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Hematological Problems in Pediatric Surgery

  • Ciara O’RaffertyEmail author
  • Owen Patrick Smith
Living reference work entry
  • 237 Downloads

Abstract

Severe hemophiliacs require recombinant factor replacement perioperatively to secure hemostasis. Many require placement of a central venous access device for delivery of factor replacement throughout the preschool years. Patients with thrombocytopenia, platelet function defects, von Willebrand disease, or acquired coagulopathy may need blood product replacement and special precautions prior to invasive procedures.

Children with sickle cell disease (SCD) may require splenectomy, cholecystectomy, or adenotonsillectomy and are at risk perioperatively of an acute sickling event.

Leukemic patients often require blood products or growth factor support before surgery and frequently in the operating theater throughout their treatment course for lumbar punctures, bone marrow biopsies, and central venous access-related issues.

Children who are splenectomized are rendered susceptible to overwhelming infection by Gram-positive encapsulated organisms. They require vaccination prior to splenectomy and should receive postoperative antibiotic prophylaxis up to the age of 16. Where possible, splenectomy should be deferred until >6 years of age, although this latter recommendation does not apply to children with SCD, who are functionally asplenic from a young age.

Keywords

Sickle cell disease Thalassemia Thrombocytopenia Leukemia Neutropenia Splenectomy Hemophilia Venous thromboembolism Disseminated intravascular coagulation Transfusion 

Introduction

Hematology is a broad specialty. It encompasses disorders of red cells such as sickle cell disease (SCD) , disorders of platelets such as Bernard-Soulier syndrome, and disorders of white cells such as severe congenital neutropenia . In addition, deficiencies of the coagulation proteins including hemophilia A and von Willebrand disease fall under the general remit of hematology (Arcesi et al. 2006).

The majority of the pediatric hematologist’s inpatient workload relates to the treatment of malignancy, usually acute leukemia , but also high-grade lymphomas. In contrast, much of the consultative work is centered around children with coagulopathies or hematological manifestation of systemic diseases. The hematology day ward is an active place, where children with hemoglobinopathies attend for transfusion , hemophiliacs present following a bleed, and children on chemotherapy attend for treatment and supportive care. In addition to clinical work, a hematologist usually heads the hematology laboratory, reporting on bone marrow biopsies and blood films; overseeing the automated blood counts, pre-transfusion compatibility testing, and coagulation testing; and ensuring that a quality control system is in place for delivering precise, accurate, and internationally standardized blood test reports.

Surgical issues may arise in hematology inpatients such as the neutropenic patient on treatment for leukemia who develops an acute abdomen or the need for an implantable central venous access device in a hemophiliac with inhibitors who needs to embark upon immune tolerance therapy (Hutchinson 2006).

Conversely, surgical patients may manifest hematological disturbances such as the neonate presenting with a rapidly enlarging vascular mass who is noted to be severely thrombocytopenic or the postoperative child who develops wound sepsis, oozing from tracheostomy and cannulation sites, and a disseminated intravascular coagulation .

A knowledge of hematological basic science and the pathophysiology and management of common hematological disorders (McCann et al. 2005) is a prerequisite for the competent pediatric surgeon (Blood 2005).

Hematological Basic Science

Blood Formation (Hematopoiesis)

The bone marrow is a mesenchymal-derived tissue divided into irregular interconnective spaces by bone trabeculae. It consists of a complex hematopoietic cellular component that continuously goes through self-replication and/or differentiation processes. These cells are supported by a microenvironment composed of stromal cells (endothelial cells, fibroblast-like cells, adipocytes), extracellular matrix, and vascular structures.
  • Embryonic hematopoiesis begins in the yolk sac at the end of the third week of gestation where it declines to an insignificant level by the end of the first trimester. By then, the liver is the dominant source of hematopoiesis. Hepatic hematopoietic activity reaches its maximum level at around the third month and gradually declines from the seventh month until birth. Bone marrow hematopoiesis begins around the fifth month of gestation and continues to increase thereafter.

  • Every day, in normal adult bone marrow, approximately 2.5 billion red cells, 1 billion granulocytes, and 2.5 billion platelets are produced per kg of body weight.

  • Hematopoiesis is sustained by a complex cellular interaction of hemopoietic and stromal elements and a network of cytokine growth factors including the interleukins and colony-stimulating factors.

  • All the cells of the hemopoietic system originate from a pluripotent hemopoietic stem cell (HSC) . HSCs have the intrinsic capacity for self-renewal and are low in number and divide infrequently. It is the committed progenitors that are responsible for the massive amount of cell proliferation required to maintain blood cell production in numbers as outlined above. The common lymphoid progenitors produce T- and B-cells, whereas the common myeloid progenitors give rise to erythrocytes , megakaryocytes , monocytes, and granulocytes .

Mechanisms of Hemostasis

Normal blood coagulation is a complex sequence of interrelated events by which the body prevents blood loss from the vascular tree. This is achieved by a multi-pathway interactive system with multiple negative and positive feedback loops, which ultimately ensure that blood is fluid within the vasculature while also ensuring that it can be transformed into a clot when there is a breach in the integrity of the vascular tree. The protein and cellular (endothelial cells, monocytes, and platelets) components have also been shown to be intimately involved in the inflammatory response, vasculogenesis, metastasis, cellular proliferation, and tissue repair.
  • Tissue factor, a cell surface glycoprotein, is the principal biological initiator of blood coagulation .

  • Exposure of circulating plasma factor VIIa to tissue factor triggers the coagulation cascade in vivo, which results in thrombin generation (Fig. 1).

  • Thrombin converts soluble fibrinogen to a fibrin network, activates platelets, and stimulates coagulation by positive feedback activators of cofactors, factors V and VIII, and the zymogens II, VII, IX, X, XII, and XIII.

  • Under physiological conditions, coagulant mechanisms are balanced in favor of anticoagulation ; however, at sites of vascular damage resulting from inflammation, trauma, etc., the anticoagulant system is downregulated and thus procoagulant forces prevail.

Fig. 1

Blood coagulation is initiated (initiation phase) when tissue factor (TF), expressed after injury to cell (endothelial, monocytic cells, etc.) wall, is exposed to FVIIa in the bloodstream. TF-FVIIa complex in turn activates FIX to FIXa and FX to FXa. FIXa with its cofactor FVIIIa in turn also activates FX to FXa (amplification phase). FXa with its cofactor FVa activates prothrombin (II) to thrombin (IIa) (propagation phase). Thrombin converts soluble fibrinogen to insoluble fibrin. Thrombin is not only prothrombotic but activates platelets and is pro-inflammatory and promotes new vessel formation. Shown in gray are three global coagulation screens and the part of the coagulation cascade that each represents: prothrombin time (PT); activated partial thromboplastin time (APTT) and thrombin time (TT) (Puri and Höllwarth 2009).

Natural Anticoagulation Control Mechanisms

Several natural anticoagulant mechanisms have been discovered that exert dampening effects upon pro-coagulation and in turn halt the generation of thrombin. The major anticoagulant inhibitors of blood coagulation include tissue factor pathway inhibitor, antithrombin, and the protein C pathway (Fig. 2).
Fig. 2

The initiation phase of coagulation is controlled by inhibiting the complex of TF, FVIIa, and FXa by tissue factor pathway inhibitor (TFPI). The amplification phase of coagulation is blocked by the protein C pathway. Protein C (PC) is activated by a complex of thrombin, thrombomodulin (Tm), and endothelial protein C receptor (EPCR) to APC which in association with protein S (PS) inactivates FVa and FVIIa. The thrombin formed in the propagation phase is controlled by antithrombin (AT) (Puri and Höllwarth 2009)

Platelets

Platelets derived from megakaryocytes play an essential role in thrombosis and hemostasis. Megakaryopoiesis in the bone marrow is governed by a complex interaction of cytokines (e.g., thrombopoietin) and their receptors (e.g., c-mpl). Platelets play a major role in primary hemostasis (adhesion, aggregation, and release). Platelets may also have functional defects. These disorders cause primary hemostatic bleeding (mucocutaneous) ranging from mild to severe.

