Neonatal Bleeding and Thrombotic Disorders

Key Points

Acquired or inherited coagulation disorders should be considered in any neonate that suffers significant hemorrhage.
Treatment for specific coagulation disorders should be provided in consultation with pediatric hematology and based on the most current guidelines.
Thromboembolism (TE) is a significant problem affecting both term and preterm neonates.
Most neonates that experience a significant TE event have acquired risk factors and/or a prothrombotic disorder.
Proper imaging is essential for accurately identifying neonatal TE events.
The use of central venous/arterial catheters significantly increases a neonate's risk for thrombosis.
Recommendations for treatment for neonatal TE events are based on expert opinion and data from case studies/series.
Care for neonates with coagulation disorders or significant TE events should occur in a tertiary referral center that has appropriate subspecialty support.

Neonatal bleeding and thrombotic disorders may present a diagnostic challenge to the caregiver. Excess and/or deficiencies of certain coagulation/anticoagulation proteins coupled with multiple acquired and/or prothrombotic risk factors and/or thrombocytopenia can result in a hemorrhagic or thromboembolic (TE) emergency in the neonatal period. The timely diagnosis of a congenital hemorrhagic disorder can potentially avoid significant long-term sequelae, while the lack of randomized clinical trials addressing the management of neonatal thromboses can leave a neonatologist guessing on what the optimum treatment strategy should be. In this chapter, we briefly review the neonatal hemostatic system. Neonatal hemorrhagic disorders are presented with a discussion of current treatment options. Congenital and acquired risk factors and common sites for neonatal thromboses are reviewed. Finally, suggested evaluations for neonates with TE emergencies as well as the latest treatment options are presented.

The Neonatal Hemostatic System

Blood vessel injury causes clinical bleeding, which can be severe. Hemostasis refers to the process in which bleeding is controlled at the site of damaged endothelium. The process of hemostasis involves the interaction between endothelium, subendothelium, platelets, circulating cells, and plasma proteins. Blood vessel injury leads to an immediate, local response of both plasma and cellular components. Thrombosis is confined to the area of injury, leading to eventual tissue repair. A model of hemostasis combining the vascular, platelet, and plasma phases is presented in . The result is a localized, firm thrombosis, leading to cessation of bleeding. The thrombosis then serves as a scaffold for tissue repair, leading to complete restoration of the endothelial lining. Fibrinolysis must then occur for blood vessel repair and return of blood flow ( ).

Hemostatic processes are regulated by natural anticoagulants ( ), whose job is to contain these processes to the site of injury and to prevent these reactions from becoming systemic and pathologic. Deficiencies in natural anticoagulant proteins, as well as decreased fibrinolysis in neonates, may lead to the formation of pathologic thromboses during the neonatal period, and these disorders are described later. The complex interaction of the hemostatic, fibrinolytic, and anticoagulant components of the hemostatic system results in a well-balanced machine that allows for hemostasis to occur at the site of injury and for fibrinolysis to follow, facilitating a localized tissue repair process.

Developmental Hemostasis

The neonatal hemostatic system differs significantly from that of older children and adults. The concentrations of the procoagulant, anticoagulant, and fibrinolytic proteins, compared with adults’, are shown in Table 67.1 , and age-related normal values should be referenced when assessing for bleeding or clotting abnormalities. Essentially, all the procoagulant proteins, except for fibrinogen, factors V and VIII, and von Willebrand factor (vWF), are lower. These lower levels are balanced by lower levels of anticoagulant proteins, except for alpha2-macroglobulin, which is the only anticoagulant protein that is elevated during the neonatal period. All the fibrinolytic proteins are reduced. These differences place a neonate in a “relative” prothrombotic state, but other factors balance the system and prevent a term or “well” premature neonate from experiencing spontaneous thrombosis. However, many acquired ( Table 67.2 ) and/or prothrombotic risk factors ( Box 67.1 ) may disrupt this balance, shifting the neonate into a prothrombotic state.

