COAGULATION AND HEMATOLOGY The bleeding neonate [haematologica reports] 2006;2(10):66-70 ABSTRACT S.ARONIS-VOURNAS Director Haemophilia The neonate is born with a combined deficiency in plasma coagulation factors, natural Center, Haemostasis Unit, inhibitors of haemostasis and components of the fibrinolytic system. In the healthy Aghia Sophia Children’s Hospital, neonate, there is a balance between haemostatic systems, therefore under normal circum- Athens, Greece stances, the healthy neonate does not present haemorrhage or thrombosis. However sev- eral coagulation disorders, congenital or acquired, may be expressed during the neona- tal period in a healthy or diseased neonate. Haemophilia A, B (Haem-A, B) and von Wille- brand disease (vWD) are the most common inherited coagulation disorders, whereas con- genital deficiencies of FI, FII, FV, FVII, FX, FXI, FXII or FXIII occur rarely. Cephalematoma, intracranial haemorrhage (ICH), bleeding from the umbilicus cord may be the first signs of congenital FXIII, FVII or FVIII deficiency. Acquired coagulation plasma factors deficien- cy is usually associated with vitamin K deficiency (early, classic, late haemorrhagic dis- ease, secondary haemorrhagic disease), liver insufficiency (hepatitis, metabolic diseases e.t.c) or disseminated intravascular coagulation, complicating severe sepsis. Platelets are produced from the 11th gestational week of the foetus. The healthy neonate, full-term or premature, is born with a normal platelet value (>150x109/L). Any value <100x109/L should be investigated. Thrombocytopenia is frequent in the neonatal period (0.7-0.9%), where- as it occurs in 20-40% of patients in a neonatal intensive care Unit. 20-40% of the cas- es are of unknown aetiology. Congenital quantitative (Tarr, Wiskott-Aldrich syndrome, amegakaryocytic thrombocytopenia, Alport syndrome, Fanconi’s anaemia, vWD type II, Mediterranean megathrombocytopenia, Flechtner syndrome, Sebastian anomaly, Trousseau syndrome, Chediak-Higashi syndrome) or qualitative platelet disorders (Glanz- man, Bernard-Soulier syndrome, May Hegglin anomaly), are rare. On the contrary, acquired thrombocytopenias or thrombasthenias occur more often. Thrombocytopenia due to increased platelet destruction is usually associated with several diseased states (bacterial/viral infections, fungal or protozoal infections) or an immune mechanism (autoimmune, isoimmune thrombocytopenia). The risk of ICH is higher in neonates with isoimmune thrombocytopenia. Finally, secondary thrombasthenias are most often asso- ciated with antibiotics anti-inflammatory drugs, anti-histamines, indomethacin e.t.c. Haemostasis screening includes thrombin time, prothrombin time, APTT, platelet count, clot retraction and bleeding time. Further investigation unmasks the defect and deter- mines the necessity and type of therapeutic intervention, taking under consideration the bleeding manifestations and infant’s clinical condition. he healthy neonate is born with com- platelets appear with a transient functional bined defects; coagulation factors II, VII, defect. The severity of the above haemosta- TIX, X, XI, XII, XIII are decreased. Natural tic abnormalities depends on the maturity inhibitors of haemostasis (TFPI, AT, PC, PS) of the liver, the gestational age, and the birth are also reduced; however, free PS is nor- weight of the neonate. However, in spite of mal. C4BP (C4 Binding Protein), which binds the multiple haemostatic defects, a dynam- PS, is deficient in the newborn. Of the anti- ic equilibrium is maintained amongst the coagulants a2MG is increased during infan- coagulation systems, thus under normal cir- cy. Plasminogen (plg), and tissue plasmino- cumstances, the healthy neonate does not gen activator (tpA) are decreased, however bleed or thrombose. Congenital or acquired plasminogen activator inhibitor (PAI) and disorders of haemostasis associated with a2-antiplasmin (a2AP) are increased. The underlying diseases may tip off the equilib- latter abnormalities are expressed by a rium towards either direction. Bleeding in decreased fibrinolytic activity. Platelets are the neonate may be the result of congenital produced from the 11th week of foetal life or acquired haemostasis disorders, which and are normal at birth, regardless of the may be the result of platelet disorders, plas- maturity of the newborn; nevertheless, ma factors deficiency or both. 66 haematologica reports 2006; 2(issue 10):September 2006 Vth International Neonatal Hematology and Immunology Meeting, Brescia, Italy Platelet disorders Table 1. Congenital thrombocytopenias. Quantitative platelet disorders Thrombocytopenia (TP) is considered any platelet Tarr syndrome value below 150x109/L (normal values; 150-400 Wiskott-Aldrich syndrome 9 9 Amegakaryocytic