55
Neutrophil and thrombotic disorders

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Neutrophil disorders

There is a physiologic rise in neutrophils between 12 and 24 hours of life and thereafter the number falls (Fig. 55.1).

Fig. 55.1 Total neutrophil count, showing the rise with age and the normal range.

(From Manroe B.L. et al. J Pediatr 1979; 95: 89–98.)

Neutrophilia

The most common causes are:

• acute bacterial infection
• maternal chorioamnionitis (usually without active infection in the baby).

Much less common causes are fungal infection and postnatal corticosteroid therapy. When neutrophilia is accompanied by a left shift, i.e. increase in immature neutrophils, such as band forms (Fig. 55.2), it is used as a marker for bacterial infection. The combination of an abnormal absolute neutrophil count and immature:total neutrophil ratio increases the likelihood of infection to about 65%. Neutrophilia from bacterial infections often develops 12–24 hours after the onset of infection. Serial measurements are more informative than isolated values. However, interpretation of the blood smear requires technical expertise. In the UK band counts have largely been replaced by measuring acute phase reactants (C-reactive protein or procalcitonin). In many units in the US both band counts and acute phase reactants are measured.

Fig. 55.2 Blood smear showing four neutrophil ‘band’ cells in a neonate with bacterial sepsis. The ‘band’ cells also show toxic granulation in the cytoplasm, another useful sign of acute bacterial infection.

Neutropenia

This is a neutrophil count of less than 1500 cells/mm³ (1.5 × 10⁹/L). Neutropenia is usually caused by sepsis, necrotizing enterocolitis, cytomegalovirus (CMV) and other congenital infections, intrauterine growth restriction (IUGR), maternal preeclampsia and the chromosome trisomies (13, 18 and 21). Alloimmune neutropenia and inherited causes are uncommon. Most types of neonatal neutropenia are self-limiting and treatment is primarily of the underlying cause. Intravenous immunoglobulin is non-specific and has not been shown to be beneficial. The recombinant hematopoietic growth factor, G-CSF (granulocyte colony stimulating factor) will increase the neutrophil count, but has not been shown to improve outcome, except in the rare disorder severe congenital neutropenia. White cell transfusions are rarely effective.

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Thrombotic disorders (thrombophilia)

These are a group of disorders characterized by an increased tendency for abnormal clot formation. Thrombosis occurs in approximately 5 per 100 000 births; 50% of episodes are arterial and 50% are venous.

Predisposing factors

These are:

• indwelling catheters (80–90% of episodes)
• acute bacterial and viral infection
• asphyxia (ischemia), shock
• cardiac abnormality
• polycythemia
• prematurity
• twin–twin transfusion
• genetic.

Maternal and familial conditions associated with thrombophilia

These include:

• multiple fetal losses
• anticardiolipin antibodies
• SLE (systemic lupus erythematosus)
• maternal diabetes
• placental abruption
• myocardial infarction
• deep venous thrombosis
• pulmonary embolism.

Inherited causes of thrombosis

Gene mutations have been identified for some of the most common thrombotic disorders:

• protein C deficiency (Fig. 55.3)
• protein S deficiency
• antithrombin deficiency
• factor V Leiden mutation (APC resistance)
• prothrombin gene mutation.

Fig. 55.3 Infant with microthrombi in the skin from protein C deficiency.

Diagnosis

Most thrombi are asymptomatic.

Clinical signs of thrombosis depend on location of the clot, which may embolize:

• Arterial – limb may become mottled in color, cool and discolored with reduced pulses. In time may become gangrenous with zone of demarcation (see Fig. 66.5). Thrombus in aorta may lead to heart failure or stroke.
• Venous – portal vein, renal vein thrombosis causing abdominal mass, hematuria, oliguria and hypertension. Thrombus in right atrium may lead to stroke.

Imaging

Depends on site:

• Ultrasound, echocardiography, MRI for diagnosis and follow-up.
• Angiography is the gold standard but may become difficult or impossible to perform or not justified, e.g. for stroke. MR angiography is now available.

Management

Options include:

• If catheter-related, may be due to arterial spasm or too large a catheter or hypovolemia. If does not respond promptly to partial withdrawal of the catheter or correction of hypovolemia, the catheter should be removed.
• Observe and follow up for increase in clot size and functional compromise.
• Anticoagulation with unfractionated or low molecular weight heparin (e.g. enoxaparin).
• Clot lysis with fibrinolytic agents (tissue plasminogen activator), but contraindicated if there has been a recent intraventricular hemorrhage.
• Surgical thrombectomy – rarely required or possible.
• Factor concentrate if thrombosis and inherited deficiency (e.g. protein C, antithrombin).

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Question

Which neonates should be screened for inherited thrombophilia?

Any neonate with clinically significant thrombosis, e.g. severe purpura, renal vein thrombosis, extensive thrombosis or a family history of severe neonatal purpura.