hemorrhagic disease of newborn

Hemorrhagic disease is a bleeding problem that occurs in a baby during the first few days of life.

1. JIGJIGA UNIVERSITY College Of Medicine And Health Science School Of Graduate Studies presentation by Nesteho Kedir MSC maternity

2. Hemorrhagic disease of newborn

3. content Introduction Hemophilia Von- Willebrand disease Liver disease Vit k deficiency DIC thrombocytopenia

4. Introduction Hemorrhagic disease is a bleeding problem that occurs in a baby during the first few days of life. The normal range for the new-born prothrombin (PT)and partial thromboplastin time (PTT) extend above than those for a healthy adult . But there is NO increased risk of bleeding in a healthy newborn.

5. Neonatal haemostatic system • At birth, concentrations of the vitamin K dependent (FII,FVII, FIX, FX) and factors (FXI, FXII) are reduced to about 50% of normal adult values and are further reduced in preterm infants (Hemorrhagic Disease of Newborn).

6. Cont… Concentrations of the naturally occurring anticoagulants, antithrombin, protein C, S and Z are low at birth and as a consequence, both thrombin generation and thrombin inhibition are reduced in the newborn period. • Plasminogen is also low in neonatal period resulting in a relatively hypofibrinolytic state.

7. Causes of hemorrhage disease in newborn • Coagulation defects • Platelet Quantitative/ Qualitative defects • Fibrinolytic dysfunction • Vascular causes • Miscellaneous

8. COMMON hemorrhagic disease of the newborn inherited Haemophilia A and B Von- willebrand disease Afibrinogenesis Liver disease Vit k deficiency DIC thrombocytopnia acquired

9. Hemophilia Hemophilia is an inherited bleeding disorder. Newborn with hemophilia can’t stop bleeding b/c they don’t have enough clotting factor in blood. There are many blood clotting factors involved in forming of clots to stop bleeding. Two common factors that affect blood clotting are factor VIII and factor IX.

10. The 3 main forms of hemophilia are: • Hemophilia A . caused by a lack of the blood clotting factor VIII . referred as to classic hemophilia /factor VIII deficiency. • Hemophilia B. caused by a deficiency of factor IX. Referred as Christmas disease or factor IX deficiency. • Hemophilia C. caused by lack of factor XI referred to factor XI deficiency .

11. causes hemophilia in newborn Hemophilia types A and B are inherited diseases. They are passed from parents to children through a gene on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. • A female carrier has the hemophilia gene on one of her X chromosomes.

12. Cont… When a hemophilia carrier female is pregnant. there is a 50/50 chance that hemophilia gene will be passed on to the baby. • If the gene is passed on to a son, he will have the disease but If the gene is passed on to a daughter, she will be a carrier.

13. The sign and symptoms of hemophilia Bleeding into the joints. Bleeding into the skin (which is bruising) muscle and soft tissue (called a hematoma). Bleeding of the mouth , nose and gums, bleeding that is hard to stop after losing a tooth. Blood found in the urine or stool Hemophilia C usually doesn’t cause problems ,but may have increased bleeding after surgery.

14. Diagnosis of hemophilia The diagnosis of hemophilia is based on patient`s family history and a physical exam. Blood tests include Complete blood count (CBC). It includes RBC, WBC platlate, hemoglobin and hematocrit • Clotting factors. levels of each clotting factor. • Bleeding times. To test the speed that blood clots. • Genetic or DNA testing. for abnormal genes

15. Hemophilia management Treatment for hemophilia is aimed to preventing bleeding complication (mainly head and joint bleeds). Bleeding in the joint may need surgery or immobilization. The rehab of the affected joint include physical therapy and exercise to strengthen the muscles of affected area. • Blood transfusions may be needed if major blood loss has occurred.