Table 67.1

Neonatal Coagulation/Anticoagulation/Fibrinolytic Protein Levels Compared With Adult Levels

Adapted from Manco-Johnson M. Controversies in neonatal thrombotic disorders. In: Ohls RY, ed. Hematology, Immunology and Infectious Disease: Neonatology Questions and Controversies . Philadelphia: Elsevier; 2008.

	Protein Levels Elevated Compared With Adult Values	Protein Levels Decreased Compared With Adult Values
Procoagulant	Fibrinogen Factor V * Factor VIII vWF	Factors II, VII, IX, X, XI, XII, XIII ^† Prekallikrein High-molecular-weight kininogen
Anticoagulant	Alpha2-macroglobulin	Antithrombin III Heparin cofactor II Protein C Protein S
Fibrinolytic	Tissue plasminogen activator Plasminogen activator inhibitor	Plasminogen α ₂ -antiplasmin

vWF , von Willebrand factor.

* Factor V levels are low on day of life 1 but reach adult values within days after birth.

† Levels are 50% of adult values.

Table 67.2

Acquired Risk Factors for the Development of Neonatal Thromboses

From Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Semin Perinatol . 2009;33:56; with permission. Data from the following references .

Maternal Risk Factors	Delivery Risk Factors	Neonatal Risk Factors
Infertility	Emergent cesarean section	Central venous/arterial catheters *
Oligohydramnios	Fetal heart rate abnormalities	Congenital heart disease
Prothrombotic disorder	Instrumentation	Sepsis
Preeclampsia	Meconium-stained fluid	Meningitis
Diabetes		Birth asphyxia
Intrauterine growth restriction		Eosinophilia
Chorioamnionitis		Respiratory distress syndrome
Prolonged rupture of membranes		Dehydration
Autoimmune disorders		Congenital nephritic/nephrotic syndrome
Fetal thrombotic vasculopathy		Necrotizing enterocolitis
		Polycythemia
		Pulmonary hypertension
		Surgery
		Extracorporeal membrane oxygenation
		Medications (steroids)

* Greatest risk factor for thrombosis with a significant risk if present ≥14-days.

Box 67.1

Prothrombotic Disorders Implicated in the Development of Neonatal Thromboembolism

Adapted from Saxonhouse MA. Thrombosis in the neonatal intensive care unit. Clin Perinatol . 2015;42:651–673.

Factor V Leiden mutation (most common)
Factor II G20210A gene mutation (1%–2% of Caucasians)
Increased apolipoprotein(a)
Methylenetetrahydrofolate reductase gene mutation ( MTHFR C677T ) genotype
Hyperhomocysteinemia
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Heparin cofactor II deficiency
Dysfibrinogenemia
PAI-1 4 g/5 G gene mutation
Increased levels of factors VIIIC, IX, XI, or fibrinogen
Antiphospholipid antibodies (including anticardiolipin antibodies, lupus anticoagulant)
Chromosome 2q
Chromosome 2q13 deletion

References .

The exact reasons for the differences in the fetal and neonatal hemostatic systems, compared with adults, are unclear but supported by recent theories surrounding overall fetal development. In the fetus, the lower levels of antithrombin III (ATIII) are balanced by elevated concentrations of alpha2-macroglobulin, allowing for unrestricted angiogenesis during intense growth while maintaining an effective anticoagulant pathway. Lower levels of vitamin K during fetal growth may reduce the synthesis of osteocalcin, preventing premature fetal cartilage maturation.

Despite having a balanced hemostatic system at birth, neonatal prothrombin time (PT) and activated partial thromboplastin times (APTT) are elevated when compared with adults. Elevated tissue factor (TF) in neonates compensates for the lower levels of tissue factor pathway inhibitor (TFPI) and ATIII. Some aspects of decreased platelet aggregation in neonates are compensated with higher levels of vWF and factor VIII (FVIII). Therefore, despite the lower levels of coagulation proteins, neonates can form effective thromboses.

