Seminar in Paediatrics

:

The Bleeding Newborn

The Bleeding Newborn
Patrick M. P. Yuen

Paediatricians who care for newborn babies are frequently confronted with neonates suffering from serious and life-threatening haemorrhages. In this article, a practical clinical approach to the rapid diagnosis and management of these neonates based on a few simple laboratory tests is described together with the treatment of various bleeding disorders. HAEMOSTASIS IN THE NEWBORN For a complete review of haemostasis in the normal newborn, the readers are urged to refer to the excellent monograph on perinatal coagulation (1). CLOTTING FACTORS Almost all the clotting factors are produced in the liver and they are present in reduced concentrations in term infants, as compared in older children and adults. The levels are even lower in the premature infants (Table 1). Only factors V, VIIIc and XIII are present in concentrations approaching those of adult levels.

PLATELETS Although platelet numbers are similar in premature, term infants and adults, their function may be somewhat impaired (2, 3). FIBRINOLYTIC SYSTEM While antithrombin III and plasminogen are low in the neonates, especially in the premature, the ^ 2 antiplasmin level is normal. PROTEIN C SYSTEM Protein C is a potent anticoagulant as well as a profibrinolytic agent (4). Mean protein C antigen level in full-term neonates is about one third of normal adults' mean level, the more premature the infant, the lower the protein C level (5). While reduced levels Vit K dependent factors (II, VII, IX and X) and contact factors (XI, XII, pre-kallikrein and high molecular weight kininogen), especially in the premature, predispose the newborn infants to bleeding

Factor
I (fibrinogen) II (prothrombin)

Normal adult range % or mg % 175-450% 60-150% 50-150% 50-120% 50-200% 50-150% 50-150% 60-120% 60-120% 80-120%

Site of production Liver Liver Liver Liver Endothelium? Liver Liver

In vivo 1/2life (hrs or days) 4-7 days 2-3 days 12-30 hr 4-6hr
12 hr 24 hr

Vit. K dependent

Levels in neonates reduced reduced normal reduced normal reduced reduced reduced reduced normal

Lab tests PT/PTT/TT PT/PTT PT/PTT

no
yes

V VII
VIIIc

no
yes

PT
PTT PTT
PT/PTT

no
yes yes

IX
X

40-48 hr
72 hr 48 hr

XI
XII
XIII

p p
? Liver

no no no

PTT PTT
solubility test in 5M urea

4-6 days

Table 1 Clotting factors in newborn

Department of Paediatrics, The Chinese University of Hong Kong, Shatin NT Patrick M.P. Yuen, M.D. (C), F.R.C.P. (C), Senior Lecturer Correspondence to: Dr. Patrick M.P. Yuen