Blood Groups and Antibodies

There are 35 blood group systems corresponding to red blood cell (RBC) surface antigens. The ABO system is the most important. Antibodies against blood group antigens A and B occur naturally in people who lack these antigens, for example, patients who are Group A will have naturally occurring anti-B antibodies, while patients who are Group O will have anti-A and anti-B. These antibodies are predominantly IgM and so can cause complement activation and acute intravascular hemolysis. Other clinically important antibodies do not occur naturally and require exposure to an antigen – either by a blood product transfusion or via feto-maternal exposure. These antigens vary in their immunogenicity, e.g., the RhD and the Kell antigen are highly immunogenic.

Hematological Disorders Encountered in Pediatric Practice: A Surgical Perspective

Hemophilia

Factor VIII deficiency (hemophilia A) is the second most common inherited bleeding disorder with a frequency of approximately 1 in 500 male births. Factor IX deficiency (hemophilia B) is approximately one sixth as common.

Clinical Features

  • The majority of severe and moderate (factor VIII levels <1% and 1–5%, respectively) cases present in the first few years of life.

  • Hemophilia A and B are X-linked recessive disorders. Thus, males are affected and females can be carriers.

  • One third of cases of FVIII deficiency have no family history (spontaneous mutations).

  • When there is no family history, infants with moderate/severe disease usually present as follows:
    • Post circumcision bleeding (Fig. 3).

    • Bad “toddler bruising.”

    • Soft tissue/muscle or joint bleeds at 6–18 months of age (once the child becomes mobile).

    • Intracranial, ilio-psoas, and intra-abdominal bleeds and hematuria occasionally occur.

    Fig. 3

    Hemophilia A: (a) Postcircumcisional hematoma in an infant with no family history of hemophilia. Mutational analyses showed the presence of the inversion 22 mutation. (b) Full hematoma resolution 1 week later following replacement with recombinant FVIII (Puri and Höllwarth 2009)

  • In children presenting with bruising/severe bleeding, it is not uncommon for the first presumed diagnosis to be non-accidental injury (NAI). True coagulation defects need to be excluded. A normal coagulation screen does not exclude all significant coagulation disorders, e.g., von Willebrand disease, FXIII deficiency, and platelet function defects. The presence of a bleeding disorder does not necessarily mean that NAI is excluded.

Treatment

  • The aim of modern management includes:
    • Prevention of chronic joint damage (Fig. 4)

    • Prevention of “life-threatening” bleeds

    • Facilitation of social and physical well-being and helping children to achieve their full potential

    • Provision of a comprehensive service to the family (genetic counseling, training in self-administration of factor, education on how to prevent and manage bleeds)

    Fig. 4

    Hemophilia B: Chronic severe hemophiliac arthropathy of the right knee joint. The quadriceps muscle is severely wasted. This adolescent was only treated intermittently with plasma throughout the first 5 years of life (Puri and Höllwarth 2009)

  • Successful treatment of a bleed involves the prompt and sufficient intravenous replacement of FVIII/FIX to hemostatic levels (Berntorp et al. 2016).

  • Prophylactic administration of factor concentrate converts a child who has severe disease to a child with mild disease. The child should no longer have spontaneous bleeds, and prophylaxis protects against hemophilic arthropathy . Because of the varied half-lives of coagulation factors, FVIII is given three times per week, and FIX is given twice a week in prophylactic programs. Prophylaxis can be timed immediately prior to sporting activities, thus allowing the child to live a relatively normal life (Keeling et al. 2008).

  • Prophylaxis usually requires a central venous access device (see below) to be placed in the child to facilitate regular intravenous administration.

  • Recombinant factor concentrates are now the gold standard.

  • Minor surgical procedures such as endoscopic biopsies will require factor levels to be brought up to 100% of normal levels by giving a bolus dose of factor concentrate immediately preoperatively. More major procedures, such as PortaCath placement or cardiac surgery, may require a continuous infusion of factor concentrate, preceded by a loading bolus. Levels are monitored periodically and rate of infusion titrated. In the postoperative days once hemostasis has been achieved, the infusion may be tapered or may be replaced with bolus once or twice-daily dosing.

  • The formation of neutralizing antibodies to FVIII/IX (known as inhibitors ) is the single biggest complication to modern management of hemophilia. Fifteen to 20% of hemophiliacs will develop an inhibitor. These patients cannot usually be treated with FVIII or FIX anymore, but require bypassing agents such as FEIBA or NovoSeven. FEIBA is plasma derived and so runs the theoretical risk of being able to transmit novel blood-borne diseases. NovoSeven is very costly. Neither agent can secure hemostasis as readily as simple factor replacement can in a hemophiliac without inhibitors. No routine laboratory test is available to monitor efficacy of treatment; thus, efficacy must be judged clinically, and a change from one agent to another may be required. Refractory bleeding may respond to concurrent treatment with both agents (Astermark et al. 2007).

  • Immune tolerance induction therapy is used to eradicate inhibitors soon after they develop. It involves giving large daily doses of FVIII or FIX, usually through a CVAD for many months or years with or without immunosuppressants. It is effective in about 80% of cases, but is extremely costly.

  • A number of long-acting FIX products have proven safe and efficacious at preventing bleeding in severe FIX deficiency. They include pegylated FIX and FIX fusion proteins. They are expected to reduce the need for frequent IV accessing and will likely improve compliance with therapy, thus reducing hemophilia-related complications. Increasing the half-life of factor VIII has proven more difficult, but advances are being made (Oldenburg and Albert 2014).

  • Gene therapy for FIX deficiency has been successfully trialed in a small number of patients. A viral vector introduces the FIX gene into hepatocytes. Sustained production of FIX has ensued, which converts the patient’s phenotype from a severe hemophiliac to that of a mild or moderate hemophiliac, such that they may no longer require prophylaxis and no longer bleed spontaneously. Progress in FVIII gene therapy is not quite as advanced as the factor VIII gene is larger and more difficult to introduce into the host using a viral vector.

Central Venous Access Devices (CVADs)

The intravenous administration of factor concentrate twice or three times per week is fraught with difficulty in the majority of young children when only using peripheral veins. Similarly, immune tolerance therapy (ITT) is almost impossible without regular venous access.

These devices can be fully implantable (PortaCath™, Deltac USA) or externalized and tunneled (single- or double-lumen Quintan™ catheters). The use of a port is preferable to an external device because it causes fewer limitations to the child’s lifestyle and there is a lower infective risk. However, despite the obvious attractions of these devices, they carry the risks of thrombosis and infection, both of which may lead to morbidity/mortality and permanent removal of the device. The rate of infection is higher in children with inhibitors.

There is now a growing consensus that long-term indwelling devices are necessary to facilitate the modern intensive treatment of congenital coagulation disorders. With improved management of the perioperative period and regular, frequent re-education, particularly in those children with inhibitors , many of the complications may be avoided. Central venous access devices are generally removed after the age of 5 with the development of robust peripheral veins that can be readily accessed.

