Overview 5/8/2017. Management Strategies for Bleeding and Thrombocytopenia in the Neonate

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1 Management Strategies for Bleeding and Thrombocytopenia in the Neonate Kyle Annen, DO Medical Director Blood Bank, Transfusion Service and Hematology Mount Sinai Beth Israel Assistant Professor, Department of Pathology Icahn School of Medicine New York, NY Overview Brief overview of coagulation Differences in neonatal vs adult hemostasis Factor deficiencies Congenital Acquired Thrombocytopenia Non-Immune Immune TEN=X Needs something extra Hoffman M, Cichon LJ. Practical Coagulation for the Blood Banker Transfusion Jul;53(7):

2 Newborn Hemostasis Coagulation in neonates is more challenging to manage as it is constantly evolving Fibrinogen, Factor V, Factor VIII and vonwillebrands are present in adult concentrations at birth Vitamin K dependent factors: II, VII, IX and X and Factors XI, XII, Prekallikrein and High Molecular Weight Kininogen are present at 50% of normal adult levels Anticoagulants: Heparin cofactor II, Prothrombin, Protein C, Protein S are also present at 50% of adult levels PT and PTT will often be prolonged if using an adult reference range. Causes of Bleeding Congenital Hemophilia (FVIII, FVIX) vonwillebrand s Disease Fibrinogen Deficiency Specific Factor Deficiency II V VII X XI XIII Acquired Liver Disease Vitamin K Deficiency Disseminated Intravascular Coagulation (DIC) Therapeutic Hypothermia Extracorporeal Life Support Congenital Causes Evaluation of Bleeding 2

3 Hemophilia Hemophilia A (Factor VIII Deficiency) X-linked genetic disorder affecting 1 in 5,000 males Present in adult levels at birth, thus a prolonged PTT or bleeding should prompt workup Factor VIII is an acute phase reactant, thus can be artificially elevated post-delivery Can mask diagnosis of mild deficiency Hemophilia B (Factor IX Deficiency) X-linked disorder affecting 1 in 20,000 males Present at 50% of adult levels at birth, thus crosses into the mild hemophilia range making diagnosis challenging Hemophilia Severity of disease is categorized by factor levels >5%-40% Mild 1-5% Moderate <1% Severe Average time to first bleed is 28.5 days ICH is more common with assisted vaginal delivery If hemophilia is suspected, factor levels should be repeated at age 6-12 mos for confirmation Management is with replacement of the appropriate factor concentrate vonwillebrand s Disease Most frequently inherited blood disorder Affects 1% of the population Inheritance is autosomal dominant or recessive (depending on type) Vast majority is type 1, a mild quantitative deficiency of vwf with mild bleeding Type 2 is more severe, due to a qualitative dysfunction. It is subcategorized (2A, 2B, 2N, 2M). Type 3 is most severe (and rarest), with virtual absence of vwf 3

4 vwf Diagnosis Diagnosis of vwf is based on three laboratory assays VWF activity in the plasma and its ability to bind platelets vwf quantitative status Factor VIII activity 0.65% Agarose Treatment depends of the type of vwf malfunction Courtesy: RR Montgomery, MD 0.65% Agarose Courtesy: RR Montgomery vonwillebrand s Disease Neonates have elevated VWF multimers and activity. Usually only type 2 or 3 will present with bleeding in the neonate Mucosal type bleeding: Epistaxis, bruising, bleeding gums, GI bleeding Can have prolonged bleeding during surgery. Management is with plasma-derived factor concentrates which contain vwf. Rare Bleeding Disorders 3-5% of inherited coagulation disorders Fibrinogen Disorders Single Factor Deficiency 4

5 Fibrinogen Disorders Fibrinogen, together with platelets, forms the structure of the clot that plug the breach in the blood vessel wall Infant may have prolonged bleeding from the umbilical stump, ICH, post-circumcision or mucocutaneous bleeding Typically inherited in a autosomal recessive pattern Two forms of fibrinogen dysfunction Low (hypofibringenemia) or absent (afibrinogenemia) Dysfunctional fibrinogen Fibrinogen Disorders Neonates have normal levels of fibrinogen when compared to adults. Aberrant fibrinogen will prolong the PT and aptt Confirmatory tests are decreased function or antifibrinogenic assays Treatment is with fibrinogen concentrates Cryoprecipitate or Plasma can be used if the primary option is not available Factor Deficiency Can result in mucocutaneous bleeding, ICH, prolonged umbilical stump bleeding, or bleeding after procedures or trauma Inherited in an autosomal recessive manner Diagnosis should start with a PT, aptt PT Factor VII Factor II Factor V aptt Factor XI Factor X Prolongation of the PT ( ) and/or aptt ( ) will direct towards the suspected factor deficiency. 5