The neonatal hemostatic system undergoes numerous changes over the first 6 months of life, and many of the lower protein levels reach adult values during this time.

Bleeding Disorders in the Neonate

When faced with either an actively bleeding infant or one that has suffered a significant hemorrhage, acquired or inherited, coagulation defects must be considered, especially if the neonate has a normal platelet count. Laboratory diagnostic criteria for the bleeding newborn are shown in Table 67.3 . Inherited and acquired coagulation defects and the most common symptoms associated with their presentations in the neonate are shown in Table 67.4 . It is important to obtain a detailed family and delivery history for any neonate experiencing significant bleeding, as information gained may allow the clinician to perform a quicker, more focused approach.

Table 67.3

Laboratory Diagnostic Criterion for the Bleeding Newborn ⁎

References .

Disorder	PT	APTT	Platelets	Fibrinogen
Hemophilia A	Normal	↑↑↑	Normal	Normal
Hemophilia B	Normal	↑↑↑	Normal	Normal
Hemophilia C	Normal	↑↑	Normal	Normal
Factor XIII deficiency	Normal	Normal	Normal	Normal
Factor II, V, and X deficiency	↑↑	↑↑	Normal	Normal
Hemorrhagic disease of the newborn	↑↑↑	Normal/↑ ^†	Normal	Normal
DIC ^‡	↑↑↑	↑↑↑	Low	Low
Liver disease ^‡	↑↑↑	↑↑↑	Low	Low
vWD	Normal	Normal/↑	Normal	Normal
Hypofibrinogenemia	↑↑↑	↑↑↑	Normal	Low
Dysfibrinogenemia	↑↑↑	↑↑↑	Normal	Normal/Low

APTT , Activated partial thromboplastin time(s); DIC , disseminated intravascular coagulation; PT , prothrombin time(s); vWD , von Willebrand disease.

* A complete blood count and coagulation screening test should be performed for any bleeding infant.

† APTT values may be prolonged but not as severe as the elevated PT value.

‡ To differentiate between DIC and liver disease, a factor VIII value should be obtained. Factor VIII values will be normal in infants with liver disease but low in infants with DIC.

Table 67.4

Acquired and Inherited Bleeding Disorders in Neonates

From Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders, Semin Perinatol . 2009;33:56; with permission.References .

Inherited	Classification	Symptoms
Hemophilia A (FVIII)	Severe (<1%) Moderate (1%–5%) Mild (>5%)	Bleeding after circumcision and/or blood draws, ICH, extracranial hemorrhage, excessive bruising, muscle hematomas, bleeding after surgery
Hemophilia B (FIX)	Severe (<1%) Moderate (1%–5%) Mild (>5%)
Fibrinogen deficiency	Decreased levels (heterozygote): hypofibrinogenemia Absent levels (homozygote): afibrinogenemia Dysfunctional Dysfibrinogenemia	Prolonged bleeding from umbilical stump, bleeding after circumcision, ICH, or mucocutaneous bleeding
Factor II (prothrombin)		Mucocutaneous bleeding, ICH, prolonged bleeding from umbilical stump, bleeding after procedures
Factor V	Commonly associated with congenital anomalies, particularly cardiac defects
Factor VII	Levels do not correlate well with bleeding phenotype
Factor X
Factor XI	Levels do not correlate well with bleeding phenotype
Factor XIII		Umbilical cord stump bleeding, ICH, bleeding after procedures

Acquired	Classification	Symptoms
DIC		Prolonged bleeding after venipuncture/heel sticks, jaundice, pulmonary hemorrhage
Liver disease
Vitamin K deficiency	Early <24 hours	Cephalohematoma, umbilical stump bleeding, ICH
	Classical 1–7 days	GI bleeding, umbilical stump bleeding, mucocutaneous, circumcision, ICH
	Late ≥2 weeks	ICH, mucocutaneous, GI bleeding

DIC , Disseminated intravascular coagulation; FVIII , factor VIII; FIX , factor IX; GI , gastrointestinal; ICH , intracranial hemorrhage.

