Congenital Bleeding Disorders

von Willebrand disease (vWD) is the most common congenital bleeding disorder, present in approximately 1% of the population. Hemophilia is the most common severe bleeding disorder and is the result of either a deficiency in factor VIII (hemophilia A) or IX (hemophilia B). The incidence of hemophilia is one in 5000 males, with 80% to 85% hemophilia A and 15% to 20% hemophilia B. There are no significant racial differences in the incidence of hemophilia.

Thrombosis

Advances in the treatment and support of critically ill children combined with an increasing awareness of thrombotic complications have likely resulted in an increase in the diagnosis of pediatric thromboembolic events. Although these events are increasing, they are still relatively rare compared with adults. This increase is most notable in comparing the rates from an older pediatric Canadian registry with an incidence of thromboembolic events of 5.3 in 10,000 hospitalizations, but a newer study from the United States reported a rate of 58 in 10,000 hospitalizations. There is a bimodal age distribution of thrombosis with peak rates in the neonatal and adolescent age groups.

Congenital Bleeding Disorders

vWD is a family of disorders caused by quantitative or qualitative defects of von Willebrand factor (vWF), a plasma protein that plays a role in both platelet adhesion and fibrin formation.

vWF is also a carrier protein for factor VIII; factor VIII unbound to vWF is rapidly degraded. vWD is classified into six types: 1, 2A, 2B, 2M, 2N, and 3. Table 54-1 provides a description and laboratory findings for all types of vWD.

Type 1 vWD is inherited in an autosomal dominant fashion and accounts for 70% to 80% of all vWD cases. It is characterized by a partial quantitative defect resulting in decreased amounts of a functionally normal vWF protein. Type 3 is a complete quantitative defect with no vWF and subsequently decreased factor VIII levels. The type 2 variants are qualitative defects.

Hemophilia A is a deficiency of factor VIII, and hemophilia B is a deficiency of factor IX. Both types of hemophilia are X-linked recessive diseases. About 30% of cases of hemophilia represent new mutations. Clinical severity is classified by the patient’s baseline factor level, severe less than 1%, moderate 1% to 5% and mild greater than 5%.

Acquired Bleeding Disorders

Children may develop bleeding disorders under various clinical conditions. The liver is responsible for the synthesis of most of the clotting factors. When synthetic liver dysfunction occurs, patients may develop abnormal coagulation profiles and clinical bleeding. Vitamin K plays a key role in the activation of coagulation proteins through the carboxylation of glutamate residues. Vitamin K deficiency can result from lack of exogenous vitamin K, as in an infant who is strictly breastfed or a child who is dependent on parenteral nutrition, or from infection or prolonged antibiotic administration. When vitamin K levels decline, the liver is unable to adequately synthesize functional factors II, VII, IX, and X, resulting in a bleeding propensity.

Disseminated Intravascular Coagulation

In disseminated intravascular coagulation (DIC), the normal physiology of coagulation is disturbed with resultant bleeding and thrombosis within the microvasculature. DIC is always secondary to a precipitating condition such as infection, tissue injury, malignancy, venom or toxin, or microangiopathic disorders. There is widespread deposition of intravascular fibrin leading to compromised organ function and capillary leak. Continued activation of this system leads to depletion of platelets and clotting factors, resulting in clinical bleeding (Figure 54-1).

Figure 54-1 Disseminated intravascular coagulation.

Thrombosis

Deep venous thrombosis (DVT) is a consequence of Virchow’s triad of venous stasis, endothelial injury, and a hypercoagulable state. More than 90% of children with DVT have an identifiable prothrombotic risk factor. The most common risk factor is the presence of a central venous catheter (CVC). More than 50% of DVTs in children and more than 80% in neonates are associated with a CVC. Venous stasis in children may be caused by a postoperative state, casting or splinting, or other causes of prolonged immobility. Endothelial injury may be caused by trauma, infection, inflammation, or CVCs. Children may also have an inherited thrombophilia such as factor V Leiden or prothrombin gene mutations, deficiencies in the anticoagulant proteins including C, S, or antithrombin, hyperhomocysteinemia, or an elevated lipoprotein A. Acquired causes of thrombophilia include dehydration, antiphospholipid antibodies, malignancy, inflammatory states, anticoagulant deficiencies from consumption, or loss and exposure to certain medications such as estrogen-containing oral contraceptive pills or L-asparaginase (Figure 54-2).

Figure 54-2 Venous thrombosis.

Congenital Bleeding Disorders

Patients with vWD typically present with mucocutaneous bleeding, including epistaxis, gingival bleeding, abnormal bruising, or menorrhagia. Patients may also present with excessive postoperative bleeding.

