibodies such as those found in mothers with ITP or other autoimmune diseases like SLE may also lead to neonatal thrombocytopenia.

8. Thus, it is prudent to check the maternal history and the maternal platelet count in instances of unexpected neonatal thrombocytopenia. Platelet dysfunction may also contribute to bleeding in infants and children, with etiologies including those that are congenital (such as in Glanzmann’s thrombasthenia or Bernard Soulier ) or medication-induced. For example, medications given to mothers prior to delivery, including Ketoralac , can potentially impact neonatal platelet function. Medications used in NICUs, including indomethacin and nitric oxide , may also impact platelet function .

9. Platelet transfusion in infants Historically, neonatal platelet transfusion guidelines have been based largely on consensus. A randomized trial of premature infants (<1500 g) in their first week of life, demonstrated that a liberal pretransfusion threshold of 150,000/ μL was not associated with fewer bleeding episodes than a more conservative transfusion threshold of 50,000/ μL . Some institutions have historically prophylactically transfused stable term and preterm infants at platelet counts of 25,000 and 30,000/ μL , respectively,whereas others have transfused stable infants at platelet counts of 50,000/ μL .

10. Table lists potential guidelines for neonatal platelet transfusions. situation Platelet transfusion threshold Clinically stable term neonate 20,000–25,000/µL Clinically stable preterm neonat 25,000–50,000/µL* Clinically unstable neonate or bleeding neonate 50,000–100,000/µL Need for invasive procedure 50,000/µL NAITP 30,000–50,000/µL ECMO 50,000–100,000/µL#

11. A randomized trial comparing preterm infants (median gestation age 26.6 weeks and median birth weight 740 g) receiving prophylactic platelet transfusions to maintain counts above 25,000 or above 50,000/ μL , reported a lower mortality and less intracranial bleeding in the restrictive arm. A subanalysis reported that these outcomes occurred in infants at both lower or higher baseline risk, with the authors suggesting that a threshold of 25,000/ μL could be safely adopted in all preterm infants. A retrospective study of newborns <32 weeks of gestational age born in two different cities showed no difference in intracranial hemorrhage rates between neonates transfused with restrictive (transfusion for platelet count less than 50,000/ μL in bleeding or sick neonates), compared to liberal (transfusion according to institutional guidelines) criteria.

12. Another study of preterm, low birth weight infants (<1500 g) demonstrated that more restrictive transfusion thresholds (transfusion for platelet count less than 50,000/ μL in sick infants or less than 25,000/ μL in stable infants) were associated with no greater bleeding than more liberal thresholds. Furthermore, a study showed there is no clear relationship between platelet count and major intracranial hemorrhage; more that 91% of neonates with platelet counts under 20,000/ μL demonstrating no bleeding. Two neonatal subpopulations worthy of additional discussion include those on ECMO and those with NAITP. Babies on ECMO are at risk of bleeding due in part to thrombocytopenia secondary to consumption, platelet dysfunction, and heparinization of the circuit. Thus, platelet transfusion thresholds between 50,000 and 100,000/ μL are typically utilized in these babies, dependen on bleeding status.

13. Neonates with NAITP are also at high risk of bleeding. Babies with NAITP and a documented intracranial bleed should be maintained at platelet counts above 50,000/ μL for at least the first week of life. Neonates with NAITP and no bleeding are typically maintained at platelet counts above 30,000/ μL and often higher for the first week of life. Random donor platelets may be transfused for babies with NAITP and will typically increase the neonate’s platelet count at least transiently. Platelets lacking HPA-1a, HPA-5b, or other offending antigens may be requested from blood donor centers for neonates thought to have NAITP mediated by these respective antibodies, though emergent transfusions should never be withheld while antigen-negative platelets are being located.

14. Maternal platelets are another therapeutic option, yet they may be difficult to obtain and they must be washed to remove offending antibodies and irradiated prior to transfusion. IVIG may be given to affected neonates in an attempt to increase the platelet circulatory half-life; it is also administered during pregnancy to women carrying fetuses at risk for NAITP,with dose and schedule determined by risk stratification. Platelet product selection for infants and children Platelets chosen for transfusion to infants and children in the United States may be from apheresis or whole blood donors, with many centers preferentially utilizing apheresis platelets.