6 Single Factor Deficiencies FV-present in adult levels at birth Only option for therapeutic replacement is FFP FII (prothrombin)-present at 50% of adult levels FVII Factor levels to do not correlate with bleeding severity FX-Present at 50% of adult levels FXI-present at 50% of adult levels Higher incidence in Ashkenazi Jewish Descent Factor levels to do correlate with bleeding severity Only option for therapeutic replacement is FFP Factor XIII Cross-links fibrin and stabilizes clots Deficiency is inherited in an autosomal recessive pattern Classic presentation is umbilical stump bleeding Also ICH and prolonged bleeding after procedures PT and aptt will not be prolonged by Factor XIII deficiency, even at very low levels Factor XIII activity assay should be performed if this deficiency is suspected Clot solubility assay is not as sensitive at very low levels Treatment with Factor XIII concentrate or Cryoprecipitate Acquired Causes Evaluation of Bleeding 6

7 Liver Failure Liver failure may cause significant coagulation dysfunction. Pro-and anti-coagulation factors (except vwf and FVIII) are manufactured in the liver Thombopoetin is also manufactured by the liver Neonates with liver failure may have any presentation of bleeding or clotting problems making management difficult Typically demonstrates prolonged PT, aptt, elevated D-Dimer, low fibrinogen, low platelets Plasma has been used as first line therapy for treatment in the neonate, however high-volumes are often necessary for adequate management and fluid balance is delicate in the neonate rfviia has been used with good results, however there is a risk of thrombosis Cryoprecipate for low fibrinogen Prothrombin Complex Concentrates (PCCs) may be used, although these also have a risk of thrombosis Vitamin K Deficiency Vitamin K is a necessary co-factor in the final step of production for Factors II, VII, IX and X, and anti-coagulants proteins C and S. Vitamin K is given prophylactically at birth in the US Vitamin K deficiency is classified as early, classical or late. Early is due to trans-placental compounds that interfere with vitamin K metabolism Classical is due to physiologic Vitamin K deficiency combined with a nutritional shortage. Late is almost exclusively found in breast-fed infants, due to inadequate amounts in breast milk. Vitamin K Deficiency EARLY CLASSICAL LATE Age <24 hours 1-7 days 2 Weeks Risk Factors Maternal medications (vitamin K antagonists, anticonvulsants, antituberculin drugs) Lack of prophylactic vitamin K treatment, poor feeding (particularly if breastfed) Exclusive breastfeeding, poor feeding, gastrointestinal disorders, liver disease, pancreatic disease, antibiotic therapy Sites of Bleeding Cephalohematoma, umbilical stump, intracranial Gastrointestinal, umbilicus, mucocutaneous, circumcision, intracranial Intracranial, mucocutaneous, gastrointestinal Frequency Less than 5% in at-risk population Without Vit K prophylaxis: <1% Variable depending on age and conditions listed above Treatment PCC, Vitamin K (may not work) Parenteral Vit K PCC for active bleeding Prothrombin complex concentrates for active bleeding, recombinant factor VIIa (for mild cases where only the prothrombin time is prolonged) Prevention Avoidance of culprit medications prior to delivery Vit K prophylaxis at birth Adequate vitamin K replacement (in many cases will need to be parenteral) Modified from Jaffray J, Young G, Ko RH. The bleeding newborn: A review of presentation, diagnosis, and Management. Seminars in Fetal & Neonatal Medicine 21 (2016)

8 Vitamin K Deficiency Management PT will always be prolonged, aptt is usually prolonged PT will be prolonged out of proportion to the aptt Prolonged PT, bleeding and lack of Vitamin K prophylaxis at birth is presumptive for Vitamin K deficiency. Parenteral Vitamin should be started immediately Other factor assays should not be ordered (or waited for): a repeat PT and aptt several hours after administration of Vitamin K should correct, confirming the diagnosis. Vitaming K does not work immediately--severe bleeding may need supplemental therapy. Disseminated Intravascular Coagulation Consumption of pro- and anti-coagulants, fibrinolytic proteins and platelets Characterized by bleeding and/or clotting. DIC is always caused by an underlying disorder: in the neonate it is usually sepsis Proinflammatory cytokines, IL-6 and TNFα stimulate the coagulation cascade and inhibit thrombotic regulators Protein C and Protein S The ultimate result in microvascular thrombi, leading to organ dysfunction and bleeding as factors are consumed DIC Bleeding can occur anywhere oozing at venipuncture sites and mucosal bleeding are most common, but catastrophic ICH can happen No specific test is diagnostic for DIC. Usually all coagulation tests will be abnormal Elevated D-Dimer and Fibrin Degradation Products is suggestive 8