83

0 mg or oral dose of 1.0 mg Vitamin K.g. Bleeding clue to Vit K deficiency occurs usually at 2nd to 4th day of age. toxoplasma. subgaleal and intracranial haemorrhage following the relatively uncomplicated birth of an infant can be the presenting signs. DIC. Bleeding characteristically occurs between the second and fourth day of life. if it occurs at all. Generalised bleeding is almost always a coagulation abnormality. Neonatal bleeding secondary to von Willebrand's disease is rare. maternally derived drug problem or a localised vascular lesion such as an ulcer or haemangioma. drugs given to mother that can affect infant's haemostasis.5 to 1. the cause of which is usually complicated and multifaceted e. subgaleal haemorrhage or bleeding from umbilical stump is usually not a generalised coagulation abnormality but it may be. It usually denotes a single factor deficiency as in severe Haemophilia A patient. tissue necrosis.g. Is there any evidence of maternal or fetal infection with GMV. vitamin K deficiency.CLINICAL APPROACH TO THE BLEEDING NEONATE A thorough history and physical examination will give the clinicans a clue as to the cause of the bleeding (6). Barbiturates Coumarin Methorbital Methusuximide Phenylhydantoin Primidone Dipyridamole ASA Depression of V'it K dependent factors Depression of Vit K dependent factors Depression of Vit K dependent factors Depression of Vit K dependent factors Depression of Vit K dependent factors Depression of Vit K dependent factors Platelet dysfunction Platelet dysfunction Thrombocytopaenia Thrombocytopaenia Thrombocytopaenia Thrombocytopaenia Quinidine Quinine Sedomid Tolbutamide Fig. haemophilia B (factor IX deficiency). The well known muscle and joint haemorrhages seen in older children with the above disorders do not usually begin until infants start to crawl and walk.0 to 2. coxsackie virus. History taking should include the following questions. HI) Has Vitamin K been given to the infant? Hemorrhagic disease of the newborn occurs primarily in breast-fed infants because human breast milk contains less than one fourth the amount of Vitamin K of cow's milk.g. hypoglycaemia. These consist of G-I bleeding. isolated clotting factor deficiencies. hypoxia. Does the mother have lupus erythematosus? Has she had or does she now have ITP? Has she had eclampsia? VI) History of maternal infection. Any infant who has prolonged bleeding following a heel prick. IV) Is the bleeding generalised or localised? Localised bleeding e. A single parenteral dose of 0. V) History of maternal illness. "Sick" infants (babies often with perinatal infection. herpes simplex and syphilis? VII) History of maternal drug intake e. Immune thrombocytopaenia causes bleeding 84 . Infants with congenital protein C deficiency can present in the neonatal period with either the occurrence of an unusally large cephahaematoma. rubella. < 1% activity). 1 Purpura fulminans in a Chinese boy homozygous for protein C deficiency Table 2 Maternal drug intake that can affect infant's haemostasis II) Is there a family history of bleeding disorder? Bleeding in the neonatal period can occur in haemophilia A (severe factor VIIIc deficiency. expistaxis. is recommended for prophylaxis (8). factor XIII deficiency and afibrinogeaaemia. Bleeding from the umbilical stump and VIII) Age of onset of bleeding. acidosis or problems related to prematurity or dysmaturity) have DIG or consumptive thrombocytopaenia. Vitamin K deficiency or severe liver disease. I) Is the infant "sick" or "well" at the onset of bleeding? Well infants (usually full-term with normal birth weight and without an obvious underlying disorder and are also alert and vigourous) generally have immune thrombocytopaenia. subgaleal and intracranial haemorrhages. needle puncture for blood taking or circumcision should be suspected of having a bleeding disorder.