15. ABO compatible or identical platelets are ideally selected for transfusion into pediatric patients, in order to minimize the passive transfer of incompatible plasma,minimize the destruction of platelets expressing incompatible antigens,and minimize transfusion reaction rates (including febrile and allergic reactions). An additional consideration in neonates is the need for chosen platelets to be compatible with maternally derived isohemagglutinins that may be transiently present in the neonate’s circulation. The same irradiation and leukoreduction indications reviewed in the RBC section also apply to platelets; HLA-matched or crossmatched platelets must always be irradiated. Pathogen reduction of platelets also inactivates T-cells, and thus pathogen-reduced platelets do not require irradiation.

16. Transfusion of Rh(D) positive platelet products into Rh(D) negative female children should be avoided when possible. Although the likelihood of an Rh(D) negative patient forming an anti-D after exposure to low amounts of residual RBCs in an Rh(D) positive apheresis platelet unit is extremely small,prophylaxis with RhIg is appropriate in female children. 300 μg dose of RhIg can suppress immunization to 15 mL of packed RBCs. 15–10 mL/kg of platelets are typically infused as a single “ dose,”with a maximum dose regardless of weight typically being 1 apheresis unit or 1 “pool” of whole-blood-derived platelets (from 4 to 8 donors). Some centers provide fractions of apheresis platelet units in a weight-based fashion (e.g., 5–10 mL/kg to infants, ¼ apheresis unit to children <15 kg, ½ apheresis unit to children between 15 and 30 kg, and a whole apheresis unit to children >30 kg), and others provide platelets derived from a single whole blood unit for every 10 kg of body weight.

17. Plasma transfusion Development of the coagulation system Quantitative and qualitative differences in coagulation factors,coagulation inhibitors, and fibrinolytic proteins exist in neonates compared to older children and adults. At one day of age, vitaminK -dependent coagulation factors (II, VII, IX, and X) and the contact factors (XII, XI, high-molecular-weight- kininogen , andprekallikrein ) are 30% or more below the levels typically seen in adults. By six months of age, levels of these coagulation factors in both premature and full-term infants are within normal adult ranges. On the other hand, levels of fibrinogen, FV, FVIII, and FXIII, and vWF are above 70% of adult values on the first day of life in both premature and full-term infants.

18. Fibrinogen levels are lower in premature infants than in full-term infants. Inhibitors of coagulation (AT, protein C, and protein S) are also lower in infantsthan adults. In the fibrinolytic system, plasminogen levels are lower in infants than adults and significantly lower in preterm than term infants. These alterations in factor concentrations affect the functioning of the coagulation system as well as standard laboratory coagulation tests. The activated partial thromboplastin time ( aPTT ) is most prolonged in premature and full-term infants on Day 1 of life as compared to adults, being 1.4–2.4 times and 1.2–1.5 times longer, respectively. This prolongation has been attributed to the quantitative and qualitative deficiencies of contact factors. In premature and full-term infants, aPTT values normalize to adult values by six and three months of age, respectively.

19. plasma transfusion indications in infants and children . To treat global coagulopathy in Bleeding patients • DIC • Sepsis • Liver disease • Vitamin k deficiency • Trauma To replace individual coagulation factors • Factor V • Factor XI For therapeutic plasma exchange TTP To reconstitute whole blood • For circuits • For neonatal exchange transfusion

20. Plasma to treat global coagulopathy Causes of coagulopathy in infants and children include DIC, liver disease, trauma, and dilutional effects. With the understanding that treatment of the underlying cause of DIC is essential, plasma may be transfused to mitigate DIC-associated bleeding. Plasma is also indicated for liver failure with active bleeding and prior to invasive procedures, though the hemostasis observed after FFP infusion is typically quite transient. Although vitamin K is the first-line therapy for neonates with congenital or acquired vitamin K deficiency, plasma or prothrombin complex concentrates are also indicated in cases of life-threatening bleeding in such patients.