Laboratory Investigation

The first approach (initial screen) to any neonate with a suspected bleeding disorder should be a complete blood count (CBC) and coagulation screen (PT, APTT, and fibrinogen). More specific testing can then be performed to make the correct diagnosis. It is important to remember that the method of sample collection may affect sample results. For example, heel-stick samples should never be used for coagulation screening, and they may result in platelet clumping, which will produce a falsely low platelet count. Elevated hematocrit levels greater than 55% may result in prolonged diluted coagulation times. In addition, the collection of blood samples through heparinized arterial or venous lines will prolong the APTT, unless the specimen has the heparin absorbed and/or adequate blood is removed from the line before sample collection to clear heparin from the line. When interpreting values from coagulation screening and more detailed testing, values should be interpreted using age-adjusted normal ranges based on gestational age and days of life; these are published elsewhere.

Hemophilia

The most common congenital bleeding disorders are hemophilia A (FVIII deficiency) and hemophilia B (factor IX deficiency), both being inherited as X-linked recessive. The incidence of hemophilia A is 1 per 5000 males and for hemophilia B is 1 per 20,000 males. Approximately one-third of cases will occur in the absence of a positive family history. Heterozygous females may have mild hemophilia as a result of nonrandom X-chromosome inactivation. The severity of hemophilia is determined by the type of mutation and the part of the protein that is affected, with severity of bleeding phenotype inversely proportional to the infant’s factor level. The lower the factor level, the greater the potential for more severe early onset bleeding. With the absence of either FVIII or factor IX, there is reduced thrombin formation on the surface of activated platelets, resulting in a thrombosis with poor structural integrity that is more susceptible to fibrinolysis, and as a result, bleeding occurs. Approximately 70% of patients with hemophilia are diagnosed during the first month of life, with the mean age of patients with hemophilia having their first bleed by 28.5 days. The most common presentation of hemophilia in the neonate is excessive bleeding, either after circumcision or surgery; but these infants can also present with severe intracranial hemorrhage. Further classifications of hemophilia A and B, based on factor activity level, and the types of bleeding that neonates may present with are shown in Table 67.4 .

Most symptomatic infants with hemophilia A and B will have significant prolongation of their APTT; however, if the diagnosis is suspected, specific factor levels should always be obtained. If there is a strong family history for hemophilia, factor levels may be screened from cord blood samples at birth, but severity of disease should always be confirmed from samples obtained after the infant is born. Infants suspected to have hemophilia, or with known family histories, should have strategies employed to reduce the risk of bleeding, such as subcutaneous vitamin K at birth, applied pressure to an intramuscular injection site for 5 minutes, use of smallest possible needles and lancets for venipunctures, and avoidance of arterial punctures.

Because FVIII levels are increased during the neonatal period, the diagnosis of mild hemophilia A may be difficult, and confirmatory testing should be done at 6 to 12 months of age. In addition, lower levels of factor IX at birth may also make the diagnosis of mild hemophilia B difficult, and testing should also be repeated at 6 to 12 months of life.

Treatment for bleeding episodes is replacement of the specific factor and should be done as quickly as possible and in consultation with pediatric hematology, as there are a number of factor concentrates that are commercially available for both FVIII and factor IX deficiency ( Table 67.5 ). Many neonates do not require treatment during the neonatal period, as they may not manifest any bleeding symptoms. Adjuvant therapies for hemophilia, such as desmopressin, may increase factors to hemostatic levels, and can be useful for management of minor bleeding or procedures in patients with mild factor VIII deficiency. Desmopressin should be used with caution in infants, and only in conjunction with pediatric hematology, as use carries a risk of symptomatic hyponatremia. Fresh frozen plasma (FFP) should only be used in the instance of acute hemorrhage when confirmatory testing is not yet available. Any infant with concern for hemophilia and intracranial bleeding should receive immediate factor replacement as this can be life-threatening if not treated rapidly and appropriately.