In patients with homozygous protein C deficiency. 85 . IX can be measured by one-stage prothrombin time test using plasmas congenitally deficient in the respective factors as substrates. increased PT & PTT This can be the result of DIG secondary to infection. PTT) A word of caution concerning the interpretation of these tests must be made. Every practising doctor should be able to interpret a blood smear. PROTEIN C ASSAY Protein C level can be measured by the method of enzyme-linked immunosorbent assay (ELISA).25 to 0. PHYSICAL EXAMINATION In physical examination. These observations to be correlated with the history will help to define the pathophysiology underlying the hemorrhage. When the Hct is > 55% the anticoagulant must be reduced i. This includes oozing from needle puncture sites and GI bleeding. These include: i) Individual factor assays ii) Fibrin degredation products (FDP) iii) Protein C assay Platelet count is a sensitive indicator of many disease processes.g DIC) which is more common or poor production (rare). COAGULATION SCREENING TESTS (PT. In the neonates. Such prolongation of PT & PTT is even more pronounced in the pre-term infants. The standard ratio of 1 part 3.V. Vitamin K deficiency. one should also look for localised clues such as the presence of a giant hemangioma (platelet trapping can occur. The PT measures the extrinsic coagulation pathway & PTT assesses the intrinsic clotting system. Depending on the clincial picture and results of screening tests. 0. the anticoagulant ratio must be based on plasma volume rather than the volume of whole blood (11). Factor IX concentrate (which is rich in protein C) or Warfarin po. In the preterm infants. Granulopaenia suggests sepsis. SICK INFANTS I) Decreased platelets. fresh platelet concentrates (1 unit usually has 30 cc) can be given every 12 to 24 hours. Secondly. Also the presence of giant platelets on smear indicates hyperutilization rather than poor production. A rise in fibrin degradation products occurs. PTT is generally not regarded as a useful screening test because of the wide range of normal values (12). wbc & differential. DIFFERENTIAL DIAGNOSIS (Table 3) CBC with platelet count. and also whether the bleeding is generalised or localised. The latter is a manifestation of DIG. Less rise than this suggests either improper collection of platelets.e. encephalitis. Commercial kits are now available in (he market. are sufficient to eliminate thrombotic complications. Normal counts suggest inherited factor deficiency. Firstly the paediatrician must ensure there is a proper dilution of the infant's blood with an anticoagulant.000/mm3. In the physical examination. e. One unit should raise the platelet count to 100. other laboratory tests may be of value in arriving at a diagnosis. Any PT greater than 17 sec in a neonate of any gestational age & a PTT greater than 45 to 50 sec in a term infant should be considered abnormal. Fresh frozen plasma (FFP) 10-15 ml/kilo/12 hr. The presence of platelet clumps in low power field would indicate platelet count is adequate. normal values vary from one laboratory to another. term infants have more prolonged PT & PTT than older children and adults. Serious generalised bleeding can occur in DIG. ii) Prothrombin time (PT) and partial thromboplastin time (FIT). outdated platelets or hyperutilization. platelet) including most importantly a blood smear. There is less tendency to use heparin in the treatment of DIG now unless there is evidence of large vessel thrombosis.g. factor VIII. some instances of maternal drug ingestion or local causes such as pulmonary or intraventricular haemorrhage as seen in preterm infants. smear. A useful screening test for factor XIII deficiency is by demonstrating the infant's fibrin clot is soluble in 5 M urea. Generally speaking. FIBRIN DEGRADATION PRODUCTS (FDP) Since fibrinolysis is an integral part of blood coagulation. 1 unit of fresh platelets will also raise the various clotting factors by 20% of normal.Seminar in Paediatrics: usually within 24 hrs of age while that due to protein C deficiency time of onset of purpura varies from 2 hrs (9) to 6 days of age (10). Therapy is aimed at treating the underlying disorder (e.5 mg Warfarin/day p.8% trisodium citrate to 9 parts of blood without taking into consideration of the Hct level would result in excess of citrate. Therefore blood for coagulation studies should not be taken via an indwelling venous or arterial catheter containing heparin even if it has been flushed with normal saline. A rough estimate of the platelet count can be achieved by counting the number of platelets in 10 oil fields and multiply that number by 2000. The Bleeding Newborn The PT and PTT are global tests of the entire blood coagulation mechanism. shock or tissue necrosis. Individual factor assays e.g. 170 cc/kilo may be helpful. microcephaly and generalised petechiae. It has been found every other day infusions of 50-75 units/kilo of protein C are sufficient to stop the thrombotic episodes. In symptomatic patients. PTT is influenced by minute quantity of heparin. In patients who continue to bleed in spite of intensive replacement therapy. activation of fibrinolytic system. They would give the number of platelet per mm3.e. the paediatrician should determine whether the infant is "sick" or "well". This approach is obviously not a practical long term therapeutic regime as it will eventually lead to hyperproteinaemia. once or twice a day. Low counts suggest a process of either excessive consumption (e.o. Protein G deficiency can either present as massive thrombosis of blood vessels or purpura fulminans. accompanied in some instances by a picture of DIC) skeletal anomalies such as bilateral absence of radii in so-called TAR (thrombocytopaenia and absent radii) syndrome characterised by congenital hypomegakaryocytic thrombocytopaenia and bilateral absence of radius and evidence of intrauterine infection such as hepatosplenomegaly. More than 10% schisocytes (fragmented rbc) suggests microangiopathy such as DIG. 10 ml/kilo of fresh frozen plasma. "2 volume exchange" transfusion with fresh blood i. infection). PT & PTT are useful tests to be done. Alternate methods include the use of I. sepsis-like picture. hypoxia. LABORATORY TESTS Screening tests should include the following: i) Complete blood count (Hb. will replace all clotting factors (including protein G) and allows adjustment of blood (but not rbc) volume. Because of the relatively large volume of fresh plasma present. with excessive clot formation there is an increase in clot lysis i.