More recently the use of arteriovenous fistulae (AVF) as a reliable means of vascular assess in children with hemophilia has been reported. Complication rates are reported to be minimal. The majority of children (>95%) achieved functional AVF that are still regularly used for home treatment over a median period of 29 months, suggesting that the creation of AVF as the first option for achieving permanent venous access in children with severe hemophilia is warranted.

von Willebrand Disease

von Willebrand factor is a large plasma protein involved in tethering the platelets to the capillary walls at sites of minor vessel injury (primary hemostasis). It also protects FVIII from premature proteolytic cleavage within the circulation.

A quantitative defect in VWF is termed type 1 VWD if partial or type 3 VWD if complete (no circulating VWF). A qualitative defect in VWF is termed type 2 VWD. Patients with VWD may or may not have an abnormal platelet count or APTT.

Most patients with VWD are diagnosed in adulthood. Children may come to clinical attention after positive screening results with a family history of the disorder, or they may be investigated after excessive surgical bleeding or mucocutaneous bleeding such as easy bruising, gum bleeding, epistaxis, or menstrual bleeding.

For a subset of patients without a significant personal or family history of bleeding, mild functional deficiencies of VWF, or undergoing minor procedures, treatment may not be required preoperatively. For some patients tranexamic acid preoperatively and for 5–7 days postoperatively may be sufficient. A preoperative DDAVP infusion can be used for minor procedures in patients with mild disease. Some patients will require plasma-derived VWF concentrates such as Wilate® pre- and postoperatively.

Platelet Disorders

The normal range of the platelet count in childhood is similar to that seen in adult life, being about 150–400 × 109/L.

Neonatal thrombocytopenia may have been acquired in the antenatal or perinatal period or may be an inherited thrombocytopenia. Inherited thrombocytopenia is sometimes accompanied by dysfunctional platelets (Bolton-Maggs et al. 2006).

The following is a list of inherited causes of thrombocytopenia:
  • Disorders of platelet number
    • MYH9 disorders, e.g., May-Hegglin anomaly

    • Congenital amegakaryocytic thrombocytopenia

    • Amegakaryocytic thrombocytopenia with radioulnar synostosis

    • Thrombocytopenia-absent radius syndrome

    • X-linked thrombocytopenia with dyserythropoiesis

  • Severe disorders of platelet function
    • Bernard-Soulier syndrome

    • Glanzmann’s thrombasthenia

    • Wiskott-Aldrich syndrome

  • Disorders of receptors and signal transduction
    • Platelet cyclooxygenase deficiency

    • Thromboxane synthase deficiency

    • Thromboxane A2 receptor defect

    • ADP receptor defect (P2Y12)

  • Disorders of platelet granules
    • Idiopathic dense granule disorder

    • Hermansky-Pudlak syndrome

    • Chediak-Higashi syndrome

    • Gray platelet syndrome

    • Paris-Trousseau syndrome

    • Idiopathic α- and δ-granule storage pool disease

  • Disorders of phospholipid exposure, e.g., Scott syndrome

It is important to confirm that the low platelet count is genuine by careful inspection of the blood sample and smear to exclude platelet clumps before initiating further investigations.

Once established, the approach to the diagnosis of the thrombocytopenia should be tailored to the individual child or infant and mother if dealing with neonatal thrombocytopenia. For example, assessment of the child’s general well-being is very important as healthy children usually have an immune or an inherited etiology, whereas the presence of lymphadenopathy, hepatosplenomegaly, mass lesions, hemangiomas (Fig. 5), bruits, and congenital anomalies point toward a different spectrum of causes.
Fig. 5

Capillary hemangioma in a 2-month-old boy with Kasabach-Merritt syndrome (KMS). The lesion involuted after 4 months of therapy involving vincristine, prednisolone, and antiplatelet agents (aspirin and ticlopidine) (Puri and Höllwarth 2009)

In neonates, it should also be emphasized that obtaining a detailed maternal history, including bleeding problems, preeclampsia, and drug ingestion in the present and past pregnancies and any history of viral infections (cytomegalovirus, rubella, herpes simplex, and HIV) or connective tissue disease (systemic lupus erythematosus), will save time and unnecessary investigation.

Immune Thrombocytopenia Purpura (ITP)

ITP is defined as an isolated platelet count <100 × 109/L in the absence of other causes of thrombocytopenia. It is the most common cause of thrombocytopenia in childhood.

Clinical Features

  • It is predominantly seen in children aged between 2 and 5 years.

  • Bleeding is uncommon when the platelet count >50 × 109/L.

  • Spontaneous bleeding (minor) is frequent when the platelet count <30 × 109/L.

  • It is a diagnosis of exclusion. Typically children will have a normal physical examination (with the exception of purpura) and a normal blood smear (with the exception of thrombocytopenia). Laboratory workup is usually limited to FBC, coagulation screen, renal profile, liver profile and bone profile, and LDH all of which are otherwise normal. An autoimmune screen is sometimes performed if a secondary ITP is suspected. A virology screen including hepatitis A, B and C, HIV, CMV, or EBV serology may be helpful in some cases.

  • Bone marrow examination is not generally required for the diagnosis to be made.

  • The vast majority of children will have had a preceding viral infection or will have been vaccinated in the previous month.

Pathophysiology

  • Antiplatelet antibody production leads to premature platelet destruction in the spleen and also impaired platelet production from megakaryocytes.

  • T-cell-mediated cytotoxicity also contributes to platelet destruction.

Clinical Course and Treatment (Provan et al. 2010)

  • In the majority of children, ITP will resolve spontaneously within 6–12 months.

  • The rate of major bleeding is low (<3%) even when platelet counts are severely depleted.

  • For these reasons, management of a child with newly diagnosed ITP presenting with cutaneous bleeding alone, even with a platelet count <20, is usually conservative (Rodeghiero and Ruggeri 2014).

  • Platelet transfusions are ineffective due to rapid platelet consumption and are generally contraindicated.

  • If treatment is required (e.g., more serious bleeding at diagnosis, other risk factors for bleeding, parental anxiety), then intravenous immunoglobulin and prednisolone are frontline treatments. The majority will respond.

  • A certain degree of lifestyle restriction will be required until platelet counts rise above 50 or 75, e.g., contact sport should be avoided, as should rough play. Parents should be warned to present urgently with any new bleeding and to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen which interfere with platelet function and thus increase the risk of bleeding.

  • Second-line treatments include rituximab (a monoclonal anti-CD20 antibody which depletes antibody-producing B-cells), anti-D immunoglobulin, azathioprine or cyclosporine, various other immune-modulating agents, or splenectomy .

  • Romiplostim and eltrombopag are novel drugs that stimulate the thrombopoietin receptor and induce increased platelet production by megakaryocytes. Although they produce sustained platelet responses in 60–70% of patients, relapse tends to occur on treatment cessation. They are used in children in persistent or chronic ITP. There is a small risk that either agent may cause bone marrow fibrosis, thus regular bone marrow biopsies are required for children on longer term treatment.

  • One third of children may develop a chronic form of ITP (thrombocytopenia lasting greater than 12 months) that can be symptomatic. Treatment can be problematic and hence splenectomy is worth considering. Eighty percent of children with chronic ITP will remain in remission after 4 years. The downsides to splenectomy are discussed in the relevant section.

  • Emergent bleeding requires a different approach to treatment, as some agents require weeks or months before a response is seen. Rapid-acting treatments include intravenous immunoglobulin (effect seen within 24–48 h), high-dose IV methylprednisolone, IV vincristine, emergency splenectomy, or some combination of these approaches. Platelet transfusions are occasionally used in the emergency setting only.