9 DIC Management The underlying cause must be addressed FFP and Cryoprecitpate is first line therapy for management of bleeding complications For severe bleeding, PCCs or rfviia can be considered Risk to benefit must be carefully addressed, as there is a higher likelihood of thrombotic complications Therapeutic Hypothermia Therapeutic hypothermia has been used to reduce or prevent sequelae from hypoxic-ischemic events (such as severe ICH). It is unclear how metabolic derangements caused by this treatment may effect coagulation. Patients should be closely monitored and FFP or cryoprecipitate administered accordingly. Extra Corporeal Life Support Neonate that ExtraCorporeal Membrane Oxygenation (ECMO) or Coronary Bypass require extra attention as these procedures stress their delicate system Coagulation derangements are likely, must be closely monitored Therapy should be targeted, using FFP, Cryoprecipitate and/or Platelets, as needed 9

10 Algorithm for Assessment and Treatment of the Bleeding Newborn Jaffray J, Young G, Ko RH. The bleeding newborn: A review of presentation, diagnosis, and Management. Seminars in Fetal & Neonatal Medicine 21 (2016) Thrombocytopenia Thrombocytopenia Defined as platelets < 150 x10 9 /L Common in the neonatal period 1-2% of healthy newborns The sicker or more premature, the higher the likelihood of thrombocytopenia 18-35% incidence Common signs are petechiae, hematoma, gastrointestinal, other mucosal or umbilical bleeding However, life-threatening bleeding or intracranial haemorrhage (ICH) is uncommon A high risk of neurodevelopmental impairment may occur in severe thrombocytopenia (platelets <50 x10 9 /L) 10

11 Timing of onset for thrombocytopenia is significant in determining the underlying cause Early Onset (<72 hours) Thrombocytopenia is usually mild neonates usually recover within 7-10d with no intervention. Severe thrombocytopenia (<50 x10 9 /L) is life-threatening and must be addressed immediately Often related to maternal complications: IntraUterine Growth Restriction (IUGR) HELLP syndrome (Hemolysis, ELevated Liver enzymes, Low Platelets) Drug abuse Maternal diabetes Acquired Thrombocytpenia: Non-immune Causes Chronic Fetal Hypoxia Occurs most often when exposed to maternal diabetes, HELLP syndrome or IUGR Caused my impaired megakaryopoesis Thrombocytopenia is rarely severe and is usually self limiting. Infant will have neutropenia and polycythemia as well Congenital Infections HIV, CMV, enterovirus, herpesvirus In CMV thrombocytopenia is common Typically mild and self-limited 11

12 Acquired Thrombocytopenia: Non-immune Causes Neonatal Infections Most common cause of late-onset thrombocytopenia; can be severe % of preterm neonates with bacterial sepsis have platelet counts of < 100 x10 9 /L Gram-Negative Sepsis is more often severe Cytomegalovirus NEC Serious gastrointestinal disorder in premature infants 90% of neonates will develop late-onset thrombocytopenia Usually below < 50 x10 9 /L and often with bleeding Severity of the thrombocytopenia and number of platelet transfusions required predict outcome Hypercoagulable states Associated consumption of platelets Severe hemangiomas (Kasabach-Merrit Syndrome) can be limited to visceral organs Ultrasound should be performed if this is suspected Low platelets my be the presenting sign in venous or arterial thrombosis Metabolic Disorders Rare inborn errors of metabolism, such as Gaucher s will present with thrombocytopenia Acquired Thrombocytopenia: Immune Causes Neonatal AlloimmuneThrombocytopenia Common: present in 1:1100 neonates Most common cause of early thrombocytopenia and intracranial hemorrhage 10-20% of untreated pregnancies have this complication ICH can occur in utero Only 10% of infants (born to HPA-1a mother) are affected HPA antigens are expressed on platelets in the first trimester Can affect first pregnancies, and can be severe before 20 weeks gestation NAIT Results from maternal antibodies to an antigen present on the fetus s platelets Human platelet antigens differ by a single nucleotide polymorphism. HPA-1a culprit in 70% of cases in the Caucasian population, followed by HPA-3 and HPA-5 HPA-4b is most common in Asian population 12