16. Cont… Self-infused factor VIII or IX can allow a newborn with hemophilia to lead a near normal lifestyle. Factor VIII concentrates: • Hemofil M(Baxter) • Immunate(Baxter) • Koate-DVI(Bayer) Factor IX concentrates: • Immunine(Baxter) • Aimafix( Kedrion

17. Complications of hemophilia hemarthrosis inflammation and Long-term joint problems • Very serious tumor-enlargements, muscle /bone • Development of antibodies against clotting factors • Infections from transfusions Hematoma Spontaneous nosebleed

18. Von Willebrand disease (VWD) VWD is a genetic disorder caused by missing or defective Von Willebrand factor (VWF), a clotting protein. VWF binds factor VIII, a key clotting protein, and platelets in blood vessel walls, which help form a platelet plug during the clotting process. • VWD is most common inherited bleeding disorder • It is carried on chromosome 12 and occurs equally in men and women

19. Sign and symptom of VWD bleeding from the gums. easy bruising. prolonged bleeding after cuts or bloodworm. frequent and prolonged nosebleeds. blood in the stool or urine. Babies with  VWD rarely bleed at birth. Babies with Type 3 VWD, surgery, including circumcision soft tissue/joint bleeding (in more severe forms).

20. Diagnosis of VWD 76% of men with VWD had been diagnosed by age 10, but 50% of women with VWD were not diagnosed until after age 12. the plasma VWF protein level Some subtypes of type II disease are associated with thrombocytopenia, which may be apparent during the neonatal period and may result in bleeding.

21. Liver Disease • Biliary obstruction impaired vit K absorption decrease synthesis FII,FVII,FIX and X. • Severe hepatocellular dz, reduced FV, fibrinogen & plasminogen activator. • Dysfunctional fibrinogen (dysfibrinogenaemia) • Low thrombopoietin production l/t thrombocytopenia • Hypersplenism associated with portal HTN l/t thrombocytopenia

22. Vitamin K Deficiency Bleeding or VKDB refers to bleeding that occurs as a consequence of vitamin K deficiency during the first six months of life. Vitamin K refers to a group of fat-soluble vitamins that  play a role in blood clotting, bone metabolism , and regulating blood calcium level

23. Cont… Coagulation factors II, VII, IX, X and other Gla-proteins ( protein C, protein S, protein Z) also depend on the presence of vitamin K for their activity. vitamin K–dependent factors is characterized by bleeding that tends to be gastrointestinal, nasal, subgaleal, intracranial, or post-circumcision. ▪

24. Classification Early-VKDB ▪ Onset: 0-24 hr ▪ Incidence: Rare ▪ Site: Cephalohematoma, Subgaleal, Intracranial, Gastrointestinal, Umbilicus, Intra-abdominal. ▪ Etiology: Maternal drugs (Phenobarbital, phenytoin, warfarin, rifampin, isoniazid) that interfere with vit K. ▪ Risk factor: Inherited coagulopathy.

25. CONT… Classical-VKDB ▪ Onset: 2-7 days ▪ Incidence: ≈2% if infant not given vitamin K. ▪ Site: Gastrointestinal, Ear-nose-throat-mucosal, Intracranial, Circumcision, Coetaneous, Injection sites. ▪ Etiology: Vitamin K deficiency, Breast-feeding .

26. Conti.. Late-VKDB Onset:1-6 month ▪ Incidence: Dependent on primary disease. ▪ Site: Intracranial, Gastrointestinal, Coetaneous, Ear-nose-throat mucosal, Injection sites and Thoracic. ▪ Etiology : Cholestasis—malabsorption of vitamin K (Biliary atresia, cystic fibrosis, hepatitis) ▪ Risk factor : Abetalipoprotein deficiency, Idiopathic in Asian breastfed infants, Warfarin ingestion.

27. causes vitamin K deficiency – Minimal transplacental passage of vitamin K – Limited hepatic storage of vitamin k in newborn – Low concentration of vitamin k in breast milk – Absence of the bacterial intestinal flora normally responsible for the synthesis of vitamin K not receive a vitamin K shot at birth. 

28. presentations of VKDB Bruises on the baby's head; External bleeding, especially from the nose or umbilical cord; Unnatural skin coloring. Vomiting blood. Stool that is dark and sticky. irritability, convulsions, poor reflexes and poor feeding.

29. Investigation ▪ Coagulation profile : Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels, and a platelet count should be included in the initial workup for VKDB in a newborn. – A prolonged PT is usually the first laboratory test result will be abnormal in VKDB – Normal aPTT, fibrinogen levels and a platelet count . – Factor assay.

