Catheter-related venous thromboembolism
Definition
Catheter-related deep venous thromboembolism (VTE) is the most common etiology of DVT in infants.
It may occur in association with catheters in the upper extremities and lower extremities as well as umbilical venous catheters.
Incidence
The incidence of symptomatic thromboembolism in infants is estimated at 0.51 per 10,000.
Over 80% to 90% of VTEs in neonates are secondary to central venous catheters.
The incidence of VTE is increasing due to increasing complexity of care.
Pathophysiology
VTE results from obstruction of blood flow, damage to the endothelium, and prothrombotic factors in the blood.
Risk factors
The primary risk factor is the catheter itself due to obstruction of blood flow and damage of the endothelium by the catheter.
Additional risk factors include dehydration, polycythemia, infection, and inherited thrombophilias. Inherited thrombophilias include protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation(s), prothrombin gene mutation(s), elevated lipoprotein (a), and hyperhomocysteinemia.
Maternally transferred antiphospholipid antibodies may also increase risk of thrombosis.
Clinical presentation
Signs and symptoms
This condition may be asymptomatic and detected as an incidental finding.
Symptoms include dysfunctional catheter and/or swelling, pain, and redness of the affected extremity.
Recurrent central line infection may be a sign of VTE.
UE VTE may be associated with superior vena cava (SVC) syndrome if there is occlusive thrombus in the SVC. SVC syndrome presents with plethora and hemodynamic instability.
Condition variability: The condition ranges from asymptomatic to life threatening with SVC syndrome.
Diagnosis
Clinical history: Review clinical history for VTE risk factors. Review family history for history of thrombosis.
Imaging: Diagnosis is made with imaging of the affected vessel(s); most often using Doppler ultrasonography (U/S). U/S depends on compression of the affected vessel. In some cases, magnetic resonance venography (MRV) may be required for diagnosis, especially in the UE. Echocardiogram may be useful to detect extension into the right atrium.
Laboratory evaluation
Baseline studies prior to anticoagulation: complete blood count, PT, PTT, fibrinogen, D-dimer, creatinine, and antithrombin activity.
Thrombophilia evaluation: Factor VIII activity, lupus anticoagulant panel, anticardiolipin antibody, anti-β2 glycoprotein 1, homocysteine, factor V Leiden, and prothrombin gene mutation.
Management
Medical: Anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). The clinician should consider the risks and benefits of anticoagulation in each neonate. Table 18-1 shows contraindications to anticoagulation. Table 18-2 shows dosing and monitoring recommendations for UFH and LMWH.
Observation: If anticoagulation is contraindicated, monitor with physical examination and imaging to detect thrombus extension. Reconsider anticoagulation if extension occurs.
UFH
Advantages: Rapid onset of action, short half-life, clearance independent of renal function, antidote available.
Disadvantages: Unpredictable dose response requires frequent monitoring, requires dedicated IV line, mechanism of action is dependent on antithrombin, which is deficient in neonates.
Side effects: Bleeding, heparin-induced thrombocytopenia (HIT), and osteoporosis with long-term use.
Duration of anticoagulation depends on extent of thrombosis, resolution of thrombosis, and ongoing risk factors (Table 18-3).
LMWH
Advantages: Longer half-life than UFH, subcutaneous mode of administration, more predictable dose response.
Disadvantages: Subcutaneous injections may not be feasible in premature infants with limited subcutaneous tissue. Requires monitoring. Monitoring is unreliable with hyperbilirubinemia. Antidote is only partially effective. Clearance is dependent on renal function; need more frequent monitoring in the setting of renal insufficiency.
Side effects: Bleeding (less than with UFH); HIT (less than with UFH); osteoporosis with long-term use.
Duration of anticoagulation: Same as with UFH.
Thrombolytic therapy
Reserved for life- and limb-threatening hemorrhage. Consult pediatric hematology for recommendations on dosing and monitoring. If pediatric hematologist is not available, consult center with pediatric hematology or request consultation from 1-800-NO-CLOTS. There are numerous dosing regimens. Most common is 0.5 mg/kg/h for 6 hours. Anticoagulation is recommended after thrombolytic therapy to prevent clot recurrence.
Surgical: If the involved catheter is not functional, it may be removed. Due to risk of paradoxical emboli at time of line removal, anticoagulation is recommended for 3 to 5 days after VTE diagnosis prior to removal of the catheter. In the case of extensive of complicated thrombus, consult interventional radiology prior to removal. Thrombectomy is not recommended due to high risk of recurrence and risk of vascular damage.
Prognosis
Early predictors: Presence of severe or multiple thrombophilia has been associated with risk of recurrence. Completely occlusive thrombosis has been associated with increased risk of VTE. Persistently elevated factor VII activity and D-dimer are markers of poor VTE outcomes.
Outcomes
Resolution: Catheter-related VTE may resolve completely or there may be residual occlusive or partially occlusive clot.
