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

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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). History taking should include the following questions. 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, vitamin K deficiency, isolated clotting factor deficiencies, maternally derived drug problem or a localised vascular lesion such as an ulcer or haemangioma. "Sick" infants (babies often with perinatal infection, tissue necrosis, hypoglycaemia, hypoxia, acidosis or problems related to prematurity or dysmaturity) have DIG or consumptive thrombocytopaenia. Infants with congenital protein C deficiency can present in the neonatal period with either

the occurrence of an unusally large cephahaematoma, subgaleal and intracranial haemorrhage following the relatively uncomplicated birth of an infant can be the presenting signs. 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. Any infant who has prolonged bleeding following a heel prick, needle puncture for blood taking or circumcision should be suspected of having a bleeding disorder. Neonatal bleeding secondary to von Willebrand's disease is rare, if it occurs at all. 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. Bleeding characteristically occurs between the second and fourth day of life. These consist of G-I bleeding, expistaxis, subgaleal and intracranial haemorrhages. A single parenteral dose of 0.5 to 1.0 mg or oral dose of 1.0 to 2.0 mg Vitamin K, is recommended for prophylaxis (8). IV) Is the bleeding generalised or localised? Localised bleeding e.g. 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. Generalised bleeding is almost always a coagulation abnormality, the cause of which is usually complicated and multifaceted e.g. DIC, Vitamin K deficiency or severe liver disease. V) History of maternal illness. Does the mother have lupus erythematosus? Has she had or does she now have ITP? Has she had eclampsia? VI) History of maternal infection. Is there any evidence of maternal or fetal infection with GMV, rubella, toxoplasma, coxsackie virus, herpes simplex and syphilis? VII) History of maternal drug intake e.g. drugs given to mother that can affect infant's haemostasis.
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. 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, < 1% activity), haemophilia B (factor IX deficiency), factor XIII deficiency and afibrinogeaaemia. Bleeding from the umbilical stump and

VIII) Age of onset of bleeding. Bleeding clue to Vit K deficiency occurs usually at 2nd to 4th day of age. Immune thrombocytopaenia causes bleeding

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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). PHYSICAL EXAMINATION In physical examination, the paediatrician should determine whether the infant is "sick" or "well", and also whether the bleeding is generalised or localised. These observations to be correlated with the history will help to define the pathophysiology underlying the hemorrhage. In the physical examination, one should also look for localised clues such as the presence of a giant hemangioma (platelet trapping can occur, 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, sepsis-like picture, encephalitis, microcephaly and generalised petechiae. LABORATORY TESTS Screening tests should include the following: i) Complete blood count (Hb, wbc & differential, platelet) including most importantly a blood smear. ii) Prothrombin time (PT) and partial thromboplastin time (FIT). Depending on the clincial picture and results of screening tests, other laboratory tests may be of value in arriving at a diagnosis. 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. Normal counts suggest inherited factor deficiency, Vitamin K deficiency, some instances of maternal drug ingestion or local causes such as pulmonary or intraventricular haemorrhage as seen in preterm infants. Low counts suggest a process of either excessive consumption (e.g DIC) which is more common or poor production (rare). Every practising doctor should be able to interpret a blood smear. The presence of platelet clumps in low power field would indicate platelet count is adequate. 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. They would give the number of platelet per mm3. Also the presence of giant platelets on smear indicates hyperutilization rather than poor production. More than 10% schisocytes (fragmented rbc) suggests microangiopathy such as DIG. Granulopaenia suggests sepsis. COAGULATION SCREENING TESTS (PT, PTT) A word of caution concerning the interpretation of these tests must be made. Firstly the paediatrician must ensure there is a proper dilution of the infant's blood with an anticoagulant. The standard ratio of 1 part 3.8% trisodium citrate to 9 parts of blood without taking into consideration of the Hct level would result in excess of citrate. When the Hct is > 55% the anticoagulant must be reduced i. e. the anticoagulant ratio must be based on plasma volume rather than the volume of whole blood (11). Secondly, normal values vary from one laboratory to another. Generally speaking, term infants have more prolonged PT & PTT than older children and adults. Such prolongation of PT & PTT is even more pronounced in the pre-term infants.