21. Trauma associated coagulopathy has been demonstrated in children independent of dilutional effects and is associated with adverse outcomes. Pediatric massive transfusion protocols typically treat trauma and dilutional coagulopathy by providing plasma, cryoprecipitate, and platelets for resuscitation, in addition to RBCs, Infants with hypoxic ischemic encephalopathy treated with therapeutic hypothermia can also benefit from plasma transfusion to treat their well-described coagulopathy. In contrast to the above clinical scenarios, empiric infusion of plasma is not recommended to correct an elevated INR in the absence of bleeding. Plasma to replace individual coagulation factors Plasma is indicated for replacement of coagulation factors in situations where specific factor concentrates are not available.If a child has a suspected congenital bleeding deficiency but the etiology is not apparent, initial therapy with 10–15 mL/kg of plasma is reasonable while awaiting definitive factor testing.

22. Plasma remains the treatment of choice in the United States for the replacement of Factors V and XI, though two Factor XI concentrates are available outside the United States. Reviewed in more the administration of recombinant or virally inactivated plasma-derived Factors VII, VIII, IX, XIII, vWF , and fibrinogen have replaced the use for plasma or cryoprecipitate in patients congenitally deficient in these factors. Plasma as a replacement fluid for therapeutic plasma exchange Plasma is typically used as a replacement fluid in therapeutic plasma exchange procedures for children with acquired TTP. The act of removing the patient’s plasma reduces levels of IgG autoantibodies against ADAMTS13, while the plasma components used for replacement replenish the ADAMTS13 cleaving enzyme

23. Plasma to reconstitute whole blood (for circuits or neonatal exchange transfusions) Transfusion support of pediatric cardiothoracic surgery patients is complex, with dual risks of thrombosis and bleeding. RBCs, fresh whole blood, plasma in combination with RBCs, or nonblood products are used to prime cardiothoracic surgery circuits. Studies show conflicting data with regard to which components in a prime result in less bleeding, fewer transfusion requirements, and better outcomes. Similarly, the priming and maintenance of ECMO circuits, which are used to treat a number of pediatric conditions nonresponsive to traditional ventilatory support, are also complicated with some institutions combining albumin, RBCs, and/or other additives for this purpose.

24. Plasma can be transfused to children on ECMO for bleeding and/or elevated INR.A protocol that includes Factor Xa monitoring, thromboelastography , and antithrombin monitoring, in addition to traditional coagulation testing, has been shown to decrease bleeding and transfusion requirements, while increasing circuit life in pediatric ECMO patients. Neonatal exchange transfusions are typically performed using group O RBCs (lacking offending cognate minor antigens), reconstituted with AB plasma to an Hct of 50–55%. The primary indication for exchange transfusion in neonates is hemolytic disease of the fetus and newborn with antibody-mediated hemolysis and hyperbilirubinemia .

25. Plasma product selection for infants and children FFP is the proper name for plasma frozen to −18 °C within 6–8 hours of phlebotomy, while PF24 is used to denote plasma frozen within 24 hours of phlebotomy. These products can be used interchangeably,unless single Factor V or VIII replacement is needed. Thawed plasma is a term used to describe FFP or PF24 stored at 1–6 °C for up to four days since these produces show degradation of coagulation factors over time. This product may be useful in situations such as traumas, in which plasma is rapidly needed; however, few pediatric studies have been completed involving thawed plasma. Plasma cryoprecipitate reduced (also known as cryo -poor plasma) is utilized in some centers as a second-line product and in others as a product equivalent to FFP or PF24 for TTP plasmapheresis .

26. Plasma chosen for transfusion should ideally be ABO compatible,though Rh(D) matching is not required. Plasma is considered an acellular product and thus irradiation is not necessary. 10–15 mL/kg of plasma typically raises coagulation factors by approximately 30%. Cryoprecipitate transfusion Cryoprecipitate is made from the cold insoluble high- molecularweight proteins removed from thawed plasma, including fibrinogen, Factor VIII, Factor XIII, vWF , and fibronectin . Each individual bag of cryoprecipitate must include 80 IU of Factor VIII and 150 mg of fibrinogen, typically in 5–20 mL of plasma.Many blood manufacturers prepool 2–10 individual bags of cryoprecipitate for transfusion convenience.