Disseminated Intravascular Coagulation (DIC)

DIC is a clinicopathological entity resulting in simultaneous and un-regulated activation of the coagulation and fibrinolytic pathways. It is a syndrome of serious clinical consequences which is encountered in all area of pediatrics particularly in the intensive care unit. DIC is not a primary disease entity; it is secondary to an underlying usually severe systemic illness. DIC is a progressive, pathological process resulting in profuse thrombin formation and excessive activity of the fibrinolytic pathway, and its most prominent clinical feature is a bleeding tendency.
  • Possible causes include sepsis; malignancy, e.g., acute promyelocytic leukemia; burns; pancreatitis; serious complications of pregnancy; trauma, e.g., crush injuries; surgery; and poisoning.

  • In DIC with hemorrhage, bleeding is typically from multiple sites, indicating the systemic nature of the process.

  • Purpura fulminans is seen in disseminated meningococcemia. The skin lesions appear hemorrhagic; however, microthromboses are underlying histological findings (Thachil et al. 2012) (Fig. 6).

  • Diagnostic tests in DIC include PT (prolonged), APTT (prolonged), fibrinogen (reduced), D-dimer (raised), platelet count (reduced), blood smear, and natural anticoagulant factor levels. Not all of these tests may be deranged, and an evolving clinical picture should be accompanied by repeat testing.

Fig. 6

Purpura fulminans secondary to severe acquired protein C deficiency in association with meningococcal septicemia (Puri and Höllwarth 2009)

Treatment

  • The patient and not the numbers should be treated, i.e., blood product replacement is required only in the setting of active bleeding or prior to a surgical intervention (Levi et al. 2009).

  • In the above settings, fresh frozen plasma (FFP) is used if the PT and APTT are >1.5 times the upper limit of normal; fibrinogen concentrate is used if fibrinogen is <1.0 g/dL, and platelets may be transfused to keep platelet count >50.

  • Other forms of intervention such as heparin and natural anticoagulant concentrates have been used in the past, but the current evidence does not support their recommendation.

  • Treatment should be directed toward the underlying process causing the consumption.

Thrombotic Disorders

Thrombotic disease in children is much less common than in adults. Idiopathic thrombosis in childhood is rare, and 95% of pediatric venous thromboembolisms (VTEs) occur in the context of serious illness. However, the incidence of childhood VTE is increasing, largely because of better imaging modalities and advances in neonatal care and tertiary pediatric care such as ECMO, cardiopulmonary bypass, hemodialysis, and the use of intra-arterial and intravenous indwelling catheters.

The peak incidence of thrombotic events is in the neonatal period. When venous thrombosis does occur in childhood, it can be fatal or associated with several sequelae such as amputation, organ dysfunction, and post-phlebitic syndrome.

Thrombotic tendency is seen in a number of clinical scenarios as outlined in Tables 1 and 2.
Table 1

Acquired thrombotic tendency (Puri and Höllwarth 2009)

Indwelling vascular catheters

 

Renal artery and vein thrombosis

 

Acquired natural anticoagulant deficiency

Nephrotic syndrome → antithrombin deficiency

Purpura fulminans → varicella and protein S deficiency and meningococcemia and protein C deficiency

Necrotizing enterocolitis (NEC)

 

Respiratory distress syndrome

 

Heparin-induced thrombocytopenia/thrombosis syndrome (HIT/HITTs)

 

Maternal anticardiolipin antibodies (lupus anticoagulant)

 

Extracorporeal membrane oxygenation (ECMO)

 

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP)

 

Birth asphyxia

 
Table 2

Inherited thrombotic tendency (Puri and Höllwarth 2009)

Defects within the protein C pathway

High circulating levels of FVIII

Protein C deficiency

Protein S deficiency

APCR and FVR506Q (factor V Leiden)

FIIG20210A (prothrombin gene variant)

Hyperhomocysteinemia

Cystathionine-B-synthase

Methionine synthase

Thermolabile methylenetetrahydrofolate reductase

Antithrombin deficiency

 

Fibrinolytic pathway

PAI-1 (4G/5G polymorphic status)

Plasminogenemia

Dysfibrinogenemia

 

Hemoglobinopathy

 

Platelet defects

 

Children with idiopathic thrombosis should be screened for an inherited gene defect predisposing to clot formation. The prevalence of thrombophilic defects in children with VTE varies between studies from 10% to 78%. It is not clear-cut whether children presenting with secondary VTE, e.g., CVAD-related thrombosis, should have thrombophilic testing performed. It is expensive, can cause significant concern for parents and other family members, and does not affect clinical management of the child and so is often felt to be unnecessary.

Treatment

  • Unfractionated heparin (UH) , low molecular weight heparin (LMWH), and VKAs (e.g., warfarin) have all been used safely and extensively in childhood. Heparin in childhood is monitored with anti-Xa levels. Warfarin is monitored using the INR. Home testing kits are available for parental use, with dosing supervised by a warfarin clinic, so that the child does not have to attend clinic.

  • VKAs take several days for anticoagulant effect to be manifest; therefore, in the setting of acute thrombosis, bridging anticoagulation is required with UH or LMWH

  • UH requires continuous intravenous infusion plus frequent phlebotomy for monitoring purposes. It is rapidly cleared in infants, meaning that very large doses may be needed. In this population, less time is spent in therapeutic range, and more bleeding complications are seen than with use in adults. Antithrombin may need to be replaced concurrently with UH therapy to achieve a heparin effect.

  • LMWH is emerging as the initial anticoagulant of choice for most episodes of acute thrombosis, although UH is still used extensively during cardiopulmonary bypass and other such procedures. LMWH is given subcutaneously, usually once daily (Newall et al. 2009).

  • In more specific disease states such as inherited or acquired protein C or antithrombin deficiencies, factor concentrate replacement is sometimes used.

  • For children who develop heparin-induced thrombocytopenia (HIT), a rare prothrombotic complication of heparin therapy, recombinant hirudin (lepirudin), danaparoid, or argatroban should be used.

  • An array of oral anticoagulants that do not require laboratory monitoring are now available for the treatment of VTE in adults. Many of these agents are currently being trialed in children, e.g., dabigatran, apixaban, and rivaroxaban. Unlike warfarin, no agent exists to rapidly reverse their anticoagulant effect.

Asplenia/Splenectomy/Hyposplenism

The most common form of asplenia or hyposplenism is surgical splenectomy. The usual hematological indications for splenectomy include:
  • Repeated splenic sequestration in children with SCD

  • Thalassemia major with associated hypersplenism

  • Hereditary spherocytosis

  • Refractory immune cytopenias

Splenectomy can be open or laparoscopic, the latter being preferred where appropriate facilities and expertise exists. The downside of splenectomy is a lifelong risk of overwhelming sepsis from Gram-positive encapsulated organisms. Vaccination should be performed a minimum of 2 weeks prior to elective splenectomy to minimize this risk or 2 weeks after emergency splenectomy. Daily antibiotic prophylaxis against pneumococcus is recommended up to the age of 16 and, in some cases, for life. There is also a possible increased long-term risk of venous thromboembolic disease and pulmonary artery hypertension.

Congenital absence of the spleen can be associated with multiple abnormalities including cardiovascular and visceral, and some of these have a genetic basis.

Loss of splenic substances as a result of infarction is seen in SCD and is usually accompanied by functional hyposplenism .
  • Assessment of splenic filtration function is made by examination of the blood smear for evidence of red cell inclusions which are pitted out during filtration by the normally functioning spleen (Fig. 7). The presence of Howell Joly bodies usually reflects significant splenic hypo-function and the risk of overwhelming infection.