The Bleeding Newborn The PT and PTT are global tests of the entire blood coagulation mechanism. The PT measures the extrinsic coagulation pathway & PTT assesses the intrinsic clotting system. 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. In the preterm infants, PTT is generally not regarded as a useful screening test because of the wide range of normal values (12). PTT is influenced by minute quantity of heparin. 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. Individual factor assays e.g. factor VIII, IX can be measured by one-stage prothrombin time test using plasmas congenitally deficient in the respective factors as substrates. A useful screening test for factor XIII deficiency is by demonstrating the infant's fibrin clot is soluble in 5 M urea. FIBRIN DEGRADATION PRODUCTS (FDP) Since fibrinolysis is an integral part of blood coagulation, with excessive clot formation there is an increase in clot lysis i.e. activation of fibrinolytic system. A rise in fibrin degradation products occurs. PROTEIN C ASSAY Protein C level can be measured by the method of enzyme-linked immunosorbent assay (ELISA). Commercial kits are now available in (he market. DIFFERENTIAL DIAGNOSIS (Table 3) CBC with platelet count, smear, PT & PTT are useful tests to be done. SICK INFANTS I) Decreased platelets, increased PT & PTT This can be the result of DIG secondary to infection, hypoxia, shock or tissue necrosis. Protein G deficiency can either present as massive thrombosis of blood vessels or purpura fulminans. The latter is a manifestation of DIG. Serious generalised bleeding can occur in DIG. This includes oozing from needle puncture sites and GI bleeding. Therapy is aimed at treating the underlying disorder (e.g. infection). In symptomatic patients, fresh platelet concentrates (1 unit usually has 30 cc) can be given every 12 to 24 hours. One unit should raise the platelet count to 100,000/mm3. Less rise than this suggests either improper collection of platelets, outdated platelets or hyperutilization. Because of the relatively large volume of fresh plasma present, 1 unit of fresh platelets will also raise the various clotting factors by 20% of normal. Fresh frozen plasma (FFP) 10-15 ml/kilo/12 hr. will replace all clotting factors (including protein G) and allows adjustment of blood (but not rbc) volume. In patients who continue to bleed in spite of intensive replacement therapy, "2 volume exchange" transfusion with fresh blood i.e. 170 cc/kilo may be helpful. There is less tendency to use heparin in the treatment of DIG now unless there is evidence of large vessel thrombosis. In patients with homozygous protein C deficiency, 10 ml/kilo of fresh frozen plasma, once or twice a day, are sufficient to eliminate thrombotic complications. This approach is obviously not a practical long term therapeutic regime as it will eventually lead to hyperproteinaemia. Alternate methods include the use of I.V. Factor IX concentrate (which is rich in protein C) or Warfarin po. It has been found every other day infusions of 50-75 units/kilo of protein C are sufficient to stop the thrombotic episodes. In the neonates, 0.25 to 0.5 mg Warfarin/day p.o.
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Journal of the Hong Kong Medical Association Vol. 39, No.2, 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. infection, renal vein thrombosis & necrotising enterocolitis. ) Maternal drug intake Liver disease, heparinization Local causes eg. ulcers or any other compromised vascular integrity Haemorrhagic disease of N. B. (Vit. K deficiency) Immune thrombocytopaenia occult infection or thrombosis, bone marrow hypoplasia (rare) Hereditary clotting factor deficiencies Bleeding due to local factors, qualitative platelet abnormalities. F XIII deficiency

I
N N

Healthy Infants

N I N N

r
N

Table 3 Differential diagnosis of bleeding in the neonate

increasing 0.25 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). II) Decreased platelets, normal PT & PTT Peripheral destruction of platelets without DIC is commonly seen in infants with infection (viral or bacterial) and tissue necrosis (NEC - necrotizing enterocolitis). Treatment should be directed to the underlying disorder, and in case of bleeding, transfuse patients with platelets. 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. III) Normal platelets, increased PT & PTT This may be either sign of severe 'liver disease or heparinization. In case of liver disease, there may be generalised bleeding as . a result of multiple clotting deficiencies. They are generally unresponsive to vitamin K administration. Thrombocytopaenia may result from hypersplenism. 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. Treatment includes Vitamin K & FFP administrations. Newborn infants may be inadvertently "heparinized" by use of heparin to keep I.V. lines open. Reversal of heparin effect can be accomplished by administering protamine on a mg-for-mg basis. IV) Normal platelet count & normal PT & PTT These laboratory findings are seen in severely ill, preterm infants who have massive intracranial or pulmonary haemorrhages without evidence of coagulation defect. The bleeding is the result of local vascular damage. Treatment with blood products is of no help to control the bleeding. HEALTHY NEWBORNS I) Decreased platelets, normal PT, PTT Healthy infants with early onset of generalised petechiae and thrombocytopaenia usually have immune-mediated thrombocytopaenia (13). There are two main types:

1) Autoimmune thrombocytopaenia - mother has ITP and the presence of thrombocytopaenia in the offspring due tc transplacental passage of an IgG antiplatelet antibody. Autoimmune thrombocytopaenia can also be associated with other maternal disorders such as systemic lupus erythematosus, lymphoproliferative disorders or hyperthyroidisms. Current therapy includes the administration oi corticosteroid to the mother during the last 2 weeks of pregnancy, fetal scalp sampling and delivery by Caesarian section with those who are severely affected, administration of corticosteroid to the affected neonate platelet transfusion, excharge transfusion with fresh blood and I.V. immunoglobulin (14). 2) Isoimmune thrombocytopaenia In contrast to neonatal autoimmue thrombocytopaenia secondary to maternal ITP, the mother's platelet count is normal and there is no history of maternal bleeding. Here the mother is platelet antigen PLA-1 negative, and the fetus is PLA-1 + ve. Fetal platelets enter into maternal circulation early in pregnancy resulting in the production of anti PLA-1 antibody. The A/B crosses the placenta and enter into the fetal circulation which results in destruction of the baby's PLA-1 + ve platelets. Rarely, antibodies are directed against HLA antigens and may cause lymphopenia and/or neutropaenia. There may be a history oi previously affected infant. 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. II) Normal platelets, 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. PT may be increased out of proportion to PTT. Treatment consists of infusion of FFP and administration of 1 mg I.V. Vit. K1. Shortening of PT & PTT is seen within 4-6 hours of I.V. Vit. K1 injection. Prophylactic use of Vit. K has virtually eliminated haemorrhagic disease of the newborn. III) Normal platelets, PT and increased PTT This is seen in factor deficiency e.g. factor VIII, IX or

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Seminar in Paediatrics :

The Bleeding Newborn

Disorder - Qualitative platelet abnormality - 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, 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 0.25 to 0.5 mg/day po ^0.25 mg/d to keep P.T. 2-3x above normal 1mg I.V. & weekly until P.T. returns to normal

Vit K def.

Vit K1

Table 4 Haemostatic therapy in N. B. von Willebrand's disease. For specific diagnosis, assay of specific factor must be obtained. In the case of moderate haemorrhage, FFP may be used. In severe haemorrhage in haemophilia A (Factor VIII deficiency), Cryoprecipitate may be used and in haemophilia B (F IX deficiency) in the presence of life-threatening haemorrhage F IX concentrate should be used. IV) Normal platelets, PT & PTT The above findings can be seen in patients with local trauma, local vascular lesions such as an ulcer, Factor XIII deficiency or a qualitative platelet disorder such as maternal Aspirin ingestion. Platelet aggregation studies will confirm the diagnosis. Bleeding as a result of qualitative platelet abnormalities generally responds to platelet transfusions. In the treatment of bleeding neonate, therapy should always be aimed at the primary disorder. Blood products (Table 4) should only be used when they are absolutely necessary because of the danger of introducing CMV, hepatitis and AIDS.
REFERENCES 1. Hathaway WE Bonnar J.: Perinatal coagulation. Grune & Stratton 1978. 2. Stuart MJ: Platelet function in the neonate. A. J. Ped. Hem./Onc. 1979; 1:227234. 3. Stuart MJ, Allen JB: Arachidonic acid metabolism in the neonatal platelet. Pediatrics 1982; 69:714-718. 4. Clouse LH, Comp PC: The regulation of haemostasis: The protein C system. N.E.J.M. 1986; 314, 20:1298-1303. 5. Malar RA: Protein C in thromboembolic disease. Semin. Thromb. & Haemostas 1985; 11, 4:387-393. 6. Glader BE, Buchanan GR: The bleeding neonate. Pediatrics 1976; 58, 4:548-555. 7. Yuen P et al: Purpura fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics 1986; 77, 5:670-676. 8. Hathaway WE: 1CTH Subcommittee on neonatal hemostasis. Thromb. & Haemostas. 1986; 55, 1:145. 9. Estelles A et al: Severe inherited "homozygous" protein C deficiency in a newborn infant. Thromb. & Haemostas. 1984; 52, 1:53-56. 10. Sills RH et al: Severe protein C deficiency. J. of Ped. 1964; 105, 3:409-413. 11. Hellem AJ: Scand. J. Clin. Lab. Invest. Suppl. 1960; 51:1-117. 12. Buchanan GR: Coagulation disorders in the neonate. Ped. Clin. of N.A. 1986; 33, 1:203-220. 13. Andrew M, Kelton J: Neonatal thrombocytopaenia: Clinics in perinatology 1984; 11, 2:359-391. 14. Colvin BT: Thrombocytopenia: Clinics in haematology 1985; 14, 3:661-681.

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