Neonatal alloimmune thrombocytopenia (NAIT) constitutes less than 5 % of cases of neonatal thrombocytopenia but is important to exclude due to its associated morbidity and mortality [13], and the requirement for specific platelet transfusion components matched for the alloantibodies. The diagnosis and management of this condition is dealt with in Chap. 16.

The toxoplasma, rubella, cytomegalovirus, herpes (TORCH) viral infections can cause thrombocytopenia although the exact mechanism is unclear. Parvovirus can also cause thrombocytopenia through suppression of bone marrow and megakaryocyte colony formation [14]. Other viruses known to cause thrombocytopenia include enterovirus, Coxsackie virus, adenovirus, Epstein-Barr virus, and dengue virus. HIV is known to infect megakaryocytes and suppress colony growth [15] and is so frequently associated with neonatal thrombocytopenia that it has been suggested as a screening tool [16].

Thrombocytopenia is common although rarely severe in the trisomies 18 (86 %), 13 (31 %), and 21 (6 %), as well as in Turner syndrome (31 %) [17]. The mechanism of thrombocytopenia in trisomies 13 and 18 is unknown although it may have its etiology in chronic fetal hypoxia. Thrombocytopenia in trisomy 21 is similar to that seen in growth-restricted infants: neutropenia, polycythemia and increased circulating normoblasts. Ten percent of infants with Down syndrome, however, develop a clonal preleukemic disorder showing increased myeloblasts and variable levels of thrombocytopenia, and 20–30 % of these babies will develop acute megakaryoblastic leukemia within the first 5 years of life [18]. It is thought that trisomy of chromosome 21 disturbs fetal hemopoiesis and predisposes to mutations in the GATA1 gene, a key megakaryocyte/erythroid transcription factor [19].

Autoimmune conditions such as maternal idiopathic thrombocytopenic purpura, which may occur in association with systemic lupus erythematosus, can also cause thrombocytopenia in the fetus and neonate. This is dealt with in Chap. 15.

In addition to anemia, neutropenia and reticulocytosis, thrombocytopenia is common in severe rhesus hemolytic disease, especially after intrauterine or exchange transfusions; this is due to platelet-poor blood product and suppression of platelet production in favor of erythropoiesis.

These are caused by reduced platelet production due to abnormal hemopoietic stem or progenitor cell development. They may be associated with defective platelet function. Many of these disorders will be diagnosed by their associated congenital anomalies.

Lysosomal storage diseases such as Gaucher’s disease can also present with thrombocytopenia [32]. These disorders are characterized by mutations in one of a series of enzymes involved in the degradation of glycosphingolipids. Patients can present with hepatosplenomegaly, cardiomyopathy, renal dysfunction, anemia, thrombocytopenia, and neurological degeneration. Thrombocytopenia associated with splenomegaly may also be secondary to infiltrative metabolic disorders such as the mucolipidoses and mucopolysaccharidoses.

Fanconi anemia is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, and aplastic anemia. It is rare to present with thrombocytopenia in the neonatal period although it should be considered in the presence of dysmorphic features and unexplained thrombocytopenia. The diepoxybutane test is almost always diagnostic of this disorder [33].

Amegakaryocytic thrombocytopenia with radioulnar synostosis (ATRUS) is caused by mutations in the HOXA11 gene and is characterized by severe thrombocytopenia from birth, radioulnar synostosis, clinodactyly, and shallow acetabula [36].

Congenital amegakaryocytic thrombocytopenia (CAMT) is an autosomal recessive condition that almost always presents early in the neonatal period with severe thrombocytopenia; 50 % of affected infants will have evidence of bleeding [37]. Although there is isolated thrombocytopenia in the newborn period, 50 % will go on to develop aplastic anemia in childhood. Stem cell transplantation is curative in cases of severe disease [38].

Thrombocytopenia occurring after 72 h of age is due to sepsis or NEC in more than 80 % of cases [14].

