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.

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

Thrombocytopenia

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