  • Immune-mediated conditions associated with functional hyposplenism include:
    • Chronic graft-versus-host disease (cGvHD)

    • HIV/AIDS

    • Coeliac disease/dermatitis herpetiformis

    • Rheumatoid arthritis/SLE

    • Thyroid disease

    • Ulcerative colitis/Crohn’s disease

Fig. 7

The arrowed red cell shows a dark dense inclusion “Howell-Jolly body.” Howell-Jolly bodes are most commonly seen in splenectomized (surgical or “auto”) patients, severe forms of megaloblastic and hemolytic anemias, and hemoglobinopathies (Puri and Höllwarth 2009)

Anemia

  • Hemoglobin (Hb) values vary with age. Neonates are relatively polycythemic with an Hb range of 15–21 g/dL. This gradually drops to a nadir of 9.5–12.5 g/dL by 2–3 months of age. Thereafter, the Hb climbs such that the normal range is 11–13.5 g/dL from 1 year to puberty.

  • Anemia can be caused by increased destruction of red cells, e.g., acute blood loss or hemolysis. This will be accompanied within a few hours by a compensatory reticulocytosis, i.e., the reticulocyte count (the number or proportion of immature red cells) will be high.

  • Conversely, a low or normal reticulocyte count in the setting of anemia indicates inadequate bone marrow activity or failure of red cell production.

  • Several factors are required for healthy erythropoiesis. Certain nutrients are prerequisite including vitamin B12, folate, and iron. A certain growth-promoting balance of cytokines is required. This can be disrupted by inflammation. The hormone erythropoietin, produced in the kidneys, is required. The bone marrow precursors need space to expand, and an infiltrating malignancy can cause anemia. Hereditary or acquired genetic defects in the hematopoietic precursors can cause abnormal erythropoiesis, e.g., Diamond-Blackfan anemia and myelodysplastic syndrome. Aplastic anemia is thought to have an immune-related pathogenesis. Infection can directly interfere with red cell precursors, e.g., parvovirus B19, or through immune stimulation and can inhibit red cell precursors, e.g., transient erythroblastopenia of childhood. Toxins can inhibit hematopoiesis, e.g., chemotherapy.

  • Hemolytic anemias are usually accompanied by raised reticulocyte counts, indirect bilirubin, and lactate dehydrogenase (LDH). Haptoglobins will be low. Raised urinary hemosiderin suggests that hemolysis is intravascular (e.g., thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, mechanical heart valves) as opposed to taking place within the spleen and reticuloendothelial system. A direct Coombs test will help determine whether there is antibody-mediated red cell destruction. Table 4 lists causes of hemolysis.

  • The mean corpuscular volume (MCV), a marker of red cell size, can also provide useful information. Iron deficiency and thalassemia cause a low MCV. A high MCV accompanies a B12 or folate deficiency, some cases of MDS, and any cause of reticulocytosis.

  • Examining the blood film can give further pointers toward the cause of anemia, e.g., spherocytes in hereditary spherocytosis and pencil cells in iron deficiency anemia.

  • An FBC will help to determine if the process is restricted to the erythrocyte lineage only, e.g., hereditary spherocytosis, or involves the hematopoiesis more generally, e.g., acute leukemia.

  • A bone marrow aspirate and biopsy are helpful in select cases only.

  • Many cases of anemia are multifactorial, e.g., combined nutritional deficiencies in inflammatory bowel disease coupled with anemia of chronic disease. Table 3 lists causes of anemia.

Table 3

Causes of anemia

Decreased red cell production

Increased red cell destruction

Nutritional: e.g., B12, folate, iron deficiency

Acute blood loss

Space related: bone marrow infiltration, e.g., leukemia/other malignancies

Hemolysis

Toxin related, e.g., chemotherapy

 

Hormone related: EPO deficiency with chronic renal disease

 

Immune related: aplastic anemia, pure red cell aplasia, transient erythroblastopenia of childhood

 

Acquired genetic disorders of erythropoiesis: myelodysplastic syndrome

 

Hereditary genetic disorders of hematopoiesis, e.g., Diamond-Blackfan anemia, congenital dyserythropoietic anemias

 

Cytokine related: anemia of chronic disease, e.g., TB, connective tissue disorders

 
Table 4

Causes of hemolysis

Intrinsic to red cell

Extrinsic to red cell

Hb variants, e.g., HbSS, HbSC, HbSβ0Thal

Mechanical hemolysis, e.g., mechanical heart valve

Globin gene deficiency, e.g., thalassemia

Burns, toxins, others

Paroxysmal nocturnal hemoglobinuria

Microangiopathic hemolytic anemia, e.g., TTP, HUS

Red cell enzyme defects, e.g., G6PD deficiency, PK deficiency

Autoimmune

Red cell membrane defects, e.g., hereditary spherocytosis, hereditary elliptocytosis, Southeast Asian ovalocytosis

Alloimmune, e.g., Rh hemolytic disease of the newborn

 

Parasites, e.g., malaria, babesiosis

Hereditary Spherocytosis

This is an autosomal dominant hemolytic anemia caused by a deficiency of a red cell membrane protein (α or β spectrin, ankyrin, band 3, or protein 4.2). It is the most common hereditary anemia in Caucasians. There is impaired interaction between the red cell membrane and cytoskeleton. Removal of redundant areas of membrane takes place in the spleen so that the red cell loses its biconcave shape and becomes spherical, with resultant splenomegaly. The abnormally shaped red cells are incapable of traversing the narrow capillary network of the spleen and hemolysis ensues.

The spectrum of clinical severity varies among different kindreds (Bolton-Maggs et al. 2004):
  • Some patients may be transfusion dependent.

  • Other patients require transfusion during infancy, puberty, intercurrent illness, or in pregnancy only.

  • Neonates may present with prolonged neonatal jaundice.

  • Early pigment gallstones are a feature.

  • There may be a family history of splenectomy or early cholecystectomy.

Children with severe disease require splenectomy , which usually “cures” the anemia. Those with moderate disease may benefit from splenectomy. In the setting of asymptomatic gallstones, controversy exists over whether those undergoing splenectomy may also benefit from cholecystectomy .

Sickle Cell Disease (SCD)

Epidemiology: SCD occurs mainly in sub-Saharan Africans and in African-Americans, but also in South and Central Americans and people from the Middle East and Mediterranean countries. It affects nearly 100,000 people in the USA.

Pathogenesis: Sickle hemoglobin (HbS) results from a point mutation in the β-globin gene. Sickling disorders are seen when two HbS genes are inherited or when HbS is coinherited with certain other β-chain variants: HbC, HbE, HbD, HbOArab, and β-thalassemia. Sickle cell trait is the term given to asymptomatic carriage of a single HbS gene.

HbS polymerizes on deoxygenation, interfering with RBC membrane structure and deformability. The distorted RBCs cannot traverse small blood vessels in the microcirculation, and thus vasoocclusion occurs leading to ischemia, pain, and local tissue damage. Hemolysis of affected RBCs also occurs, and the presence of free hemoglobin in the microvasculature that acts as a nitric oxide scavenger contributes to the pathogenesis.

Diagnosis: Blood smear is characteristic (Fig. 8). High-performance liquid chromatography (HPLC) confirms the diagnosis and Hb electrophoresis, or isoelectric focusing may be required if there is doubt about the nature of the abnormal Hb. Many countries including the USA and UK now have universal neonatal screening programs.
Fig. 8

A 9-year-old Nigerian boy with HbSS. The arrowed cells are markedly elongated with two pointed ends. Also note the other classic findings of target cells (TC), microcytes (MC), spherocytes (SC), and polychromatophilic cells (PC) (Puri and Höllwarth 2009)

Clinical Features and Management (Yawn et al. 2014)

  • Vasoocclusion is often precipitated by cold, dehydration, or infection. It causes severe pain. Infants may experience their first vaso-occlusive event, often dactylitis , at around 6 months of age, when HbS replaces Hb F as the predominant form of Hb.