Table 67.5

Treatment for Congenital/Acquired Bleeding Disorders

From Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Semin Perinatol . 2009;33:56; with permission.References .

Factor	Replacement Therapy
Hemophilia A	Factor VIII concentrate
Hemophilia B	Factor IX concentrate
Fibrinogen	Fibrinogen concentrate FFP or cryoprecipitate if concentrate unavailable
Factor II	Prothrombin complex concentrate (if available) FFP if concentrate unavailable
Factor V	FFP
Factor VII	Recombinant factor VIIa or prothrombin complex concentrate (if available)
Factor X	Factor X concentrate (if available) FFP if concentrate unavailable
Factor XI	Factor XI concentrate (if available; use with caution)FFP if concentrate unavailable
Factor XIII	Plasma derived and recombinant (only for A subunit deletions) FXIII concentrate Cryoprecipitate if concentrate unavailable
Early vitamin K deficiency	Parenteral vitamin K Prothrombin concentrates for active bleeding Recombinant factor VIIa for severe active bleeding
Classical vitamin K deficiency
Late vitamin K deficiency
DIC *	FFP and cryoprecipitate, platelets
Liver disease *	Cryoprecipitate, FFP, prothrombin complex concentrates, platelets, vitamin K, recombinant factor VIIa

DIC , Disseminated intravascular coagulation; FFP , fresh frozen plasma; FXIII , factor XIII.

* Therapies for bleeding patients, not abnormal laboratory testing.

Von Willebrand Disease

The primary plasma protein required for platelet adhesion, vWF, also has a role in platelet aggregation and serves as the carrier for FVIII. Absence, reduction, or abnormal function of vWF results in defects in platelet adhesion and aggregation, increasing one's risk for bleeding. The effectiveness of vWF as an adhesive protein relies on multimerization of the protein, resulting in very large molecules comprising what are known as high-molecular-weight multimers. Neonates have higher plasma concentrations of vWF and an increased proportion of high-molecular-weight vWF multimers than older children or adults. As a result, presentation of von Willebrand disease (vWD) during the neonatal period is rare.

The spectrum of vWD is presented in Table 67.6 . Suspicion for vWD in a neonate requires specialized testing. Coagulation testing may demonstrate an isolated prolonged APTT and prolongation of epinephrine and ADP closure times as measured by the PFA-100. Further testing would evaluate the levels of vWF (vWF antigen assay), platelet-binding function (ristocetin cofactor assay), and FVIII-binding function (FVIII activity). Assistance by a pediatric hematologist should occur if a diagnosis is suspected.

Table 67.6

Spectrum of Neonatal von Willebrand Disease

References .

Type	Description	Clinical Findings
1	Quantitative	Reduced amounts of vWF due to decreased production/secretion of vWF or increased clearance
3		Complete absence of vWF due to severe gene mutations *
2 A	Qualitative	Defects in multimerization resulting in absence of large and medium-sized multimers
2B		Mutation that leads to increased binding of the high-molecular weight multimers to platelets
2 M		Mutation leading to inability of vWF to bind to platelets
2 N		Affects vWFs ability to bind to FVIII

vWD , von Willebrand Disease; vWF , von Willebrand factor; FVIII , factor VIII.

* Highest potential for presentation during the neonatal period

The management of type 3 vWD should consist of factor replacement using an intermediate purity FVIII concentrate containing the high-molecular-weight multimers of vWF. Desmopressin should be reserved for those patients with type 1 vWD but, as noted above, should only be used after consultation with a pediatric hematologist, as it carries a risk of symptomatic hyponatremia in infants.