Recurrence: Risk of recurrence is not defined.
Postthrombotic syndrome: Postthrombotic syndrome (PTS) is a long-term complication of VTE. Signs of symptoms of PTS include edema, visibly dilated superficial collateral veins, venous stasis dermatitis, and venous stasis ulcers.
Management is most often symptomatic care.
Convalescent care
While on therapeutic LMWH, such as enoxaparin, monitor LMWH levels weekly while inpatient. Levels should be drawn 4 hours after am dose. If dose change is made, then repeat level 4 hours after second dose. Will need more frequent monitoring if there is bleeding or change in renal function.
While on anticoagulation monitor CBC weekly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult hematology prior to any invasive procedures.
Initiate parent teaching if they will need to administer anticoagulation at home.
Arrange for postdischarge anticoagulation management through primary care physician or pediatric hematology.
Follow-up care
Monitor LMWH levels monthly. Levels should be drawn 4 hours after am dose. Will need more frequent monitoring if there is bleeding or change in renal function.
Monitor CBC monthly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult pediatric hematology prior to any invasive procedures.
Consult pediatric hematology regarding duration of anticoagulation and indications for thromboprophylaxis after discontinuation of treatment.
Monitor for PTS at every visit, at least once per year.
Portal vein thrombosis
Definition
Portal vein thrombosis (PVT) involves venous occlusion of the PVT within the liver.
PVT may occur in isolation or with extension into the inferior vena cava (IVC).
Incidence
Wide range of reports
1/100,000 live births
36/1000 NICU admissions
Pathophysiology
Most cases of PVT in infants are associated with umbilical venous catheters (UVC). UVC are placed into the umbilical vein to go up through the ductus venosus, but the UVC may go into the left branch of the portal vein. The UVC can damage the vessel wall and obstruct blood flow, which predisposes to thrombosis.
Intravenous infusions through the UVC can also damage the vessel wall.
Risk factors
Risk is highest when UVC is placed in portal vein.
Infection can be a contributing risk factor.
See above (Section A4) for additional risk factors.
Clinical presentation
Signs and symptoms
PVT may be asymptomatic in neonatal period.
PVT may be associated with hepatic insufficiency and splenomegaly.
Extension into the IVC may result in lower leg edema, ascites, and/or pleural effusions.
May be complicated by embolus through ductus venosus and foramen ovale to the cerebral circulation.
Condition variability: Condition ranges from asymptomatic with spontaneous regression to life threatening with long-term consequences.
Diagnosis
Clinical history: Review clinical history for risk factors. Review family history for history of thrombosis.
Imaging: Diagnosis is most often made with Doppler U/S.
Laboratory evaluation
Liver function: Transaminases.
Baseline studies: See Section I.A.6c (first bullet entry).
Thrombophilia evaluation: See Section I.A.6c (second bullet entry).
Management
Medical: See above.
Observation: If there is a significant coagulopathy or other contraindication to anticoagulation. If observation, repeat U/S in 5 to 7 days. If extension, then reconsider anticoagulation.
Anticoagulation: Repeat U/S in 10 days. If PVT not resolved, then anticoagulate for 3 months. If PVT resolved, then stop anticoagulation. Repeat U/S in 5 to 7 days. If PVT present, then anticoagulate for 3 months.
Thrombolytic therapy: Consider for symptomatic extension into the IVC, right atrium, or right ventricle despite anticoagulation.
Surgical: N/A.
Prognosis
Early predictors: Nonocclusive PVT is more likely to resolve than occlusive PVT.
Outcomes
Resolution: PVT may resolve completely or there may be residual occlusive or partially occlusive clot.
Recurrence: Risk of recurrence is low.
PVT may transform into cavernoma with collateral vessels. Need to monitor for development of portal hypertension, which can be associated with splenomegaly, hypertension, gastrointestinal hemorrhage, and hepatic atrophy.
Convalescent care
While on LMWH, such as enoxaparin, monitor LMWH levels weekly while inpatient. Levels should be drawn 4 hours after am dose. If dose change is made, then repeat level 4 hours after second dose. Will need more frequent monitoring if there is bleeding or change in renal function.
While on anticoagulation, monitor CBC weekly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continued beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult hematology prior to any invasive procedures.
Initiate parent teaching if they will need to administer anticoagulation at home.
Arrange for postdischarge anticoagulation management through primary care physician or pediatric hematology.
Follow-up care
Monitor LMWH levels monthly. Levels should be drawn 4 hours after am dose. Will need more frequent monitoring if there is bleeding or change in renal function.
Monitor CBC monthly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult pediatric hematology prior to any invasive procedures.
Consult pediatric hematology regarding duration of anticoagulation and indications for thromboprophylaxis after discontinuation of treatment.
Monitor for PTS and portal hypertension at every visit, at least once per year.
Renal vein thrombosis
Definition
Renal vein thrombus involves occlusion of one or both renal veins.
RVT may occur in isolation or with extension in the IVC.