30. CONTI.. Imaging study : CT scan ,MRI,USG ▪ CBC ▪ LFT ▪ Stool for occult blood ▪ ERCP ▪ Liver biopsy

31. Differential DX of VKDB ▪ Alloimmune Thrombocytopenia ▪ Consumption Coagulopathy ▪ Hepatobiliary Disease ▪ Maternal Isoimmune Thrombocytopenia ▪ Pediatric Von Willebrand Disease ▪ Uncommon Coagulopathies ▪ Swallowed blood syndrome

32. Types of vitamin k K 1 : Phylloquinone is predominantly found in green leafy vegetables, vegetable oils, and dairy products. ... K 2 : Menaquinone is synthesized by gut flora. K 3 : Menadione is a synthetic, water soluble form that is no longer used medically because of its ability to produce hemolytic anemia .

33. Management The disease may be effectively treated with a slow IV infusion of 1-5 mg of vitamin K1. ▪ Serious bleeding, particularly in premature infants or those with liver disease, may require a transfusion of fresh frozen plasma or whole blood .

34. CONT… Surgical Care ▪ Normally, VKDB infants do not require surgical care but in rare cases, an infant may need neurosurgical evaluation and treatment. ▪ Other conditions, such as those associated with short bowel syndrome and Hepatobiliary disease may require surgical evaluation

35. Complication ▪ Intracranial hemorrhage is the primary serious complication of VKDB ▪ Complications of treatment include anaphylactoid like reactions during intravenous (IV) vit K admin, hyperbilirubinemia or hemolytic anemia after high doses of vitamin K, and hematomas at the site of injection.

36. Prevention ▪ Early-VKDB : Administrations of vitamin K to infant at birth or to mother (20 mg) before birth. ▪ Classical-VKDB: Parenteral vitamin K at birth. ▪ Late-VKDB: Parenteral and high-dose oral vitamin K during periods of malabsorption or cholestasis.

37. Disseminated intravascular coagulation DIC is an acquired syndrome characterized by excessive systemic activation of coagulation, resulting in both hemorrhage and thrombosis. DIC can progress rapidly into life-threatening multiorgan failure DIC always occurs as a secondary event, and a number of prenatal and neonatal problems are associated with.

38. Etiology birth asphyxia, acidosis, respiratory distress syndrome, infection, necrotising enterocolitis, meconium aspiration, aspiration of amniotic fluid, brain injury, hypothermia, giant haemangioma, homozygous protein C/S deficiency, thrombosis, malignancy.

39. The laboratory diagnosis of DIC typical pattern of reduced platelets, PT, APTT with or without thrombin clotting time), reduced fibrinogen, and increased  D - dimers Although this pattern is likely to be present in a neonate with fulminating DIC, findings can vary, and a number of factors complicate the diagnosis during the neonatal period.

40. manifestations of DIC in neonate Bleeding , bruising , low blood pressure, shortness of breath, confusion. Managemanet Treatment by underlyding cause Fresh frozen plasma (10–15 ml/kg) can be used to replace haemostatic proteins,  cryoprecipitate (5–10 ml/kg) is a better source of fibrinogen, which should be kept above 1 g/l

41. Neonatal thrombocytopenia Thrombocytopenia in neonates is traditionally defined as a platelet count <150000/mcL over all incidence of neonatal thrombocytopenia is (0.7%–0.9%) In Neonatal Intensive Care Unit (NICU) it is very high (22%–35%)

42. classifications Mild- (PC = 100000 – 150000/ mcl ) Moderate (PC = 50000 – 99000/ mcl ) Severe (PC < 50000/ mcl )

43. CONDITION Fetal Alloimmune condition Congenital infection (e.g., CMV, toxoplasma, rubella, HIV) Aneuploidy (e.g., trisomy 18,13, or 21, or triploidy) Autoimmune condition (e.g., ITP, SLE) Severe Rh hemolytic disease Congenital/inherited (e.g., Wiskott- Aldrich syndrome)