13 NAIT Diagnosed by detection of platelet-specific antibodies or HLA genotyping The Monoclonal Antibody-Specific Immobilization of Platlet Antigens Assay (MAIPA) is the gold standard for detection HPA genotyping can be performed and risk of future affected pregnancies can be calculated by assessing paternal heterozygosity Recurrence rates are 70-90% PCR assays are also available NAIT Treatment If NAIT is suspected, HPA mismatch assessment of parental blood should be initiated. But therapy must not wait for results! If otherwise healthy, transfusion threshold is <30 x10 9 /L If ICH is present, threshold is > 100 x10 9 /L Transfusions of matched platelets should be used if possible. Washed maternal platelets is the ideal option but rarely used IVIG has been used, but there is still a delay in the neonatal platelet response. It is recommended to use alongside platelet transfusion Washed Maternal Platelets vs. Random Donor Platelets Washed maternal platelets are ideal Antibody removed Known absence of culprit antigen A study published in Blood in 2006 looked at 27 newborns affected by NAIT who were given random-donor platelets. 13

14 NAIT-Random Donor Platelet Study 27 infants were given random-donor platelets, as washed maternal or antigen-matched were not available. 24 of 27 newborns showed a moderate to significant platelet increase above the threshold of > 40 x10 9 /L Concluded that random donor platelets were appropriate, effective and safe in unexpected, severe NAIT. Acquired Thrombocytopenia: Immune Causes AUTOimmune Neonatal Thrombocytopenia Mothers with Autoimmune Thrombocytopenia (ITP) produce antiplatelet antibodies These can cross the placenta resulting in thrombocytopenia in the fetus Occurs in about 10% of affected neonates Mostly mild, <1% develop ICH IVIG is first line treatment, platelet transfusion for severe lifethreatening bleeding. 14

15 Hereditary Thrombocytopenia Normal Platelet Function Thrombocytopenia and absent radii (TAR syndrome) Amegakaryocytic thrombocytopenia and radio-ulnar syndrome (ATRUS) Congential amegakaryocytic thrombocytopenia (CAMT) Fanconi Anemia MYH-9 related thrombocytopenia Thrombotic Thrombocytopenic Purpura (inherited: Upshaw- Shulman Syndrome) Abnormal Platelet Function Wiscott-Aldrich Syndrome X-linked thrombocytopenia Chediak-Higashi Syndrome Bernard-Soulier Syndrome Paris-Trousseau Syndrome (Jacobsen s Syndrome) Therapeutic Approach for Neonatal Thrombocytopenia No consensus on transfusion threshold in the neonate Bleeding risk is highest in the first week of life and in very preterm neonates Bleeding is common in NAIT, NEC and Sepsis and is high risk In cases of bleeding, a threshold of >100 x10 9 /L should be targeted. All platelets should be Leukocyte reduced and irradiated CMV negative for infants <1500g Always consider the risks and benefits of any transfusion decision Key Points Newborn hemostasis is delicate Factors are present in only 50% of normal adult ranges Vitamin K dependent factors: II, VII, IX and X and Factors XI, XII, Prekallikrein and High Molecular Weight Kininogen are present at 50% of normal adult levels. Will prolong the PT and aptt Bleeding or thrombosis will point to a need to search for an underlying abnormality Thrombocytopenia is the most common hematological abnormality in the neonate. Often mild and self-limiting Severe should prompt an immediate search for a cause Bleeding risk is the highest in the first week of life. 15

16 Questions? References Jaffray J, Young G, Ko RH. The bleeding newborn: A review of presentation, diagnosis, and Management. Seminars in Fetal & Neonatal Medicine. 21 (2016) Holzhauer S, Zieger B. Diagnosis and Manangement of Neonatal Thrombocytopenia. Seminars in Fetal and Neonatal Medicine 16 (2011) Delaney M, Mayock D, Et al. Postnatal cytomegalovirus infection: a pilot comparative effectiveness study of transfusion safety using leukoreduced-only transfusion strategy. Transfusion Aug;56(8): Patel RM, Knezevic A, et al. Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA March 1; 315(9): doi: /jama KiefelV, Bassler D, et al. Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT). Blood 2006 May 1;107(9): Epub 2006 Jan 10. Berardi A, Spaggiari E, et al. Persistent intestinal bleeding due to severe CMV-related thrombocytopenia in a preterm newborn. The Journal Of Maternal-Fetal & Neonatal Medicine. Epub 2017 Apr 11. BloodCenter of Wisconsin Pediatric Transfusion Guidelines