Neonatal thromboembolism is a rare but increasingly reported condition in the neonatal unit that can cause significant neonatal mortality and morbidity. Ninety percent of thromboembolism is associated with thrombosis of arterial or venous catheters and central venous lines, but stroke is also prevalent, and the incidence of perinatal stroke ranks second only to the strokes of the elderly population (1 in 2,300 to 1 in 5,000 births) [53].

Idiopathic thromboembolism accounts for less than 1 % of cases of newborn thromboembolism as compared to 40 % in the adult population [54]. Usually at least one risk factor can be identified, either maternal or fetal, including maternal diabetes or SLE with antiphospholipid syndrome, pre-eclampsia, IUGR, maternal autoimmune conditions, maternal thrombophilia, placental vasculopathy, infection, hypovolemia, dehydration, hypoxia, acidosis, and neonatal prothrombotic disorders [55–62].

The prothrombotic disorders that have been linked with neonatal thromboembolism include deficiencies in protein C, protein S, antithrombin, and plasminogen [63–66]. Homozygous deficiencies of these factors usually present with severe clinical symptoms and require urgent management. However, diagnosing heterozygous states can be difficult in the neonate because physiological values are lower than in older children and adults [67]. Diagnosis can also be complicated by the coexistence of acquired disorders – present in over 80 % of newborns with systemic thromboembolism [68]. Of note, homozygous plasminogen deficiency is associated with ligneous conjunctivitis, and in some cases with occlusive hydrocephalus [66], the pathogenesis of which is unclear. Both homozygous and heterozygous plasminogen deficiency do not appear to be associated with spontaneous thrombotic events, although repeated thrombotic occlusion of implanted catheters has been described [66, 69, 70]. It has been suggested that patients with heterozygous type I plasminogen deficiency who develop thrombosis may have additional risk factors such as deficiency or protein C or S or antithrombin deficiencies [70].

The clinical presentation of homozygous protein C deficiency in the neonatal period is purpura fulminans, cerebral stroke, and/or large-vessel thrombosis. The diagnosis is confirmed in the presence of these clinical features with an undetectable protein C level and both parents testing as heterozygotes for protein C deficiency. Heterozygous protein C deficiency does not normally present with thrombosis in early infancy [71], but cohort studies have indicated an increased prevalence of protein C heterozygosity in neonates with thromboembolism and additional risk factors [72]. Babies with homozygous protein S deficiency also present with purpura fulminans, but like protein C deficiency, the heterozygous state is only uncommonly associated with thromboembolic phenomena in infancy or childhood [73]. Homozygous antithrombin (AT) deficiency, where levels are less than 10 % of normal, is rare but can be associated with severe thromboembolic events, venous or arterial [74]. Heterozygous AT deficiency is associated with diverse but less severe thrombotic events.

The presence of Factor V Leiden or the prothrombin G20210A mutation have also been linked to neonatal thromboembolism [61, 62, 75, 76]. Approximately 5 % of Caucasians are heterozygous for the factor V Leiden mutation (R506Q) at the cleavage site for activated protein C (APC), which decreases the rate of inactivation of factor V, leading to a reduced anticoagulant effect of APC (APC resistance [77]); and 2 % for the prothrombin G20210A mutation, that is associated with increased prothrombin levels possibly due to increased mRNA stability [78]. A homozygous polymorphism in the C677T methylene tetrahydrofolate reductase (MTHFR) gene has been linked to an increased thrombotic risk in infants with perinatal arterial stroke [79]. Homozygosity for this polymorphism, in the presence of folate deficiency, may predispose to hyperhomocystinaemia, with the phenotypic expression silenced by folic acid supplementation. An elevated homocysteine level has also been associated with an increased thrombotic risk [80], but the contribution of these risk factors to neonatal thrombosis is unclear.

Treatment options for neonatal thrombosis include supportive care, anticoagulation and thrombolysis. In the past, clinicians have been reluctant to use anticoagulant therapy in neonates due to the possible risks of bleeding. The German registry of neonatal thrombosis reported rates of major hemorrhage of 2 % for heparin anticoagulation and 15 % for thrombolysis [90]. The American College of Chest Physicians (ACCP) guidelines suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism; and when this is not possible, a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric haematologist [106].