  • Vasoocclusion most frequently causes bone pain, but it can also cause nonspecific abdominal pain (may mimic an acute abdomen) or chest pain. Pain control is essential – parenteral opiates are frequently required. Patients should be well hydrated and antibiotics given if there is any suspicion of infection.

  • Chest Crisis: This can be rapidly progressive and life-threatening. Children present with dyspnea, fever, cough, and/or chest pain. Physical examination may reveal reduced air entry, crepitations, or wheeze. CXR may show pulmonary infiltrates. Infection often underlies the pathogenesis. Bone marrow embolus or intra-pulmonary vasoocclusion may also contribute. Treatment is with supplemental oxygen, hydration, antimicrobials, top-up or exchange transfusion, incentive spirometry, analgesia, and supportive care.

  • Cerebral Disease: Up to a third of children will have silent cerebral infarcts visible on MRI brain that lead to progressive cognitive impairment (Fig. 9). This may present as behavioral difficulties or a decline in school performance. Ten percent of children will have overt stroke. Raised middle cerebral artery velocity by transcranial color Doppler (TCD) ultrasound scanning is a predictive factor for stroke.

  • Splenic or Hepatic Sequestration: Sequestration is usually seen in those under 5 years. The spleen or liver becomes engorged by sickled RBCs and may cause rapid hemodynamic collapse, and transfusion is usually required. The more common splenic sequestration is a major cause of mortality in young children. Parents should be taught to palpate the child’s spleen daily, as sequestration can occur without warning.

  • Priapism mainly occurs in adolescents and adults with SCD and can lead to impotence. Up to 5% of prepubertal boys may be affected.

  • Hyposplenism : Autoinfarction of the spleen occurs in early childhood, resulting in functional hyposplenism. This puts patients at risk of overwhelming sepsis from encapsulated organisms, most frequently Streptococcus pneumoniae. From early infancy, patients should take daily prophylactic penicillin, and all patients should be vaccinated with Pneumovax.

  • Aplastic Crisis: Parvovirus infection suppresses erythropoiesis and in SCD can cause an acute drop in Hb with an accompanying reticulocytopenia.

  • Other complications include obstructive sleep apnea with nocturnal hypoxia, nocturnal enuresis, and increased incidence of pregnancy-related complications.

Fig. 9

About 25% of patients with SCD develop cerebrovascular complications and about 80% of these are under 15 years of age. The MRI brain shows an area of infarction (I) secondary to vessel occlusion (stenosis (S) and absence (A)) (Puri and Höllwarth 2009)

Chronic Complications

  • Pulmonary hypertension

  • Chronic renal impairment

  • Chronic osteomyelitis or avascular necrosis (AVN)

  • Pigment gallstones

  • Proliferative retinopathy

  • Chronic leg ulceration in young adults

Disease-Modifying Therapy

  • Chronic Transfusion Therapy: Patients are placed on a transfusion program after a stroke or if they have abnormal TCDs. They are transfused every 3–4 weeks, which suppresses HbS production. Recent evidence indicates that chronic transfusion therapy may preserve cognitive function in patients with silent infarctions. Transfusion therapy is also used for other indications. However, the benefits of transfusion must be weighed against the impracticalities of such programs and the complications that include iron overload and red cell antibody formation.

  • Hydroxyurea : Originally used as an oral chemotherapy, hydroxyurea functions in SCD to increase the quantity of HbF synthesized, thus reducing the relative proportion of HbS in the circulation. Hydroxyurea can reduce the number of painful episodes suffered. It can also reduce the incidence of dactylitis and ACS and reduce the frequency of hospitalization and blood transfusion . For many children, it brings about a marked improvement in quality of life, although not all children respond and some lose their response over time. It is now recommended in the USA for all children above the age of 9 months with SCD.

  • Hematopoietic Stem Cell Transplantation : This is potentially curative, although the procedure is more complicated for those with a more complex SCD history, who paradoxically are those most in need of cure. HSCT is not feasible in every patient and is generally considered for those with previous stroke, severe sickle-related pain, or recurrent chest crises with a fully histocompatible unaffected sibling donor.

Surgery in Sickle Cell Disease

  • Any child of the correct ethnic origin who is to undergo surgery and whose sickle status is not known should have a preoperative screening test performed, e.g., sickle solubility test and HPLC. The “SICKLEDEX,” a solubility test, is unreliable in children under 6 months old or in those who have been recently transfused.

  • Common surgeries performed in SCD include splenectomy for recurrent splenic sequestration, cholecystectomy for pigment gallstones, and adenotonsillectomy for obstructive sleep apnea.

  • Surgery and anesthesia can precipitate sickling. Anemia and obstructive sleep apnea also contribute to surgical risk. Mortality rates vary in the literature from 1% to 10%.

Key Principles of Perioperative Management
  • Keep the child well hydrated and maintain an adequate ambient temperature.

  • Maintain adequate oxygen saturations using supplemental oxygen.

  • Consult with hematology and anesthetic colleagues regarding the need for preoperative top-up or exchange transfusion. There is only one randomized controlled trial, which showed that a conservative transfusion regimen that raised hemoglobin to 10 g/dl was as effective in preventing perioperative complications as an aggressive exchange regimen which reduced HbS to <30%. A randomized trial is currently being run in the UK that compares those who receive no transfusion with those who receive transfusion.

  • Incentive spirometry postoperatively reduces the frequency of ACS .

Thalassemia

Thalassemia is a hemoglobinopathy caused by deletion of either an α- or β-globin gene. Thalassemia is found most frequently in Southeast Asia, but it also occurs in Northern Africa, the Middle East, Mediterranean Europe, India, and Central Asia. Children with the mildest forms show only a microcytosis without anemia. At the other end of the spectrum, deletion of all four alpha globin genes results in hydrops fetalis and is incompatible with extrauterine life.

Children with β-thalassemia major present in infancy with transfusion-dependent microcytic anemia and failure to thrive. In the first decade of life, they develop the complications of chronic transfusion-related hemosiderosis including diabetes, hypoparathyroidism, and osteoporosis. They may have delayed puberty. In order to prevent death in the teenage years, an aggressive iron chelation program must accompany chronic transfusion therapy. In addition to oral iron chelators, this usually involves nocturnal subcutaneous desferrioxamine therapy, which is administered five to seven nights per week for 8–15 h (Standards for the clinical care of children and adults with thalassaemia in the UK; 2008.). Adherence to therapy often becomes an issue. Even with maximal chelation therapy, affected persons can develop hepatic and cardiac failure in later life. Bone marrow transplantation is potentially curative.

Neutropenia

Newborns often have neutrophilia for the first 2 weeks, mean count 11 × 109/L, whereas children between 1 month and 8 years have mean levels of 3.6 × 108/L. Above this age counts are similar to adult levels.
  • Neutropenia can be inherited or acquired and transient or chronic.

  • The workup for a child with neutropenia requires documentation of the neutropenia over time and elimination of possible precipitating causes by history and bone marrow examination.

  • Children with neutrophil counts of <0.5 × 109/L are at increased susceptibility to bacterial infections. An untreated bacterial infection in a severely neutropenic patient can progress within hours to septic shock and death. Treatment usually involves dual intravenous broad-spectrum antibiotics. Chronic severe neutropenia renders patients susceptible to deep-seated fungal infection.

  • Acquired transient causes of neutropenia include infections (viral, bacterial), burns, drugs (e.g., chemotherapeutics, carbimazole), hemodialysis, and B12 or folic acid deficiency.