Other Rare Inherited Coagulation Disorders

There are other rare factor deficiencies, inherited as autosomal recessive, in 1 in 500,000 to 1 in 2,000,000 live births, representing 3% to 5% of all coagulation disorders. A complete listing of the disorders and their potential symptoms are displayed in Table 67.4 . Severe deficiencies of fibrinogen, factor VII, factor X, and factor XIII are the most likely (of the rare coagulation disorders) to present during the neonatal period. The majority of these deficiencies will present with an abnormality in the coagulation screen (see Table 67.3 ). Further testing for the specific abnormality will then confirm the diagnosis. One must remember that newborn levels of many of these factors are lower at birth, and therefore diagnosis may be difficult and must be confirmed by 6 to 12 months of life. Treatment for the various deficiencies is shown in Table 67.5 .

Factor XIII is composed of two subunits and cross-links with fibrin to stabilize clots. Factor XIII deficiency is extremely rare, with an incidence of one per 1 to 3 million people but can cause a range of bleeding symptoms in the neonatal period from skin or umbilical cord bleeding, to severe intracranial hemorrhage. Low levels of factor XIII do not prolong the PT or APTT. Therefore, any neonate with concerns for a coagulation disorder that has a normal platelet count, normal fibrinogen levels, and normal PT and APTT values should be screened for factor XIII deficiency via a quantitative assay. Treatment of factor XIII deficiency is shown in Table 67.5 .

Acquired Coagulation Disorders

Vitamin K Deficiency

Vitamin K is found in leafy green vegetables as vitamin K ₁ (phytonadione) and is synthesized as vitamin K ₂ in intestinal bacteria. It is an essential cofactor for the γ-carboxylation process of procoagulant factors II, VII, IX, and X and anticoagulant proteins C and S. Insufficient bacterial colonization of the colon at birth, inadequate dietary intake in solely breastfed infants, poor intestinal absorption of vitamin K, and poor transfer across the placenta place neonates at risk for vitamin K deficiency bleeding (VKDB). Further, preterm infants are at higher risk for VKDB than term infants, due to hepatic and gut flora immaturity. The different forms of VKDB and their clinical presentation are shown in Table 67.4 . Treatment is shown in Table 67.5 .

Early VKDB may be due to maternal malabsorption disorders or maternal ingestion of oral medications which inhibit vitamin K such as warfarin, anticonvulsants, and antituberculosis agents. These agents cross the placenta and interfere with vitamin K metabolism. Classical VKDB occurs because of a physiologic deficiency in vitamin K at birth combined with a sole breast milk diet (low vitamin K in breast milk), inadequate vitamin K prophylaxis at birth, or inadequate feeding. Late VKDB presents in an infant that is either solely breastfed who receives an inadequate dose of vitamin K (none or one oral dose) or has an associated disease process that interferes with the absorption or supply of vitamin K such as diseases of malabsorption or cholestasis like diarrhea, cystic fibrosis, α ₁ -antitrypsin deficiency, biliary atresia, hepatitis, and celiac disease. In the absence of vitamin K prophylaxis, the incidence of late VKDB is 4 to 10 per 100,000 births. When intramuscular (IM) vitamin K prophylaxis is provided, the incidence of late VKDB decreases to 0.24 to 3.2 per 100,000 live births.

If VKDB is suspected, coagulation screening should be performed and will usually demonstrate isolated prolongation of the PT, followed by prolongation of the APTT. The prolongation of the PT is usually out of proportion to the elevation of the APTT. Fibrinogen concentration and platelet counts will be normal. In addition, decreased concentrations of factors II, VII, IX, and X will occur. An alternative is to obtain an undercarboxylated or abnormal coagulation factor II measurement. This factor is released into the bloodstream in the very early stages of vitamin K deficiency, and it can be detected well before changes in the PT become manifest. The adoption of this single test in clinical practice may improve the early diagnosis of VKDB, resulting in decreased incidences of intracranial hemorrhage (ICH).