thrombocytopenia x10 /L). Platelets count <100x10 /L should be investi- Alport syndrome gated. The incidence of TP in the neonatal population Fanconi’s anaemia is 0.7-0.9%, and in ICU (intensive care units) 20-40%. Von Willebrand disease type IIb 20-40% of the cases are of unknown aetiology. Of the Mediterranean macrothrombocytopenia thrombocytopenic neonates, 20% present platelet Bernard- Soulier syndrome count <50x109/L. In this group of patients the mortal- May-Hegglin anomaly ity rate is high, as is the rate of neurological sequelae, Sebastian syndrome following an intracranial haemorrhage (ICH). Fechtner syndrome Trousseaux syndrome Chediak-Higashi syndrome Congenital thrombocytopenias Patients with congenital TPs may have one or more of the following characteristics; macrothrombocytope- nia/microthrombocytopenia, immunological defects, Table 2. Acquired thrombocytopenias. skeleton abnormalities, mental retardation, deafness / cataract/albinism, renal dysfunction, cardiac defect Congenital neuroblastoma e.t.c. The mode of inheritance may be sex linked Congenital leukaemia Letterer Swive (rarely) or autosomal, recessive or dominant. Bacterial/viral infections Tarr syndrome (TP + absent radii), Wiskott Aldrich Fungal/protozoal infections syndrome (TP + low platelet volume + immunologic Immune thrombocytopenia defect + eczema, x-linked transmission), amegakaryo- DIC (disseminated intravascular coagulation) cytic thrombocytopenia (TP without limb abnormali- Necrotizing enterocolitis ties) are rare quantitative platelet disorders. Alport Kasabach-Merritt syndrome syndrome (macrothrombocytopenia + renal function- HELLP syndrome al defect + congenital abnormalities), Fanconi’s Torch syndrome anaemia (pancytopenia + congenital abnormalities, RDS Phototherapy autosomal recessive inheritance) are known congeni- HUS/TTP tal syndromes. von Willebrand disease type IIb Neonatal hyperviscosity syndrome (macrothrombocytopenia, abnormal platelet aggluti- TP after exchange transfusions nation + low vWF, autosomal dominant transmission), Metabolic diseases Mediterranean macrothrombocytopenia (low grade TP Intrauterine growth retardation + macrothrombocytes, autosomal dominant inheri- tance), Bernard-Soulier syndrome (glycoprotein Ib deficiency + macrothrombocytopenia + abnormal platelet agglutination, autosomal recessive inheri- platelet production may be caused by bone marrow tance), May - Hegglin anomaly, Sebastian anomaly infiltration, as in congenital neuroblastoma, congeni- (autosomal dominant inheritance) are all associated tal leukaemia or Letterer-Swive. TP due to increased with macrothrombocytopenia. Fechtner syndrome (TP platelet destruction may occur in the following disease + renal functional defect + cataract + inclusions in the states or conditions; bacterial or viral infections, fun- polymorfonuclear cells, autosomal dominant inheri- gal and protozoal infections, immune thrombocytope- tance), Trousseau syndrome (PT + 11q23 deletion + nias, DIC (disseminated intravascular coagulation), normal platelet volume + abnormal inclusions, auto- necrotizing enterocolitis, Kasabach-Merritt syndrome, somal dominant inheritance), Chediak-Higashi syn- HELLP syndrome, TORCH syndrome. TP may also occur drome ( TP + thrombocytopathy + immunologic defect in RDS, phototherapy, HUS/TTP (haemolytic uremic + albinism, autosomal recessive transmission) are rare syndrome/thrombotic thrombocytopenic purpura), disorders. neonatal hyperviscosity syndrome (congenital cyan- otic cardiac diseases), metabolic diseases, intrauterine Acquired thrombocytopenias growth retardation, after exchange transfusions e.t.c. The mechanism of acquired TPs may be the result of In neonatal sepsis, TP is an early laboratory evidence, decreased platelet production, abnormal release of both in septicaemia caused by Gram- or Gram+ bac- platelets from megakoryocytes, increased platelet teria. Progressive increase of platelet count (PC) is an destruction or a combination of them. Decreased indication of response to therapy, whereas persistence haematologica reports 2006; 2(issue 10):September 2006 67 S. Aronis-Vournas of TP is an indication of non-response to therapy and ening haemorrhage or PC < 10x109/L, therapeutic necessitates change in antibiotics. TP may occur as intervention with IVIG (1g/kg/d x 2d) is justified. isolated or at the setting of DIC. Washed platelets from the mother or compatible Neonatal Immune TP may be the result of platelet platelets from typed donors could be infused. If the destruction in the circulation due to an autoimmune neonate does not bleed, U/S is performed for docu- or alloimmune mechanism. Neonatal autoimmune TP mentation of a possible ICH. The overall duration of (NATP) may occur, if the mother suffers from ITP NITP is approximately