27. Cryoprecipitate may be used to increase fibrinogen levels in infants and children with hypofibrinogenemia and hemorrhage due to liver disease . Cryoprecipitate may also be used to increase fibrinogen levels in older adolescents/young women with postpartum hemorrhage and to replenish fibrinogen levels in pediatric trauma patients, a subset of whom have been reported to have trauma-associated hypofibrinogenemia independent of dilutional coagulopathy. In addition, cryoprecipitate can be used in combination with FFP to replace fibrinogen plus coagulation factors in instances of dilutional coagulopathy. Cryoprecipitate has also been used as a second-line therapy to treat uremia associated bleeding.

28. While cryoprecipitate has historically been used to treat bleeding or for prophylaxis in patients with hemophilia , vWD , Factor XIII deficiency, or congenital afibrinogenemia , hypofibrinogenemia , or dysfibrinogenemia , these diseases are now largely treated with recombinant or human-derived concentrates. Nonetheless, cryoprecipitate remains a second-line therapy should such concentrates be unavailable. Transfusion thresholds for fibrinogen have not been extensively studied in children, though extrapolation of adult guidelines would suggest that fibrinogen levels should be maintained above 80–100 mg/ dL . Recent adult studies suggest that fibrinogen levels above 150 mg/ dL may be more ideal, depending on the transfusion indication . In children, 1 unit of cryoprecipitate per 5–10 kg of body weights estimated to raise the fibrinogen level by 60–100 mg/ dL

29. The half-life of fibrinogen (3–5 days), along with the indication for transfusion, will determine the recommended frequency of cryoprecipitate transfusion . Cryoprecipitate is considered an acellular product and thus does not require irradiation for recipients at risk for transfusion associated graft- versushost disease. Potential adverse effects of cryoprecipitate transfusioninclude the risk of thrombosis

30. Consideration for cryoprecipitate in infants and childern To increase fibrinogen • DIC • Liver disease • Trauma • Postpartum hemorrhage • Dilutional coagulopathy To replace fibrinogen Afibrinogenemia • Hypofibrinogenemia • Dysfibrinogenemia To replace Coagulation factors • Factor XIII deficiency • Factor VIII deficiency • vWD To improve platelet function • Uremia

31. Platelet, Plasma, and Cryoprecipitate Dosing for Infants and Children Platelets for infants • 5–10 mL/kg Platelets for children • 5–10 mL/kg* • 10 –15mL/kg • 2 –3 mL/kg • Fractions of apheresis units may be ordered: • ¼ apheresis unit if 10–15 kg • ½ apheresis unit if 15–30 kg • 1 apheresis unit if >30 kg Plasma for infants and children • 10 –15mL/kg Cryoprecipitate for infants and children • 2 –3 mL/kg

32. Selection of donor unit in neonates and infants (till 4 months of age)

33. Fresh frozen plasma Fresh frozen plasma should be ABO identical/compatible with the recipient’s red blood cells. In neonates, ABO identical plasma should be preferred. No considerations for matching RhD should be made as far as plasma component selection is concerned. Cryoprecipitate does not require ABO/ Rh grouping except in neonates . Platelet concentrate Platelet concentrate should be ABO and Rh (D) type-specific with the recipient blood as far as possible. In case of shortage of ABO and Rh (D) type-specific whole blood-derived / random donor platelets, any ABO/ Rh group should be used provided there is no visual red cell contamination of the platelet concentrate/ In the case of single donor platelets prepared by apheresis, plasma should be reduced, or the use of platelet additive solutions should be considered if the component is used across the blood group barrier (e.g., use of ‘O’ group SDP to B patient). Infants should be provided ABO identical platelets (both whole blood-derived and single donor) till the age of