44. CONDITION Early-onset neonatal ( < 72 hr) Placental insufficiency (e.g ., IUGR, diabetes) Perinatal asphyxia Perinatal infection (e.g., Escherichia coli , GBS, Haemophilus influenzae ), DIC Alloimmune condition Autoimmune condition (e.g., ITP, SLE) Congenital infection (e.g., CMV, toxoplasma, rubella, HIV) Thrombosis (e.g., aortic, renal vein) Bone marrow replacement (e.g., congenital leukemia) Kasabach-Merritt syndrome Metabolic disease (e.g., proprionic and methylmalonic acidemia) Congenital/inherited (e.g., TAR, CAMT) CONDITION Early-onset neonatal ( < 72 hr) Placental insufficiency (e.g ., IUGR, diabetes) Perinatal asphyxia Perinatal infection (e.g., Escherichia coli , GBS, Haemophilus influenzae ), DIC Alloimmune condition Autoimmune condition (e.g., ITP, SLE) Congenital infection (e.g., CMV, toxoplasma, rubella, HIV) Thrombosis (e.g., aortic, renal vein) Bone marrow replacement (e.g., congenital leukemia) Kasabach-Merritt syndrome Metabolic disease (e.g., proprionic and methylmalonic acidemia) Congenital/inherited (e.g., TAR, CAMT)

45. Immune thrombocytopenia Immune thrombocytopenia occurs due to passive transfer of antibodies from the maternal to the fetal circulation. Types: 1) Neonatal Alloimmune thrombocytopenia (NAIT) 2) Autoimmune thrombocytopenia

46. Neonatal Alloimmune thrombocytopenia (NAIT) antibody is produced in the mother against specific human platelet antigen (HPA) present in the fetus but absent in the mother. The antigen is inherited from the father of the fetus. Early onset severe thrombocytopenia. combination of severe neonatal thrombocytopenia with a parenchymal (rather than intraventricular) intracranial hemorrhage is highly suggestive of NAIT.

47. Diagnosis and management of NAIT Investigation : 1) Antigen screening (HPA 1,3,5,9,15,4) 2) Brain imaging studies Management: 1) Suspected NAIT in an unknown pregnancy 2) Known case of NAIT 3)Antenatal mgt of pregnant woman with previous history of NAIT

48. Management of the neonate with suspected NAIT in an unknown pregnancy. 1) Random-donor platelet transfusion 2)IVIG (1g/kg/day for 2 days) 3) Antigen-negative platelet transfusion 4) Methylprednisolone (1 mg/kg bid for 3–5 days) Management of the neonate with known NAIT Antigen-negative platelet transfusion Antenatal management of pregnant women with previous history of NAIT IVIG is given to mother.

49. Guidelines for platelet transfusion

50. Platelet Count (*10000mcl) <30 Transfuse all 30-49 Transfuse if: BW <1,500g and & 7 days old Clinically unstable Concurrent coagulopathy Previous significant hemorrhage (i.e., grade 3 or 4 IVH) Prior to surgical procedure Postoperative period (72 hours) 50–100 Transfuse if: Active bleeding NAIT with intracranial bleed Before or after neurosurgical procedures Dose: 10 -15 ml/kg

51. Complications: Transfusion-transmitted CMV infections Graft-versus-host disease (GVHD) TRALI

52. Clinical Evaluation Platelets PT PTT Likely diagnosis Sick D- 1+ 1+ DIC D- N N Platelet consumption ( infection, necrotizing enterocolitis, renal vein thrombosis ) N 1+ 1+ Liver disease N N N Vasculitis (hypoxia, prematurity, acidosis, hyperosmolality ) Healthy D- N N ITP, occult infection, thrombosis, B.M. hypoplasia or infilteration N 1+ 1+ Hemorrhagic disease of newborn ( vit. K deficiency ) N N 1+ Hereditary clotting factor deficiencies N N N Bleeding due to local factor ( trauma, anatomic anomalies); PT = prothrombin time; PTT = partial thromboplastin time; D- = decreased; 1+ = increased; DIC = disseminated intravascular coagulation; N= normal .

53. References ▪ Nelson Textbook of Pediatrics ▪ Manual of Neonatal Care- Cloherty ▪ oxford handbook of neonatology ▪ Medscape Clinicalkey

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