Incidence
Wide range of reported incidence
2.2 per 100,000 live births
0.5 per 1000 NICU admissions
Pathophysiology
Unlike most VTE in neonates, RVT is usually not associated with central venous catheter placement.
Pathophysiology is unclear.
Any factor that reduces blood flow within the renal vasculature will predispose to thrombosis.
Onset may be in utero.
Risk factors
Infants of diabetic mothers are at higher risk for RVT compared to healthy infants.
Additional risk factors include male gender, perinatal asphyxia, prematurity, dehydration, and infection.
Clinical presentation
Signs and symptoms: Abdominal mass, hematuria, proteinuria, and thrombocytopenia. Bilateral cases may present with anuria associated with renal insufficiency and failure. Rarely present with hypertension.
Condition variability: Condition ranges from asymptomatic to life-threatening renal failure and long-term morbidity.
Diagnosis
Clinical history: Review clinical history for risk factors. Review family history for history of thrombosis.
Imaging: Diagnosis is supported by findings of vessel occlusion on U/S.
Laboratory evaluation
Baseline studies: See Section I.A.6c (first bullet entry).
Thrombophilia evaluation: See Section I.A.6c (second bullet entry).
Management
Medical
Observation
If there is a significant coagulopathy or other contraindication to anticoagulation. If observation, repeat U/S in 5 to 7 days. If extension, then reconsider anticoagulation.
Consider if unilateral without IVC extension.
Anticoagulation: Anticoagulation is recommended for unilateral RVT with IVC extension and bilateral RVT thrombosis. Anticoagulation is also considered for unilateral RVT.
Thrombolytic therapy: Consider for bilateral RVT with renal impairment. Anticoagulation is recommended after thrombolytic therapy to prevent clot recurrence.
Surgical: N/A
Prognosis
Early predictors: unknown
Outcomes
Resolution: RVT/IVC thrombosis may resolve completely or there may be residual occlusive or partially occlusive clot.
Recurrence: Risk of recurrence is not defined.
Long-term complications include hypertension, tubular dysfunction, and renal dysfunction.
Convalescent care
While on LMWH, such as enoxaparin, monitor LMWH levels weekly while inpatient. Levels should be drawn 4 hours after AM dose. If dose change is made, then repeat level 4 hours after second dose. Will need more frequent monitoring if there is bleeding or change in renal function.
While on anticoagulation, monitor CBC and creatinine weekly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult hematology prior to any invasive procedures.
Initiate parent teaching if they will need to administer anticoagulation at home.
Arrange for postdischarge anticoagulation management through primary care physician or pediatric hematology.
Follow-up care
Monitor LMWH levels monthly. Levels should be drawn 4 hours after am dose. Will need more frequent monitoring if there is bleeding or change in renal function.
Monitor CBC and creatinine monthly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult pediatric hematology prior to any invasive procedures.
Consult pediatric hematology regarding duration of anticoagulation and indications for thromboprophylaxis after discontinuation of treatment.
Monitor for PTS and hypertension at every visit, at least once per year.
Cerebral sinovenous thrombosis
Definition: Cerebral sinovenous thrombosis (CSVT) involves complete or partial occlusion of the cerebral venous system.
Incidence: 2.6 to 12 per 100,000 full-term infants per year.
Pathophysiology: Occlusion of cerebral venous systems.
Risk factors
A high percentage of CSVT occurs in neonates and in males.
Risk factors include hypoxic encephalopathy, complicated delivery, congenital heart disease, dehydration, sepsis, and prematurity.
Clinical presentation
Signs and symptoms: Presents similar to stroke with seizures and encephalopathy (lethargy, confusion, irritability, and coma).
Condition variability: Variable extent of thrombosis, infarction, and hemorrhage and associated neurologic symptoms. May result in death.
Diagnosis
Imaging: Diagnosis may be made with computed tomography (CT) or magnetic resonance imaging (MRI) and MRV.
Laboratory evaluation
Baseline studies: See Section I.A.6c (first bullet entry).
Thrombophilia evaluation: See Section I.A.6c (second bullet entry).
Management
Medical
Observation/supportive care: May be considered for neonates with associated intracranial hemorrhage. However, there is new evidence that neonates with CSVT and ICH can be safely anticoagulated. If anticoagulation is not started, reimage after 5 to 7 days and reconsider anticoagulation if there is thrombus extension.
Anticoagulation: Anticoagulation recommended for most cases of CSVT.
Unfractionated heparin
Low molecular weight heparin
Thrombolytics: Not recommended unless there is a life- or limb-threatening complication
Surgical: N/A
Early developmental/therapeutic interventions: Children with associated stroke will require close developmental follow-up and intervention as clinically indicated.
Prognosis
Early predictors: Venous infarction and perinatal complications are associated with outcome.
Outcomes
Resolution: CSVT may resolve completely or there may be residual occlusive or partially occlusive clot.
Progression: More common in neonates who are not anticoagulated.