The characteristic bleeding manifestations of hemophilia include palpable bruises, bleeding into joint spaces (hemarthroses), muscle hemorrhages, and excessive bleeding after surgery or trauma. The frequency and severity of bleeding correlate with the baseline measured factor activity. Whereas patients with severe hemophilia have spontaneous bleeding, patients with moderate hemophilia have bleeding with minimal trauma, and patients with mild hemophilia may only experience bleeding after a significant trauma or a surgical procedure.

In the newborn period, about 50% of boys with hemophilia have excessive bleeding with circumcision, and 3% to 4% have an intracranial hemorrhage. Muscle bleeds can also occur at the site of intramuscular immunization administration. Hemarthrosis is unusual in an infant and typically occurs after a child is ambulating. Patients with hemarthroses have pain, tenderness, warmth, swelling, and decreased range of motion of the affected joint. Muscle bleeds present with pain and swelling, and any muscle can be affected. Intracranial hemorrhage is the most serious type of bleeding for patients with hemophilia with the highest mortality rate and can be the result of head trauma or spontaneous in patients with severe hemophilia (Figure 54-3).

Figure 54-3 Hemophilia A and B.

Thrombosis

Presenting symptoms of an extremity DVT include swelling, erythema, or pain of the affected limb. Thrombosis of the jugular vein can present with neck pain, stiffness, or fullness. The clinical manifestation of cerebral sinus venous thrombosis is strongly influenced by the age of presentation, thrombosis location, and the presence of a venous infarction. Symptoms are diverse and nonspecific, including most commonly the triad of headache, emesis, and depressed mental status. Presenting signs and symptoms of pulmonary embolism (PE) may be mild to severe and may include cough, pleuritic chest pain, dyspnea, tachypnea, hypoxia, tachycardia, syncope, hemoptysis, and in the case of a massive PE, significant hemodynamic instability.

Congenital Bleeding Disorder

In any patient that presents with findings concerning for a bleeding diathesis, it is appropriate to obtain a prothrombin time (PT), partial thromboplastin time (PTT), and a complete blood count (CBC). Hemophilia causes an isolated prolongation of the PTT; the same abnormality may be seen in patients with vWD, but the screening coagulation study results are frequently normal. Evaluation for vWD includes a vWF antigen, which indicates the quantity of vWF; a vWF activity, which represents the ability of vWF to cause platelet aggregation; and a factor VIII level. vWF levels, similar to factor VIII levels, may be elevated by illness or inflammation. As a result, vWF studies are routinely repeated to confirm the presence or absence of the disorder. A bleeding time is highly operator and patient dependent with unreliable results and is not recommended in children at this time.

Many types of vWD can be treated with DDAVP (desmopressin), which causes release of endogenous endothelial stores of vWF and factor VIII. DDAVP is ineffective in type 3 vWD and contraindicated in type 2B. DDAVP may be administered intranasally or intravenously. Both formulations have an antidiuretic effect, and total fluid should be limited to two-thirds maintenance for 24 hours after its administration to prevent hyponatremia and seizures. For significant bleeding or situations in which DDAVP cannot be used, a plasma-derived product containing vWF and factor VIII, such as Humate-P, can be used. In some anatomic areas, clot stabilization can be improved with the addition of antifibrinolytic therapy in the form of aminocaproic or tranexamic acid.

For pediatric patients with severe hemophilia prophylaxis, the routine replacement of factor to prevent bleeding and progressive joint damage is the standard of care. Treatment of bleeding episodes in patients with hemophilia begins with administration of the deficient factor. The target factor level depends on the severity of bleeding. There are several formulations of recombinant factor VIII available and only one formulation of recombinant factor IX. Various adjuvant therapies can also be used depending on the site of bleeding. For example, hemarthroses should be treated with factor replacement, immobilization, and ice. Oral bleeding in hemophilia may be managed with topical thrombin and antifibrinolytic therapy with factor administration if these initial measures are insufficient.

Patients with severe hemophilia may develop inhibitory antibodies against exogenous factor, leading to poor or no response to standard treatment. In some cases, a low titer inhibitor may be overcome with administration of higher doses of the deficient factor. However, some patients may be completely unresponsive to factor administration. In that case, bypass agents such as FEIBA (factor eight inhibitor bypass agent) or recombinant activated factor VII may be necessary.