heparinization Local causes eg. PTT Healthy infants with early onset of generalised petechiae and thrombocytopaenia usually have immune-mediated thrombocytopaenia (13). IV) Normal platelet count & normal PT & PTT These laboratory findings are seen in severely ill. Here the mother is platelet antigen PLA-1 negative. In case of liver disease. They are generally unresponsive to vitamin K administration.V.g. Treatment should be directed to the underlying disorder. Reversal of heparin effect can be accomplished by administering protamine on a mg-for-mg basis. IX or 86 . Vit. III) Normal platelets. Affected infants with a platelet count of less than 30 x 109/1 or are symptomatic should be infused with maternal platelets washed and resuspended in AB + ve plasma. a result of multiple clotting deficiencies. Prophylactic use of Vit. III) Normal platelets. ) Maternal drug intake Liver disease. Vit. and the fetus is PLA-1 + ve.V. increased PT & PTT The above findings are found in neonates suffering from haemorrhagic disease of the newborn which typically occurs between 2nd to 4th day of life. immunoglobulin (14). PT and increased PTT This is seen in factor deficiency e. 39. excharge transfusion with fresh blood and I. HEALTHY NEWBORNS I) Decreased platelets. increased PT & PTT This may be either sign of severe 'liver disease or heparinization. Autoimmune thrombocytopaenia can also be associated with other maternal disorders such as systemic lupus erythematosus. The bleeding is the result of local vascular damage. normal PT & PTT Peripheral destruction of platelets without DIC is commonly seen in infants with infection (viral or bacterial) and tissue necrosis (NEC . 1987 Platelets Sick Infants 1 PT t N t N t N N N PTT T N T N t N Likely diagnosis DIC (including protein C deficiency) Platelet consumption (eg. Fetal platelets enter into maternal circulation early in pregnancy resulting in the production of anti PLA-1 antibody.V. A jaundiced patient with an enlarged liver on P/E with direct hyperbilirubinaemia and elevated liver on P/E with direct hyperbilirubinaemia and elevated liver enzymes will help the paediatricians to make the diagnosis.Journal of the Hong Kong Medical Association Vol. (Vit. Current therapy includes the administration oi corticosteroid to the mother during the last 2 weeks of pregnancy. preterm infants who have massive intracranial or pulmonary haemorrhages without evidence of coagulation defect. transfuse patients with platelets. lymphoproliferative disorders or hyperthyroidisms. K1. infection.V. factor VIII.25 mg/day to keep the prothrombin time 2 x 3 times above normal can also be an effective form of treatment to be supplemented either by FFP or cryoprecipitate if necessary (7). qualitative platelet abnormalities. normal PT. K1 injection. the mother's platelet count is normal and there is no history of maternal bleeding. Thrombocytopaenia may result from hypersplenism. fetal scalp sampling and delivery by Caesarian section with those who are severely affected. 2) Isoimmune thrombocytopaenia In contrast to neonatal autoimmue thrombocytopaenia secondary to maternal ITP. II) Normal platelets. Shortening of PT & PTT is seen within 4-6 hours of I. B.2. Rarely. No. and in case of bleeding. Treatment consists of infusion of FFP and administration of 1 mg I. PT may be increased out of proportion to PTT. lines open. antibodies are directed against HLA antigens and may cause lymphopenia and/or neutropaenia. Treatment includes Vitamin K & FFP administrations. Decreased platelets with normal PT & PTT may be secondary to underproduction of platelets as seen in patients with congenital leukaemia and with TAR (Thrombocytopenia with absent radii) syndrome. renal vein thrombosis & necrotising enterocolitis. K deficiency) Immune thrombocytopaenia occult infection or thrombosis. Treatment with blood products is of no help to control the bleeding. bone marrow hypoplasia (rare) Hereditary clotting factor deficiencies Bleeding due to local factors. ulcers or any other compromised vascular integrity Haemorrhagic disease of N. Newborn infants may be inadvertently "heparinized" by use of heparin to keep I. F XIII deficiency I N N Healthy Infants N I N N r N Table 3 Differential diagnosis of bleeding in the neonate increasing 0. K has virtually eliminated haemorrhagic disease of the newborn.mother has ITP and the presence of thrombocytopaenia in the offspring due tc transplacental passage of an IgG antiplatelet antibody. administration of corticosteroid to the affected neonate platelet transfusion. There may be a history oi previously affected infant. There are two main types: 1) Autoimmune thrombocytopaenia . The A/B crosses the placenta and enter into the fetal circulation which results in destruction of the baby's PLA-1 + ve platelets. there may be generalised bleeding as . II) Decreased platelets.necrotizing enterocolitis).