Recurrence: Risk of recurrence is low.
Long-term consequences include seizures/epilepsy and developmental delay.
Convalescent care
While on LMWH, such as enoxaparin, monitor LMWH levels weekly while inpatient. Levels should be drawn 4 hours after am dose. If dose change is made, then repeat level 4 hours after second dose. Will need more frequent monitoring if there is bleeding or change in renal function.
While on anticoagulation monitor CBC weekly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult hematology prior to any invasive procedures.
Initiate parent teaching if they will need to administer anticoagulation at home.
Arrange for postdischarge anticoagulation management through primary care physician or pediatric hematology.
Follow-up care
Monitor LMWH levels monthly. Levels should be drawn 4 hours after am dose. Will need more frequent monitoring if there is bleeding or change in renal function.
Monitor CBC monthly.
Perform repeat imaging 6 weeks after diagnosis. If anticoagulation continues beyond 6 weeks, repeat imaging 3 months after diagnosis.
Consult pediatric hematology prior to any invasive procedures.
Consult pediatric hematology regarding duration of anticoagulation and indications for thromboprophylaxis after discontinuation of treatment.
Monitor for evidence of neurologic impairment, seizure disorder, and developmental delay. Refer to appropriate specialists as needed.
Perinatal and neonatal arterial ischemic stroke
Definition: Arterial ischemic stroke (AIS) is occlusion of cerebral artery(ies), resulting in brain ischemia.
Incidence: 18 per 100,000 per year; 1 in 5000 live birth.
Pathophysiology: Perinatal and neonatal AIS results from occlusion of cerebral arteries from local thrombosis or thrombosis from a cardioembolic source.
Risk factors
Risk of AIS is higher in neonates compared to older children.
Male gender is a risk factor.
Maternal and acquired neonatal risk factors contribute to stroke.
Inherited thrombophilias and antiphospholipid antibodies have been associated with AIS.
Clinical presentation
Signs and symptoms: Depends on the location and extent of the infarction. Primary acute symptom is seizures; apnea and feeding difficulty are other symptoms. Neonates may initially be asymptomatic and later diagnosed based on hemiparesis, spasticity, or motor delay.
Condition variability: Condition ranges from asymptomatic to life threatening.
Diagnosis
Clinical history: Review history for neurologic symptoms and family history of thrombosis.
Imaging: Head CT or brain MRI/MRA. ECHO should be done to evaluate for cardioembolic source.
Laboratory evaluation
Management
Medical
Observation: Recommended for noncardioembolic stroke.
Aspirin: Not recommended for first AIS.
Anticoagulation: Anticoagulation is recommended for cardioembolic stroke.
Thrombolytics: Not recommended.
Surgical: N/A
Early developmental/therapeutic interventions: Children with associated stroke will require close developmental follow-up and intervention as clinically indicated.
Prognosis
Early predictors: Clinical outcome will depend on the location and extent of the stroke.
Outcomes: Long-term complications may include seizure disorder, hemiparesis, and neurocognitive impairment.
Convalescent care (infants with cardioembolic stroke)
While on LMWH, such as enoxaparin, monitor LMWH levels weekly while inpatient. Levels should be drawn 4 hours after am dose. If dose change is made, then repeat level 4 hours after second dose. Will need more frequent monitoring if there is bleeding or change in renal function.
While on anticoagulation, monitor CBC weekly.
Perform repeat ECHO 6 weeks after diagnosis. If anticoagulation continued beyond 6 weeks, repeat ECHO 3 months after diagnosis.
Consult hematology prior to any invasive procedures.
Initiate parent teaching if they will need to administer anticoagulation at home.
Arrange for postdischarge anticoagulation management through primary care physician or pediatric hematology.
Follow-up care (infants with cardioembolic stroke)
Monitor LMWH levels monthly. Levels should be drawn 4 hours after am dose. Will need more frequent monitoring if there is bleeding or change in renal function.
Monitor CBC monthly.
Perform repeat ECHO 6 weeks after diagnosis. If anticoagulation continued beyond 6 weeks, repeat ECHO 3 months after diagnosis.
Consult pediatric hematology prior to any invasive procedures.
Consult pediatric hematology regarding duration of anticoagulation and indications for thromboprophylaxis after discontinuation of treatment.
For all infants with AIS: Monitor for evidence of neurologic impairment, seizure disorder, and developmental delay. Refer to appropriate specialists as needed.
Arterial thrombosis
Definition
Thrombosis of an artery
May affect vessels providing blood flow to the extremities, intestines, kidneys, liver, and lung
Incidence
Vast majority are related to peripheral arterial catheters in children.
Incidence depends on type of catheter and patient characteristics.
Pathophysiology
Occlusion of an artery leads to decreased perfusion of the end organs.
Need to differentiate from vasospasm.
Risk factors
Vast majority are secondary to arterial catheters including umbilical artery catheters (UAC).