  • Acquired chronic causes include bone marrow infiltration (e.g., leukemia), myelodysplasia, immune-mediated (alloimmune and autoimmune), hypersplenism, viral bone marrow suppression, and idiopathic.

  • Severe congenital neutropenia (Kostmann syndrome) can be caused by mutations in several different genes encoding mitochondrial proteins (HAX1, AK2), endoplasmic reticulum proteins (ELANE/ELA2 and G6PC3), cytoskeletal regulator proteins, (WAS) and transcriptional repressor proteins (GFI1). Affected children have severe neutropenia and recurrent bacterial infections. The untreated mortality is high (70%). >20% of children treated with GCSF will go on to develop acute myeloid leukemia within 10 years.

  • Other causes of isolated neutropenia are cyclical neutropenia, WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis), and benign chronic neutropenia (BCN). BCN is autoimmune in etiology and is associated with a much milder phenotype than SCN. It is a transient cytopenia occurring in the preschool years that lasts an average of 20 months and is associated with minor ENT and skin infections. It is the most common cause of chronic neutropenia in childhood.

  • Neutropenia may also be associated with complex syndromes including cartilage-hair hypoplasia, Chediak-Higashi syndrome, dyskeratosis congenita, primary immunodeficiency syndromes (e.g., X-linked immunodeficiency with hyper-IgM), Fanconi anemia, Shwachman-Diamond syndrome, and metabolic disorders, e.g., glycogen storage disease type 1B.

  • Treatment involves supportive measures such as antibiotics, G-CSF (a recombinant cytokine that stimulates granulopoiesis), and, in some cases, bone marrow transplantation.

Leukemia

Leukemia is the most common pediatric malignancy. Eighty percent of these children have acute lymphoblastic leukemia (ALL), 15% have acute myeloid leukemia (AML), and the remainder present with rare pediatric leukemias such as chronic myeloid leukemia and juvenile myelomonocytic leukemia.
  • Acute leukemia presents with a prodromal illness lasting a few days to a few months. Symptoms include lethargy, anorexia, general malaise, dislike of being handled (bone pain), fever and infection, and bruising or bleeding. Untreated acute leukemia is fatal within days to weeks.

  • White cell count may be high or low at presentation, and there are usually blasts (leukemic cells) circulating in the blood. Pancytopenia (anemia, neutropenia, and thrombocytopenia) is common. Biochemistry may show an elevated LDH and urate.

  • Examination may reveal hepatosplenomegaly, palpable adenopathy, gum hypertrophy, skin infiltration, petechiae, or purpura. Papilledema may be present with central nervous system (CNS) involvement.

  • A preliminary diagnosis can usually be made from the blood smear. The lineage (myeloid or lymphoid) of the leukemia is then confirmed by flow cytometry. In cases of pancytopenia , a bone marrow aspirate or trephine biopsy may be needed to make a diagnosis.

Management of Acute Leukemia

  • Hyperhydration to prevent tumor lysis syndrome (TLS) on commencement of chemotherapy. TLS is manifest by electrolyte disturbances and accumulation of uric acid crystals in the kidneys with acute renal failure.

  • Blood product support.

  • Broad-spectrum antibiotics intravenously if there are infectious issues.

  • Urgent placement of a tunneled CVAD and the commencement of cytotoxic chemotherapy.

  • Treatment of ALL is now response stratified, i.e., those who respond promptly to chemotherapy without evidence of minimal residual disease (MRD) by molecular techniques at the end of induction are treated on a less drug-intense regimen. Those who have MRD at the end of induction are escalated to a more intense regimen. This allows individualized treatment to maximize cure while minimizing toxicity.

  • Treatment for ALL lasts for approximately 3.5 years in boys and 2.5 years in girls. There is an initial induction phase of therapy, followed by consolidation, delayed intensification, and maintenance therapy. Maintenance therapy involves daily oral chemotherapy with intermittent pulses of intravenous chemotherapy and is delivered as an outpatient. All phases of treatment are generally accompanied by intrathecal chemotherapy, drugs delivered usually by lumbar puncture directly into the CNS to prevent CNS relapse.

  • >85% of cases of ALL can be cured by chemotherapy alone.

  • Relapse treatment involves salvage chemotherapy with or without a bone marrow transplant.

Surgical Issues in the Leukemic Patient

  • CVAD : The child requires the urgent placement of a tunneled CVAD for ease of delivery of supportive care, but also to allow safe delivery of vesicant chemotherapy. If a vesicant (e.g., daunorubicin) is administered through a peripheral vein, thrombophlebitis and associated extravasation can occur, with extensive localized tissue destruction. This is a limb-threatening complication. Prior to CVAD placement, the child may require blood product replacement to achieve Hb >8.0 g/dL, platelets >50 × 109/L, or plasma replacement to correct a coagulopathy.

  • Typhlitis or neutropenic coliti s (inflammation of the cecum due to Gram-negative bacteria of the gut flora) is a diagnosis unique to the neutropenic patient. Its diagnosis is relatively common on the hemato-oncology wards where intensive chemotherapeutic protocols are routinely used. Patients are febrile and usually have right-sided or generalized abdominal pain. It should be remembered that no clinical findings differentiate typhlitis from other abdominal diseases. CT and ultrasound imaging show distention and thickening of the cecum and bowel wall thickening with associated marked pseudopolypoid formation of the mucosa. Neutrophil recovery is a good prognostic factor. Conservative management with broad-spectrum antibiotics and antifungals with or without bowel rest is the treatment of choice. Surgical intervention should only be considered in the most severe cases.

  • Asparaginase-associated pancreatitis (AAP) : Asparaginase is a cornerstone drug in ALL therapy; however, in 5–10% of cases, it can cause pancreatitis (Raja et al. 2012). The pathogenesis of AAP is unknown. As with other causes of pancreatitis, patients present with abdominal pain and vomiting and may have deranged blood biochemistry including an elevated amylase or lipase, low calcium, and a raised CRP. Ultrasound or CT confirms the diagnosis, and serial imaging may be required to detect the emergence of complications. Management involves drug cessation, antibiotics until sepsis can be excluded, initial bowel rest, total parenteral nutrition, and supportive care. There may be a role for octreotide and continuous regional arterial infusion of protease inhibitors. Complications include systemic inflammatory response syndrome and multiorgan failure, pseudocyst formation, insulin-dependent diabetes mellitus, and chronic pancreatitis.

  • Mediastinal mass at presentation: Acute lymphoblastic lymphoma is a variant of ALL which may present with a mediastinal mass without derangement of the FBC. The differential diagnosis includes a variety of other malignancies, and a histological diagnosis may be required. Sometimes mediastinoscopy can be avoided if flow cytometry of microscopically normal bone marrow or of pleural fluid or biopsy of an enlarged peripheral node reveals the diagnosis. Patients may develop superior vena cava obstruction syndrome and airway encroachment. Steroids may shrink the mass; however, they may also obscure the histological diagnosis and are therefore only used pre-biopsy if the patient is in a critical condition. Early senior anesthetic involvement is imperative in order to protect the airway during surgery.

Blood Products and Their Transfusion

A list of blood products used in children in the surgical setting is shown below:
  • Red blood cells (RBCs): Dose (ml) = (desired rise in Hb) × 3× recipient weight (kg).

    The selection of a unit of blood is geared to prevent inadvertent exposure to a foreign antigen and consists of:
    1. 1.

      ABO and RhD grouping of the recipient

       
    2. 2.

      Antibody screen of the recipient (or mother in the case of neonatal transfusion) – serum is tested against a “panel” of commercially available RBCs which carry all clinically important antigens between them

       
    3. 3.