B. FFP may be used. 12. 69:714-718. Thromb. 58. therapy should always be aimed at the primary disorder.A. 1984. 1:53-56.Seminar in Paediatrics : The Bleeding Newborn Disorder . 20:1298-1303.M. J. J. 3:661-681. 2. 5. Yuen P et al: Purpura fulminans in a Chinese boy with congenital protein C deficiency. Clin. 11. Cryoprecipitate may be used and in haemophilia B (F IX deficiency) in the presence of life-threatening haemorrhage F IX concentrate should be used. Clouse LH.V. 87 .Qualitative platelet abnormality . N. 77. Thromb. Malar RA: Protein C in thromboembolic disease. 3:409-413. Pediatrics 1976. Stuart MJ. Hathaway WE: 1CTH Subcommittee on neonatal hemostasis. Ped. 33. 13. 1986. 2-3x above normal 1mg I. Grune & Stratton 1978. Ped.T. 10. 314. Platelet aggregation studies will confirm the diagnosis. In severe haemorrhage in haemophilia A (Factor VIII deficiency). Semin. Bleeding as a result of qualitative platelet abnormalities generally responds to platelet transfusions./Onc. & Haemostas 1985. 1986. Estelles A et al: Severe inherited "homozygous" protein C deficiency in a newborn infant. Hathaway WE Bonnar J. For specific diagnosis. 4. of Ped. 14. 7. Pediatrics 1982. Factor XIII deficiency or a qualitative platelet disorder such as maternal Aspirin ingestion. Clin. 105. 1960. hepatitis and AIDS. Vit K1 Table 4 Haemostatic therapy in N.Sepsis Afibringenaemia Haemophilia A Moderate bleeding Severe bleeding Von Willebrand Haemophilia B Moderate bleeding Severe bleeding Life-threatening Other factor deficiencies Product Platelet Concentration 7-8 x 1010 platelets/u Dose 1 u/5 kilo q 12-24 hrs Cryoprecipitate 200-300 mg/bag Fibrinogen 75-100 u VIIIc/bag 75-100 u VIIIc/bag 75-100 u VIIIc/bag 1 F IX u/ml 1 F IX u/ml 20 F IX u/ml 1 bag/3 kilo Cryoprecipitate Cryoprecipitate Cryoprecipitate FFP FFP F IX concentrate 20 u/kilo 50 u/kilo 20 u/kilo 10-15 u/kilo 20-25 u/kilo 50-75 u/kilo 10-15 ml/kilo FFP DIC FFP Fresh whole blood Heparin 10-15 ml/kilo 2-volume exchange (170ml/kg) 50 u/kg loading dose. assay of specific factor must be obtained. Thromb. 52. Allen JB: Arachidonic acid metabolism in the neonatal platelet. Glader BE. 1986. 1:227234. Blood products (Table 4) should only be used when they are absolutely necessary because of the danger of introducing CMV. local vascular lesions such as an ulcer. & Haemostas.25 to 0. REFERENCES 1. 6. A. Buchanan GR: The bleeding neonate.J. 4:387-393. Suppl. 3. 2:359-391. Invest. 1964. Colvin BT: Thrombocytopenia: Clinics in haematology 1985. 8. returns to normal Vit K def. Stuart MJ: Platelet function in the neonate. Kelton J: Neonatal thrombocytopaenia: Clinics in perinatology 1984. Sills RH et al: Severe protein C deficiency.25 mg/d to keep P. J. 51:1-117. followed by 20-25 u/kg/hr Protein C deficiency FFP F IX conc Warfarin 15-30 Protein C u/ml 10-15 ml/kg q12hr 50-75 u/kilo 0. PT & PTT The above findings can be seen in patients with local trauma. 9. 4:548-555. 11. Hem. Comp PC: The regulation of haemostasis: The protein C system. 14. 55. Andrew M. In the case of moderate haemorrhage. IV) Normal platelets. von Willebrand's disease. Hellem AJ: Scand.5 mg/day po ^0. & Haemostas. Pediatrics 1986. & weekly until P.T. In the treatment of bleeding neonate. of N. 5:670-676. Lab.E.: Perinatal coagulation. 1:145. 1:203-220. 11. Buchanan GR: Coagulation disorders in the neonate. 1979.

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