Additional risk factors include sepsis, dehydration, polycythemia, maternal diabetes, and asphyxia.
Clinical presentation
Signs and symptoms: May be asymptomatic. Organ-specific symptoms are listed in Table 18-4.
Condition variability: Condition ranges from asymptomatic to limb and life threatening.
Diagnosis
Clinical history: Review history for risk factors and family history of thrombosis.
Imaging: Most often detected on ultrasound.
Laboratory evaluation
Evaluation for ischemia: Lactic acid.
Baseline studies: See Section I.A.6c (first bullet entry).
Thrombophilia evaluation: See Section I.A.6c (second bullet entry).
Management
Medical
Observation
Anticoagulation with UFH or LMWH
Thrombolytics: More commonly used for arterial thrombosis if life or limb threatening
Surgical
Catheter removal: Associated arterial catheters should be removed immediately.
Thrombectomy: Not standard due to high rate of reocclusion. Recommended for life- or limb-threatening femoral artery thrombosis when thrombolytic therapy is contraindicated.
Debridement and amputation: Arterial thrombosis with significant ischemia may require surgical debridement and/or amputation.
Prognosis
Early predictors: Outcome depends on extent of ischemia.
Outcomes: Long-term complication is limb length discrepancy.
Convalescent care
While on LMWH, such as enoxaparin, monitor LMWH levels weekly while inpatient. Levels should be drawn 4 hours after am dose. If dose change is made, then repeat level 4 hours after second dose. Will need more frequent monitoring if there is bleeding or change in renal function.
While on anticoagulation monitor CBC weekly.
Consult pediatric hematology on case-by-case basis for optimal timing of repeat imaging; often after 5 to 7 days.
Consult pediatric hematology prior to any invasive procedures.
Initiate parent teaching if they will need to administer anticoagulation at home.
Arrange for postdischarge anticoagulation management through primary care physician or pediatric hematology.
Follow-up care
Monitor LMWH levels monthly. Levels should be drawn 4 hours after am dose. Will need more frequent monitoring if there is bleeding or change in renal function.
Monitor CBC monthly.
Perform repeat ECHO 6 weeks after diagnosis. If anticoagulation continued beyond 6 weeks, repeat ECHO 3 months after diagnosis.
Consult pediatric hematology prior to any invasive procedures.
Consult pediatric hematology regarding duration of anticoagulation and indications for thromboprophylaxis after discontinuation of treatment.
Monitor for evidence of neurologic impairment, seizure disorder, and developmental delay. Refer to appropriate specialists as needed.
Coagulopathy associated with liver disease
Definition
Liver disease results in decreased synthesis of the vitamin K–dependent clotting factors II, VII, IX, and X as well as anticoagulant proteins C and S.
Liver disease is also associated with thrombocytopenia and hypofibrinogenemia.
The coagulopathy associated with liver disease can be complicated by both hemorrhage and thrombosis.
Incidence: Varies based on the underlying etiology.
Pathophysiology
The liver produces vitamin K dependent clotting factors (II, VII, IX, and X) and anticoagulants (C and S). The liver also produces fibrinogen, FVIII, FXI, and FXIII. Hepatic insufficiency results in low levels of these factors with the exception of FVIII, which is elevated in liver disease.
Platelets are often decreased due to hypersplenism and decreased production.
Risk factors: Severe liver disease; coagulopathy may be compounded by DIC or vitamin K deficiency.
Clinical presentation
Signs and symptoms: Bleeding symptoms include ecchymosis, petechiae, mucosal hemorrhage, and internal hemorrhage. Thrombosis may occur.
Condition variability: Condition varies based on underlying liver disease. More severe liver disease is associated with worse coagulopathy.
Diagnosis
Clinical history: Suspect in a neonate with significant liver disease.
Laboratory evaluation: Complete blood count, PT, aPTT, fibrinogen, D-dimer.
Management
Medical: Medical management is controversial. Correction of coagulopathy is required for bleeding or prior to invasive procedures. There is unclear benefit of treatment based on numerical values.
Platelets
FFP
Cryoprecipitate
rVIIa: Can be considered on an individual basis for bleeding unresponsive to other measures
Surgical: In many cases, children with significant liver disease will require liver transplantation.
Prognosis
Early predictors: Depends on underlying etiology
Outcomes: Depends on associated bleeding and/or thrombosis and resolution of underlying etiology
Convalescent care: Resolves with treatment of underlying disorder
Follow-up care: N/A
Congenital bleeding disorders
Definition: A spectrum of inherited bleeding disorders affecting one or more of the following: platelet number, platelet function, clotting factor activity, clotting factor function.
Incidence: Ranges from 1:100 to 1:1,000,000.
Pathophysiology: Congenital bleeding disorders are related to inherited mutations in the genes responsible for production of clotting factors (Table 18-5).
Risk factors: N/A.
Clinical presentation
Signs and symptoms: Varies based on degree and type of factor deficiency (see Table 18-5).