When presented with a patient with suspected VKDB, parenteral treatment (intravenous, IM, or subcutaneous injection) with vitamin K should immediately occur. Improvement of the PT and APTT 2 to 6 hours after the administration of parenteral vitamin K will confirm the diagnosis. However, if a patient suspected of having VKDB presents with severe hemorrhage, additional therapy with prothrombin complex concentrates (contain all the vitamin K-dependent factors; not available at every institution; use FFP if not available) aimed at immediate correction of factor deficiencies should occur. Additionally, recombinant factor VIIa can be used in the treatment of severe intracranial hemorrhage due to vitamin K deficiency.

Common practice in the United States is to provide all infants 1.0 mg (0.3 mg/kg for infants <1000 g and 0.5 mg for infants >1000 g but <32 weeks' gestation) of IM vitamin K on the first day of life. This single dose has been found to prevent both classical and late VKDB, even in infants with cholestatic jaundice. The safety of IM vitamin K has been questioned because of the reported association between IM vitamin K administration in newborns and an increased incidence of childhood cancer. Further studies have concluded no association between IM vitamin K and childhood leukemia or other cancers. Further research has suggested a prenatal origin of childhood leukemia, further weakening the plausibility of a causal relationship between IM vitamin K and cancer.

Proper oral administration of vitamin K has been shown to have an efficacy similar to that of IM vitamin K in the prevention of early and classical VKDB. However, cases of late VKDB began to increase and surveillance data from four countries revealed oral prophylaxis failures of 1.2 to 1.8 per 100,000 live births, with higher rates of 2 to 4 per 100,000 cases when incomplete oral dosing was observed. More recent data have demonstrated that weekly or daily oral dosing of vitamin K until 3 months of age protects almost all babies from VKDB, and late VKDB remains confined to breastfed infants who received no vitamin K or just one oral dose.

A more recent study evaluated the association of VKDB in breastfed infants with unrecognized biliary atresia and oral versus IM dosing of vitamin K. Of 91 breastfed infants diagnosed with biliary atresia, 25 received a 2-mg IM dose after birth compared with 55 and 11 infants receiving 25-μg and 150-μg oral daily dosing, respectively; 4% of the infants that received IM dosing experienced vitamin K deficiency bleeding compared with 82% (both groups) of the infants that received only oral dosing. More importantly, 0% of the infants who received IM dosing experienced ICH compared with 40% and 27%, respectively, in the oral dosing groups. Thus, a single dose of IM vitamin K at birth remains standard of care for preventing vitamin K deficiency bleeding; but repeated oral vitamin K until 3 months of age is an option for those who decline or refuse the IM dose.

Disseminated Intravascular Coagulation

A complex process involving the activation and dysregulation of the coagulation and inflammatory systems, disseminated intravascular coagulation (DIC), results in massive thrombin generation with widespread fibrin deposition and consumption of coagulation proteins and platelets, ultimately leading to multiorgan damage and hemorrhage. DIC always occurs as a secondary event, and many perinatal and neonatal problems are associated with its development. These include birth asphyxia, respiratory distress syndrome, meconium aspiration syndrome, infection, necrotizing enterocolitis, hypothermia, severe placental insufficiency, homozygous protein C/S deficiency, and thrombosis.

The diagnosis of DIC is made in an ill neonate with supporting laboratory parameters (see Table 67.3 ). The most important aspect of treatment for DIC is to treat the underlying disorder. However, once DIC is established, it can be difficult to control. The focus of acute management in the neonate is to support adequate hemostasis to reduce the risk of spontaneous hemorrhage. This is usually achieved with platelet transfusions, FFP, and/or cryoprecipitate. Another option is to inhibit the activation of the coagulation system using heparin. However, trials in neonates have not been conclusive, and the risk of bleeding may be increased, so this is generally not advised.

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