Possible anticoagulants for use in neonates include unfractionated heparin (UFH), low molecular weight heparin (LMWH). However, target therapeutic ranges are based on adult rather than neonatal ranges. Neonates often require high doses of UFH to maintain the target therapeutic range; this is because of physiologically decreased levels of antithrombin, increased volume of distribution, rapid heparin clearance, and non-specific protein binding in plasma [107, 108]. Advantages of LMWH in this population relates mostly to its subcutaneous administration and reduced requirement for monitoring compared with UFH, particularly given that venous access is often limited in infants. There is limited dosing data regarding LMWH use in neonates. Small pharmacokinetic studies of enoxaparin and dalteparin in pediatric patients demonstrate wide ranges of dose requirements, with neonates requiring the highest doses [109–111]. The majority of neonates reach a therapeutic anti-Xa activity level using 1.625 mg/kg/dose. Anti-Xa activity levels effectively monitor LMWH therapy in neonates [112].

Thrombolytic therapy should be considered for neonates with acute thrombosis, such as aortic, atrial or peripheral arterial thrombosis, that is life-threatening or that could potentially lead to loss of a limb, that presents within 2 weeks of symptomatic onset. Thrombolytic agents can be administered systemically or locally. Systemic thrombolysis avoids the requirement for interventional radiologic procedures (often challenging in small children), a requirement for anesthesia, and the delay to therapy potentially encumbered during the organization of local invasive thrombolysis. Higher-dose recombinant tissue plasminogen activator (rt-PA, alteplase) (0.1–0.5 mg/kg/h) in short courses of 6–48 h are generally chosen for arterial clots and can also be used for venous thrombi. Low-dose (0.03–0.06 mg/kg/h) longer duration systemic infusions of t-PA for 12–96 h have been shown to be effective for lysis of venous thrombi [112–114]. Coagulation screening tests including PT, APTT, fibrinogen, plasminogen and D-dimer or FDP levels, should be monitored during therapy to ensure hemostatic levels of platelets and fibrinogen and to determine baseline fibrinolytic potential (plasminogen concentration) and activation (D-dimer levels). The therapeutic action of t-PA requires plasminogen and therefore its effect may be improved by the administration of fresh frozen plasma (FFP) 10 mL/kg daily for plasminogen concentrations less than 50 %. Infusions of thrombolytic agents should be discontinued as soon as clot lysis has been achieved, as there is no potential for further improvement and bleeding complications increase with increasing dose and duration of thrombolytic therapy. Therefore repeated imaging should be undertaken. In addition, cranial ultrasound imaging is recommended prior to initiation of therapy and daily thereafter [114].

Supportive care is usually provided to infants with renal vein thrombosis, and anticoagulant and thrombolytic therapy are controversial in the treatment of this condition. Unilateral renal vein thrombosis with thrombus extending into the inferior vena cava may warrant treatment with LMWH. In bilateral renal vein thrombosis, thrombolysis should be considered [115].

In neonates with clinical presentations of homozygous protein C deficiency, the ACCP recommends administration of either 10–20 mL/kg of FFP every 12 h or protein C concentrate, when available, at 20–60 units/kg until the clinical lesions resolve. For neonates with homozygous protein C deficiency, after initial stabilization, the ACCP recommends long-term treatment with a vitamin K antagonist (VKA) such as warfarin, LMWH, protein C replacement, or liver transplantation [106].

There are no trials supporting the efficacy or safety of anticoagulant therapy for treatment of stroke in the neonate, and currently there are no recommendations for anticoagulation or aspirin for this condition. For neonates with a first arterial ischemic stroke (AIS), in the absence of a documented, ongoing cardioembolic source, the ACCP suggests supportive care over anticoagulation or aspirin therapy. For AIS secondary to cardioembolic causes, the ACCP suggests anticoagulant therapy with LMWH or VKA for at least 3 months. For AIS secondary to cardioembolic causes in children with demonstrated right-to-left shunts (e.g. patent foramen ovale, PFO), the ACCP suggests surgical closure of the shunt [106].