Condition variability: Conditions range from asymptomatic to life-threatening hemorrhage.
Diagnosis
Clinical history: Review history for bleeding and sites of invasive procedures.
Family history: Review family history for history of bleeding.
Physical examination: Evaluate for signs and symptoms of bleeding.
Laboratory evaluation
At birth: Send cord blood for testing. Understand that fibrinogen and FVIII levels should be normal at birth. Other factor levels are low at birth; absent or very low levels may be indicative of inherited bleeding disorder.
After birth: Send venous sample for testing.
Interpretation: Use age-based norms for interpretation
Blood smear: Review of the blood smear is particularly important for evaluation of inherited platelet disorders. Platelets should be assessed for size. Microthrombocytes are associated with Wiskott-Aldrich syndrome whereas as macrothrombocytes are associated with Bernard-Soulier syndrome, MYH9-related disorders, and gray platelet syndrome. White blood cells should be inspected for inclusion bodies, which can be present in inherited platelet disorders.
Management
Medical (see Table 18-5)
Factor replacement: Specific factor replacement products are available for hemophilia A (factor VIII deficiency), hemophilia B(factor IX deficiency), von Willebrand disease: factor VII deficiency, factor XIII deficiency, and a/hypofibrinogenemia.
FFP/cryoprecipitate: FFP may be given for factor deficiency when specific factor replacement is not available; use cryoprecipitate for von Willebrand disease, FXIII deficiency, and a/hypofibrinogenemia if factor concentrate is not available.
Platelet transfusion: Platelet transfusions and/or rFVIIa are indicated for inherited platelet disorders.
Adjunctive measures: Pressure, ice, and topical agents may be used at sites of bleeding.
Surgical: There is no surgical intervention. However, congenital bleeding disorders may complicate surgical and other invasive procedures.
Antenatal management: When a pregnancy is complicated by a known or suspected bleeding disorder in the fetus, the delivery must be carefully coordinated between obstetrics, pediatric hematology, and neonatology. If a fetus has known or suspected hemophilia or other severe bleeding disorder, traumatic delivery should be avoided. Cesarean section has been recommended as one method of preventing intracranial hemorrhage at delivery. Alternatively, vaginal delivery without the use of forceps or vacuum may be performed with low threshold to convert to cesarean for failure to progress.
Early therapeutic interventions
Hemophilia and other severe bleeding disorders
Perform a head U/S or CT to evaluate for intracranial hemorrhage.
If child is diagnosed with hemophilia, avoid circumcision.
Arterial punctures and lumbar punctures should only be done after clotting factor replacement.
Hold pressure for heel sticks and venipunctures for 10 minutes. Observe for 24 hours afterward.
If vitamin K is given intramuscularly, apply firm pressure to site for 5 to 10 minutes. Alternative is oral vitamin K.
Hepatitis B immunization should be given intramuscularly and pressure applied to the injection site for 10 minutes.
Circumcision is strongly discouraged due to risk of bleeding.
Prognosis
Early predictors: Severity of the factor deficiency predicts bleeding phenotype, but there is still high variability.
Outcomes: Clinical outcomes depend on the severity of the bleeding phenotype.
Convalescent care
Consult pediatric hematology prior to any invasive procedures.
Follow-up care
Establish care with pediatric coagulation specialist.
Thrombocytopenia (Table 18-6)
Definition: Low platelet count based on age-specific normal values.
Incidence: 0.12% (<50 × 109/L); 0.04% (20 × 109/L); much higher in ill premature infants.
Pathophysiology: The etiology and pathophysiology of thrombocytopenia are highly variable.
Risk factors: Depends on the underlying etiology.
Clinical presentation
Signs and symptoms: Symptoms of thrombocytopenia include petechiae, ecchymoses, and mucosal bleeding. Intracranial may occur with severe thrombocytopenia. Other signs and symptoms depend on underlying etiology.
Condition variability: Condition ranges from asymptomatic to life-threatening hemorrhage.
Diagnosis
Clinical history: Review clinical and family history for clues to underlying etiology.
Physical examination: Perform physical examination for evidence of bleeding and for clues of underlying etiology. Congenital anomalies may be a sign of an associated chromosomal defect, bone marrow failure syndrome, or inherited platelet disorder.
Laboratory evaluation
Complete blood count: To quantitate degree of thrombocytopenia and to determine if there are associated cytopenias.
DIC panel: If the infant is ill or consumptive process is suspected, obtain DIC panel to evaluate for concomitant coagulopathy.
Blood smear: Evaluate for platelet size. Evaluate for platelet clumping.
Management
Medical
Treatment of underlying condition.
Platelet transfusion: Transfusion threshold depends on clinical status of neonate and bleeding symptoms.
Surgical: N/A
Early therapeutic interventions: N/A
Prognosis
Outcomes: Clinical outcomes depend on severity of bleeding as well as etiology of the thrombocytopenia.
