Bleeding disorders

Newborns (preterm in particular) have relatively low levels of pro-coagulation factors (vitamin K dependent factors), diminished platelet functions (their levels are similar to adults), as well as low anti-coagulation factors (antithrombin III, protein C). Nevertheless, both pro- and anti-coagulation systems are in balance and hemorrhagic or thrombotic events are not usually observed. The levels of fibrinogen, factor V, 8 and 13 are comparable to values seen in adults.

ParameterTerm newbornsPreterm newborns
Platelets (x 109 / l)150 – 450150 – 450
Prothrombin time (PT)normalprolonged
Activated partial thromboplastin time (APTT)prolongedsignificantly prolonged
Fibrinogen (g/l)1.5 – 3.01.5 – 3.0

The basic division of bleeding disorders in newborns:

  • thrombocytopenia
    → congenital (infection) or inherited (genetic syndromes)
    → acquired (immune thrombocytopenia)
  • coagulation deficits
    → hemorrhagic disease of newborn (morbus hemorrhagic neonatorum)
    → disseminated intravascular coagulopathy (DIC)
    → hemophilia

TROMBOCYTOPENIA

Congenital and inherited thrombocytopenia

  • congenital (intrauterine infection – cytomegalovirus)
  • inherited (genetic syndromes – trisomy 13, 18, 21, TAR (Thrombocytopenia with Absent Radius), Wiskott-Aldrich)

Alloimmune thrombocytopenia

  • Human Platelet Antigen (HPA 1-5) on fetal thrombocytes (inherited after father) => missing in maternal platelets => platelets crossing placenta during pregnancy sensitize mother to produce antibodies IgG => crossing placenta to cause fetal/neonatal thrombocytopenia => petechiae, hemorrhage (can be severe)
  • clinically most relevant = HPA-1
  • postnatal gradual reduction in antibodies titre and restoration of platelet counts in newborns => however, subsequent pregnancies can have worse course with more severe thrombocytopenia
  • diagnosis: cordocentesis and full blood count with thrombocytes
  • therapy:
    antenatal => immunoglobulins to mother; thrombocyte infusion to fetus; C-section indicated due to risk of hemorrhage during vaginal delivery
    postnatal => immunoglobulins; thrombocyte infusion (HPA-1 negative from donor or mother); exchange transfusion

Autoimmune thrombocytopenia

  • newborns of mothers with autoimmune thrombocytopenia
  • antibodies against both mother and newborn (see alloimmune thrombocytopenia above)
  • the severity of thrombocytopenia does not have to correlate between mother and newborn
  • therapy:
    antenatal => C-section if maternal platelets < 50 x 109 / l
    postnatal => immunoglobulins; thrombocyte infusion (HPA-1 negative from donor or mother); corticosteroids; exchange transfusion

Other thrombocytopenia

  • maternal factors (preeclampsia, lupus erythematodes)
  • consumption (sepsis, polycythemia, cavernous hemangiomas, congenital infection – CMV)

COAGULATION DEFICITS

Hemorrhagic disease of newborn

  • deficiency of vitamin K-dependent coagulation factors (2, 7, 9, 10)
  • breastmilk contains small amounts of vitamin K
  • early form => gastrointestinal bleeding (hematemesis, melena) during the first days of life
  • late form => subdural hemorrhage during the first weeks of life
  • diagnosis: normal thrombocytes, prolonged PT, normal APTT
  • therapy: vitamin K 1 mg, fresh frozen plasma (FFP), coagulation factors
  • prevention: vitamin K given after birth
    → intramuscular (1 mg for term / 0.5 mg for preterm infants, one time)
    → oral (2 mg, then 1 mg once weekly for 12 weeks)

Disseminated intravascular coagulopathy (DIC)

  • can be caused by a number of conditions (perinatal asphyxia, cardiac failure, sepsis)
  • intravascular coagulation => thrombotic complications => consumption of platelets and coagulation factors => bleeding symptoms (hemorrhage in the skin, mucosa, organs)
  • diagnosis: thrombocytopenia, low fibrinogen, antithrombin III (AT III), prolonged coagulation times, elevated D-dimers
  • therapy: treatment of the original cause of DIC, thrombocyte infusion, fresh frozen plasma (FFP), coagulation factors, AT III

Hemophilia

  • hemophilia A (factor 8 deficiency), hemophilia B (factor 9 deficiency) => X-linked => males are symptomatic
  • clinical findings depend on the level of coagulation factors => bleeding from the umbilical stump, soft tissue (subgaleal hemorrhage), intracranial haemorrhage
  • diagnosis: significantly prolonged APTT, other parameters normal; antenatal diagnosis possible (hemophilia A)

Von Willebrand disease (vWD)

  • quantitative or qualitative deficiency in vWF (von Willebrand factor) that serves as a factor 8 carrier and associates with adhesion and aggregation of platelets
  • less significant hemorrhagic symptoms than hemophilias (affects both males and females)
  • Type 1 (60-80 % of vWD cases) = quantitative (mostly asymptomatic – problems after surgery, dental procedures, menorrhagia)
  • Type 2 (15-30 % of vWD cases) = qualitative
    → 2A => inability to form large vWF multimers
    → 2B => enhanced ability of defective vWF to bind to glycoprotein Ib (GPIb) receptor on platelets, leading to spontaneous binding to platelets their rapid clearance together with large vWF multimers – causes thrombocytopenia (can occur in neonatal period; autosomal dominant)
    → 2M => decreased ability to bind to GPIb receptor on the platelet membrane
    → 2N => deficiency of the binding of vWF to coagulation factor 8
  • Type 3 = the most severe form of vWD (autosomal recessive) due to complete absence of production of vWF => low vWF and factor 8 => symptoms similar to hemophilia A
  • therapy: substitution of missing factors

Factor 13 deficiency

  • rare (autosomal recessive) disorder
  • bleeding from the umbilical stump in the first month of life (risk for intracranial hemorrhage)
  • diagnosis: coagulation tests normal, low level of factor 13
  • therapy and prevention: factor 13

REFERENCES

① Chakravorty S, Murray N, Roberts I. Neonatal thrombocytopenia. Early Hum Dev. 2005;81(1):35-41. doi:10.1016/j.earlhumdev.2004.10.013

② Ree IMC, Fustolo-Gunnink SF, Bekker V, Fijnvandraat KJ, Steggerda SJ, Lopriore E. Thrombocytopenia in neonatal sepsis: Incidence, severity and risk factors. PLoS One. 2017;12(10):e0185581. Published 2017 Oct 4. doi:10.1371/journal.pone.0185581