Disorders of Hemostasis

In this section, we cover the diagnosis and management of the following hemostatic conditions in children:

• Hemophilia

• von Willebrand disease

• Thrombosis and thromboembolic disease

Hemophilia

Hemophilia is an inherited bleeding disorder (X-linked recessive) that is caused by the deficiency of either factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B). The severity of bleeding is dependent on the factor level of the patient; patients with severe deficiencies (<1 IU/dL or <1% of normal) have more clinical manifestations than those with moderate (1-5 IU/dL or 1%-5% of normal) or mild (5-40 IU/dL or 5%-<40% of normal) factor deficiencies. Factor VIII deficiency is more common than factor IX deficiency.

Clinical features

• easy bruising

• spontaneous bleeding into joints or muscle (risk of compartment syndrome)

• excessive bleeding after trauma or surgery

• serious bleeds (e.g., intracranial or gastrointestinal hemorrhage)

Diagnosis

• history and physical examination, including detailed family history

• prothrombin time (PT), activated partial-thromboplastin time (aPTT), and platelet count as screening tests

• factor VIII and factor IX quantitative assays

Treatment

Factor concentrate infusion: Management of patients with hemophilia relies on the use of clotting factor concentrate infusions for prophylaxis or treatment of bleeding. The World Federation of Hemophilia (WFH) recommends the use of viral-inactivated plasma-derived or recombinant concentrates for the treatment of hemophilia. Various manufactured products are on the market, and selection of a factor product should depend on availability and parent and physician decision.

Inhibitors: Patients with hemophilia who are treated with clotting factor concentrates can develop immunoglobulin G (IgG) antibodies (known as inhibitors) to the infused factor products. Inhibitors may render infused factor products ineffective, particularly if the inhibitor is present in high titers and necessitates the use of bypassing agents (factor eight inhibitor bypass activity [FEIBA] or activated recombinant factor VII [rFVIIa], NovoSeven). High-dose factor product infusion can be effective if the inhibitor is present in low titers (see table below).

Other Available Treatments: While replacement therapy has long been the mainstay of treatment for hemophilia, newer therapies have been developed to improve quality of life in patients with hemophilia. The most common of these is emicizumab.

• Emicizumab is a bispecific antibody designed to replace the hemostatic function of activated FVIII. It is approved for patients with and without inhibitors.

Management of Bleeding in Hemophilia

• Assess vital signs and assure hemodynamic stability; resuscitate if needed.

• Obtain complete blood count if there is concern for prolonged bleeding and excessive blood loss; transfuse if needed.

• Perform physical examination:

  • Conduct a careful neurologic examination if there is concern for head trauma.

  • Assess for compartment syndrome in cases of extremity bleeding.

• Do not delay treatment while waiting for laboratory results. When in doubt, give the factor.

• If the patient needs imaging, give the factor first.

• Titrate subsequent doses based on severity of bleeding, factor troughs, and presence or absence of inhibitors.

The following table describes recommended peak factor levels based on the severity of the bleed.

Other Pharmacologic Options for Management of Bleeding:

• Cryoprecipitate and fresh frozen plasma (FFP) are discouraged to control bleeding in patients with hemophilia due to concerns about product quality and safety. Therefore, they should only be used if concentrated factor products are not available. Cryoprecipitate contains significant quantities of FVIII but not FIX and is therefore preferable to FFP for the treatment of FVIII deficiency.

• Desmopressin (DDAVP) increases plasma levels of FVIII and von Willebrand factor (VWF). It does not affect FIX levels and therefore should not be used in patients with FIX deficiency. DDAVP can be administered intravenously or intranasally, although the latter route is less reliable.

• Tranexamic acid should not be given to patients with FIX deficiency who receive prothrombin complex concentrates because it can increase the risk of thromboembolism.

• Aminocaproic acid should not be used concurrently with FEIBA because it can increase the risk of thromboembolism.

Von Willebrand Disease

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is characterized by the deficiency or dysfunction of the von Willebrand factor (VWF), which is responsible for platelet adhesion and aggregation. Patients present most often with mucocutaneous bleeding (e.g., bruising, epistaxis, prolonged bleeding from wounds or postsurgical bleeds, menorrhagia). The different types of VWD depend on the underlying mutation and are described in the table below.

Diagnosis

• History and physical examination, including detailed family history of bleeding (including postoperative bleeding, menorrhagia, pregnancy complications, etc.)

• Laboratory investigations:

  • Initial tests:

    • VWF antigen level (VWF:Ag)

    • VWF ristocetin cofactor activity (VWF:RCo)

    • Factor VIII level (FVIII)

  • If initial tests are abnormal, subsequent testing may include the following to diagnose the subtype of VWD and should be sought in consultation with a hematologist:

    • VWF multimer test

    • ristocetin-induced platelet aggregation (RIPA)

    • VWF collagen-binding activity

(Source: Von Willebrand Disease. NEJM 2016.)

Treatment

Thrombosis and Thromboembolic Disease

Most pediatric thrombotic events are provoked, which means that an identifiable underlying etiology exists for the thrombosis. This section covers evaluation and treatment of thrombosis and thromboembolic disease in some common scenarios that you might encounter in the pediatric population.

Risk Factors

Risk factors for thrombosis in children and adolescents include the following:

• central venous catheters

• malignancy

• systemic infection or inflammation

• immobility

• congenital heart disease

• anatomic abnormalities

• inherited thrombophilias

Evaluation and Treatment

Suggested Initial Thrombophilia Testing

• activated protein C resistance assay

• antithrombin III functional assay

• lupus anticoagulant

• anticardiolipin antibody (IgG and IgM)

• antiphospholipid antibody (IgG and IgM)

• protein C functional assay*

• protein S functional assay*

• prothrombin mutation 20210 assay

• methyltetrahydrofolate reductase (MTHRF) mutation

*Should not be ordered if patient is already on anticoagulation; levels are also expected to be low in the setting of recent thrombosis and should be repeated later to confirm

Treatment of Thrombosis and Thromboembolic Disease in Children: The following three treatment algorithms provide overviews of anticoagulation in children by age; catheter-related venous thrombosis; and idiopathic, lower-extremity DVT:

(Source: How I Treat Pediatric Venous Thromboembolism. Blood 2017.)

(Source: How I Treat Pediatric Venous Thromboembolism. Blood 2017.)

(Source: How I Treat Pediatric Venous Thromboembolism. Blood 2017.)