Convalescent care
Monitor platelet count every 3 to 5 days until resolution of thrombocytopenia; more frequently if symptomatic.
Avoid invasive procedures while the neonate has thrombocytopenia.
Consult pediatric hematology for symptomatic and/or persistent thrombocytopenia and prior to invasive procedures.
Follow-up care
Follow-up with pediatric hematology if there is an underlying hematologic disorder.
Polycythemia
Definition: A venous hematocrit of 65% or higher or venous hemoglobin of 22 g/dL or higher within the first week of life.
Incidence: 0.4% to 4% of all births.
Pathophysiology
Polycythemia is associated with increased blood viscosity.
Polycythemia may be due to hypertransfusion from a twin, from the mother, or from the placenta/cord.
Risk factors
Increased risk with intrauterine hypoxia, endocrine abnormalities (congenital adrenal hyperplasia, neonatal thyrotoxicosis, congenital hypothyroidism, and maternal diabetes).
Rare conditions associated with neonatal polycythemia include chromosomal abnormalities, Beckwith-Wiedemann syndrome, maternal use of propranolol, high-altitude conditions, and high-oxygen affinity hemoglobinopathies.
Clinical presentation
Signs and symptoms: Infants appear plethoric. In addition, infants may have hypoglycemia, hypocalcemia, and hyperbilirubinemia. Significant increase in viscosity may result in cardiac, respiratory, and CNS complications.
Condition variability: Condition ranges from asymptomatic to life threatening depending on degree of polycythemia and underlying etiology.
Diagnosis
Clinical history: A careful maternal history and delivery record may provide clues to the underlying etiology.
Physical examination: Physical examination may identify dysmorphic features associated with a chromosomal abnormality or Beckwith-Wiedemann syndrome (hemihypertrophy and visceromegaly).
Laboratory evaluation
Complete blood count: Venous sampling is more accurate compared to capillary samples.
Electrolytes to detect associated anomalies.
Note that coagulation studies can be falsely abnormal when hematocrit is >60% to 65%. Consult coagulation laboratory prior to sending any testing in light blue top tube.
Management
Medical: Treatment is required for symptomatic neonates.
Partial exchange transfusion
Surgical: N/A.
Prognosis
Early predictors: Outcomes depend on degree of polycythemia underlying etiology.
Outcomes: Outcomes depend on underlying etiology. Worse outcomes are associated with CNS complications.
Convalescent care: Depends on underlying etiology
Follow-up care: Depends on underlying etiology
ABO incompatibility and Rh disease
Definition: Hemolytic anemia resulting from maternal red cell antibodies directed at fetal/neonatal red cells
Incidence: Common
Pathophysiology
In Rh disease, the mother is Rh negative and the infant is Rh positive. When mothers are exposed to Rh-positive red blood cells, they produce red cell antibodies that cross the placenta and attach to the fetal/neonatal red cells, causing red cell destruction with hemolytic anemia.
ABO incompatibility occurs with a group O mother and an infant is group A or B. Individuals with group O blood have naturally occurring anti-A and anti-B that can cross the placenta and attach to fetal/neonatal red cells, causing red cell destruction with hemolytic anemia.
Risk factors: Depends on maternal and neonatal blood types
Clinical presentation
Signs and symptoms: Primary symptoms are anemia and jaundice. Jaundice presents within the first 24 hours of life.
Condition variability: Condition ranges from asymptomatic to severe anemia with hydrops fetalis and/or severe hyperbilirubinemia with kernicterus.
Diagnosis
Clinical history: If the mother is Rh negative and Rh disease is suspected review maternal history of prior pregnancies and miscarriages and administration of Rhogam.
Physical examination: Examine for presence of jaundice and signs of anemia including murmur and hepatosplenomegaly.
Laboratory evaluation
Complete blood count: To assess degree of anemia.
Blood smear: Expect to see anemia, reticulocytosis, and nucleated red blood cells; most infants with ABO incompatibility will have spherocytes.
Fractionated bilirubin: To assess degree of hyperbilirubinemia; expect the majority to be unconjugated.
Blood typing of infant and mother: To determine if there is setup for maternal antibody production.
Red cell antibody testing (direct and indirect Coombs test): To detect and identify antibodies in the infant.
Management
Medical
Red cell transfusion
Red cell exchange
Phototherapy
Surgical: N/A
Early therapeutic interventions
Prevention of Rh disease: Mothers are screened as early as possible in pregnancy for Rh antibodies. Pregnant women with positive titers have close monitoring (ultrasound, percutaneous umbilical vein blood sampling, amniocentesis) to detect signs of fetal anemia. Women who are Rh negative with negative Rh titers are given Rhogam at 27 to 28 weeks’ gestation.
In utero transfusion: Affected fetuses may receive in utero transfusion fit there is significant anemia before the infant is mature enough for delivery.
Prognosis
Early predictors: A history of poor outcome with Rh-disease-affected newborns and high Rh titer are associated with worse outcome. Clinical outcome depends on degree of anemia and hyperbilirubinemia.