      A comparison of these results with any available historical record (a “group and screen” finishes at this point)

       
    4. 4.

      Testing of patient serum against the RBCs to be transfused (a crossmatch)

       
  • Platelets : Dose =15 ml/kg. Usual maximum dose is one unit (“adult dose”) unless the patient is bleeding or a specific target platelet count must be achieved.

  • Frozen Plasma (FP): Usual dose 15 ml/kg, used as source of clotting factors in DIC and hemorrhagic disease of the newborn. “Pathogen-reduced plasma” is standard, which has undergone a viral inactivation process.

  • Fibrinogen Concentrate: This has replaced cryoprecipitate as the product of choice for fibrinogen replacement as it can be rapidly reconstituted in a small volume, is virally inactivated, and contains a standardized fibrinogen content. In a massive hemorrhage situation, fibrinogen can be the most significantly depleted clotting factor; therefore, levels must always be checked. Usual dose is 70 mg/kg.

  • RBCs and platelets are leukodepleted to remove WBCs which can cause immune reactions and harbor infections (e.g., CMV).

  • CMV-negative and/or irradiated products are usually required for immunosuppressed patients – refer to local guidelines.

Acute Complications of Blood Transfusion

  • Hemolytic reaction: fever, dyspnea, back pain, and hemoglobinuria.

  • Allergic reaction (urticarial and anaphylactic reactions).

  • Bacterial contamination – usually seen with platelets (stored at 22 °C).

  • Transfusion-related acute lung injury (TRALI): occurs due to anti-WBC or HLA antibodies in donor or recipient. This causes an ARDS-like picture.

  • Febrile non-hemolytic reaction: nonspecific reaction to foreign antigen. These must be differentiated from more serious reactions

  • Volume overload: Deaths have been described in the Serious Hazards of Transfusion (SHOT) report. All children should be medically assessed for risk factors prior to transfusion, blood volumes should be carefully calculated, and patients should be continuously assessed throughout transfusions.

The various acute reactions have similar presentations (Bolton-Maggs et al. 2015). In practice, all the above possibilities need to be considered. When faced with a suspected transfusion reaction:
  1. (a)

    Stop the transfusion.

     
  2. (b)

    Assess hemodynamic stability – resuscitate if necessary.

     
  3. (c)

    Check the patient identification against the blood product.

     
  4. (d)

    Examine the product for abnormal appearance suggesting contamination.

     
  5. (e)

    Order full septic screen (include product if bacterial contamination a possibility), and check a FBC, renal profile, and coagulation screen (looking for indices of hemolysis, renal failure, and DIC),

     
  6. (f)

    Order CXR if dyspnea/hypoxia.

     
  7. (g)

    Repeat crossmatch and antibody screen.

     
  8. (h)

    Alert the hematology laboratory to the possibility of a transfusion reaction as another product recall may be necessary.

     

Other Adverse Reactions to Blood Product Transfusion

  • Delayed hemolytic reactions occur after 5–10 days – there is evidence of hemolysis (decreased Hb, raised LDH, raised bilirubin, reduced haptoglobins) and possibly renal impairment.

  • Infection can be bacterial, viral, protozoal (Chagas’ disease), or prion related (vCJD).

  • Iron overload is seen with chronic RBC transfusion, e.g., thalassemia major.

  • Post-transfusion purpura: there is a reaction to an antigen on transfused platelets that the recipient’s immune system recognizes as foreign. Severe thrombocytopenia ensues 7–10 days later. This is rare.

  • Transfusion-associated graft-versus-host disease is a rare but universally fatal complication of blood transfusion. It occurs in immunocompromised hosts or where the donor shares HLA types with the host. It can be prevented by irradiating blood for certain immunocompromised recipients and avoiding interfamily donations.

Conclusion and Future Directions

Hematology is a rapidly evolving field of medicine with many advances in recent decades in the molecular understanding of hematological disorders. Pharmaceutical companies invest large proportions of their drug development budgets in hemato-oncology drugs. This has a knock-on effect on government healthcare budgeting. Due to the need for extensive experience of a drug in adults before it can be considered for use in children, there is some delay before changes in adult practice filter into pediatrics. The following is a summary of treatments on the horizon for the most common pediatric hematological disorders.

ALL is now curable in >85% of cases with chemotherapy alone. Current clinical trial focus is on reducing long-term toxicities of treatment regimens for patients with low-risk disease. For those children with high-risk disease who cannot afford a de-escalation of therapy, biologically targeted therapies offer the potential to increase cure rates without contributing much in the way of toxicity (Sadelain et al. 2015; Ai and Advani 2015). Blinatumomab, a bispecific T-cell engager, directs the immune system to target B-ALL cells that express surface CD19. A substantial proportion of adults with relapsed or refractory ALL achieved a complete response in early-phase clinical trials. Phase III trials are underway in children and adults, and blinatumomab has received early FDA approval for B-ALL. Inotuzumab is a cytotoxic agent conjugated to a humanized monoclonal antibody directed against CD22, often expressed on the surface of ALL blasts. It can induce molecular remissions in relapsed or refractory ALL. One of the most exciting new developments for the treatment of B-ALL is chimeric antigen receptor (CAR) T cells. These are T-cells taken from the patient (autologous) or from a third party (allogeneic) that are genetically engineered in vitro to recognise a marker expressed on the blasts of the patient's leukemia (eg. CD19 or CD22). Results of early phase trials in children have shown a very high response (60-100%) and cure rate, including in patients with disease that would previously have been considered incurable. At present, CAR T cell therapy for ALL is only available in certain countries as part of a clinical trial, although it is likely to change the landscape of ALL treatment in the years ahead.

Drug development for hemophilia aims to address the following problems with recombinant factor and bypassing agents: short half-life, poor ease of delivery, suboptimal potency, and immunogenicity. Biologically engineered longer-acting factor concentrates and concentrates that allow for subcutaneous administration, as well as novel recombinant factor products, are on the horizon for hemophilia treatment. Gene therapy has proven successful in a small group of trial patients. In addition to reducing spontaneous bleeding, new therapies for hemophilia may make surgery safer in this population.

In spite of improved survival in SCD through neonatal screening programs, screening to prevent complications, and hydroxyurea therapy, the current life expectancy in the USA is only 50 years. Fifty percent of patients will not benefit in the long term from hydroxyurea therapy, either through poor response, reluctant therapists, inadequate dosing, toxicities, or noncompliance. More widespread use of hydroxyurea, coupled with optimization of dosing, should further impact on mortality. Novel therapies are needed, and treatments in the pipeline focus on modifying effects downstream of sickling such as vascular adhesion, inflammation, and hemolysis. Increasing experience in transplanting patients with SCD will likely make transplant safer. SCD patients may benefit in the future from gene therapy. Likewise, more patients with thalassemia may benefit from transplant, and gene therapy may one day provide a curative solution.

In the 1950s, children with leukemia died within weeks of diagnosis, hemophiliacs were bed-bound throughout childhood and died in early adulthood, patients with thalassemia major died in early childhood, and patients with SCD died in infancy or childhood. Advances in the understanding of these disorders mean that in hemophilia, thalassemia, and SCD, long-term survival is expected, and focus of treatment has moved toward reducing long-term complications and improving quality of life. Elective surgeries are now more frequently performed in these populations, and emphasis should be on reducing perioperative morbidity.

Cross-References

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Copyright information

© Springer-Verlag GmbH Germany 2016

Authors and Affiliations

  1. 1.Department of HaematologyOur Lady’s Children’s HospitalCrumlin, Dublin 12Ireland
  2. 2.University College DublinDublin 4Ireland

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