Acquired Bleeding Disorders

Bleeding diatheses related to vitamin K deficiency and liver dysfunction are often discovered on screening coagulation profiles, although they may present with bleeding. For vitamin K deficiency, evaluation of coagulation factors may show a deficiency in factor II, VII, IX, and X. Factor V is often useful to differentiate between the two diagnoses because it is synthesized by the liver but is not vitamin K dependent. Treatment of vitamin K deficiency is most directly addressed by administration of oral, subcutaneous, or intravenous vitamin K. Coagulation factor deficiencies caused by liver dysfunction resolve when the underlying abnormality resolves. In the acute setting, bleeding from either cause may be treated with administration of fresh-frozen plasma (FFP).

Disseminated Intravascular Coagulation

Typical laboratory findings in DIC include thrombocytopenia, prolongation of the PT and PTT, and low fibrinogen. The fibrin degradation product elevation is quite sensitive but not specific for DIC. Fibrinogen levels are expected to decrease but must be considered carefully; because it is an acute phase reactant, fibrinogen may initially maintain elevated or normal levels.

Treatment of patients with DIC must be directed at the underlying cause. In a patient who has clinical bleeding or severe laboratory derangements, administration of FFP and platelets may be helpful in maintaining hemostasis. At this time, multiple drugs, including activated protein C and antithrombin, were developed to correct the coagulopathy in DIC, but results have been disappointing.

Thrombosis

In a patient with a suspected DVT, imaging is the first diagnostic step. Although venography is the traditional gold standard, its invasiveness and technical difficulty have lead to the increased use of other modalities. Lower extremity, upper extremity, and jugular venous DVTs may all be visualized with Doppler ultrasonography. However, proximal extension of a lower extremity DVT into the inferior vena cava, intracranial extension of a jugular venous thrombosis, and subclavian vein thrombosis may not be appreciated with ultrasonography alone. For further evaluation of these thromboses or of other suspected DVTs, computed tomography (CT) or magnetic resonance venography is generally the modality of choice. PE may be evaluated with a high-resolution or spiral CT or CT angiography. Ventilation/perfusion scans are used by some, but expertise with this modality is limited in many pediatric institutions.

Laboratory studies for evaluation of DVT and PE include a PT and PTT as well as a CBC (Figure 54-4). Renal function should be assessed. A D-dimer can be elevated in the presence of a DVT or PE but is not specific and can be elevated in other clinical settings and therefore is not diagnostic of the presence of thrombosis. A pregnancy test should be obtained in menstruating women. In many cases, it may be appropriate to evaluate a child for a predisposing thrombophilia, including factor V Leiden and prothrombin G20210 mutation analyses, protein C activity, protein S activity, antithrombin, homocysteine, lipoprotein(a) levels, dilute Russell Venom time, anticardiolipin, and anti-β2-glycoprotein antibodies.

Figure 54-4 Hemostasis tests.

When a DVT or PE is identified, anticoagulation is the definitive treatment but a decision must be made as to whether anticoagulation is appropriate, weighing the risk of bleeding versus the risk of clot propagation, embolization, or both. Acutely, therapy should be initiated with a continuous infusion of unfractionated heparin (UFH) or a subcutaneous administration of a low-molecular-weight heparin (LMWH) (Figure 54-5). Warfarin is an alternative anticoagulant that may be considered for maintenance therapy after adequate anticoagulation has been established with either heparin or a LMWH. The duration of anticoagulation depends on the clinical circumstances, size, site, and resolution of clot, as well as the presence of any thrombophilia.

Figure 54-5 Cascade of clotting factors and sites of action of heparin and warfarin.

Thrombolysis should be considered in patients who have a life- or limb-threatening thrombosis, such as an occlusive arterial clot with limb ischemia, sinovenous thrombosis unresponsive to anticoagulation with neurologic decompensation, or massive PE with hemodynamic instability. The most commonly used thrombolytic agents are tissue plasminogen activator and urokinase. Both agents act by catalyzing the conversion of plasminogen to plasmin, which then cleaves crosslinked fibrin. Lysis may be systemic, administered through an intravenous line, or directed, administered through a catheter positioned very close to the clot. Directed lysis may also use mechanical methods of clot disruption and removal. Thrombolysis carries a higher risk of bleeding than anticoagulation, and the risks and benefits must be weighed carefully. When a life- or limb-threatening thrombosis is present and thrombolysis is contraindicated or otherwise not possible, surgical thrombectomy may be considered.

Indications for the placement of an inferior vena cava filter include patients with an acute lower extremity DVT and a contraindication to anticoagulation or recurrent thrombosis despite adequate anticoagulation. A temporary filter is preferred because of the high risk of thrombosis below the filter.