Outcomes: Outcomes range from resolution to long-term complications of kernicterus.
Convalescent care
Follow hemoglobin and bilirubin per NICU protocol until resolution of hyperbilirubinemia and anemia.
Follow-up care
If severe hyperbilirubinemia, the infant will need long-term follow-up for neurologic and neurocognitive outcomes.
Thrombocytosis
Definition: Elevated platelet count; various definitions. Extreme thrombocytosis is defined as a platelet count of >1000 × 109/L.
Incidence: Unknown; extreme thrombocytosis is rare.
Pathophysiology: Thrombocytosis in the infant is a reactive process secondary to an underlying disorder.
Risk factors: Prematurity, iron deficiency, congenital adrenal hyperplasia, trisomy 21, asplenia.
Clinical presentation
Signs and symptoms: Most often asymptomatic. Reactive thrombocytosis is not associated with increased risk of thrombosis.
Condition variability: Most often benign.
Diagnosis
Clinical history: Review clinical and medication history.
Physical examination: Perform physical examination to evaluate for clues of underlying diagnosis.
Laboratory evaluation
Complete blood count.
Blood smear: The blood smear should be reviewed to exclude pseudothrombocytosis when red or white cell fragments are incorrectly counted as platelets in automated cell counters. Microspherocytes, bacteria, and Pappenheimer bodies may also be counted as platelets. Red cells should be inspected for Howell-Jolly bodies (nuclear remnant), which indicated functional or anatomic asplenia.
Management
Medical: Treat the underlying condition.
Surgical: N/A.
Prognosis
Early predictors: Clinical outcomes depend on the underlying condition.
Outcomes: Thrombocytosis is expected to resolve as underlying condition resolves.
Convalescent care
Vitamin E supplementation per institutional guidelines
Follow-up care: Depends on underlying etiology
Newborn screening for hemoglobinopathies
Definition: Hemoglobin identification methods (eg, hemoglobin electrophoresis, isoelectric focusing, high-performance liquid chromatography, DNA analysis) are included as part of newborn screening to detect abnormal hemoglobins. There are hundreds of hemoglobin variants. Many hemoglobin variants are not clinically significant. However, it is important to recognize clinically significant hemoglobinopathies. Hemoglobinopathies are inherited red blood cell disorders affecting hemoglobin synthesis and/or structure. These include sickle cell disease (Hb SS, Hb SC, Hb SE, Hb SD, Hb S β thalassemia) and α and β thalassemias. The age of presentation depends on the evolution of globin chain synthesis. The predominant globin chains at birth are α and γ. β-Globin synthesis replaces γ-globin synthesis within the months after birth.
Incidence: Vary based on the particular hemoglobinopathy.
Pathophysiology: Hemoglobinopathies result from alterations in structure or synthesis of hemoglobin chains.
Risk factors: These conditions are inherited in an autosomal fashion.
Clinical presentation
Signs and symptoms
β-Globin defects: Sickle cell disease is asymptomatic at birth due to presence of high levels of γ-globin production and fetal hemoglobin. β Thalassemia is also asymptomatic at birth until γ-globin production decreases and β-globin production predominates. In circumstances of increased red cell turnover such as with blood loss or ABO incompatibility can unmask a β-globin defect since new red cell production will depend on β-globin synthesis.
α-Globin defects: Most of these conditions are not detected at birth. However, hydrops fetalis with fetal or very early neonatal death results from four α-globin gene deletions. In this condition, there is no α chain production. The predominant hemoglobin, hemoglobin Bart, has inefficient oxygen delivery.
Condition variability: The clinical phenotype of these conditions is highly variable.
Diagnosis: Diagnosis is most often made on newborn screening (Table 18-7). Prenatal diagnosis may be made through chorionic villus sampling or amniocentesis. Confirmation by hemoglobin electrophoresis.
Management
Medical
Infants with abnormal hemoglobin testing on newborn screen should have hematology consultation during the hospitalization or be referred to a pediatric hematology clinic after discharge.
If prenatal diagnosis of four α-globin gene deletions is made, intrauterine and postnatal transfusions may be given.
Surgical: N/A
Ongoing therapeutic interventions
Children with hemoglobinopathies require comprehensive care for health care maintenance, preventive strategies, and management of complications.
Children with β thalassemia, major and some children with other thalassemias and SCD will require life-long transfusion.
Stem cell transplantation is sometimes an option for cure.
Prognosis
Outcomes
Sickle cell disease: Lifelong condition that requires ongoing care. Only cure is stem cell transplantation.
β-Thalassemia major: Lifelong condition that requires ongoing care. Only cure is stem cell transplantation.
Convalescent care
Infants with sickle cell disease should be started on prophylactic penicillin VK by 2 months of age (125 mg PO bid).
Follow-up care
Children with hemoglobinopathies should establish care with pediatric hematologist as soon as possible after discharge.
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