Blood leaks or vascular occlusions may compromise blood delivery with potentially fatal consequences. The role of the hemostatic system is to maintain blood fluidity and to stop leaks once the vessel wall is damaged. It is a dynamic system maintained by a balance of factors that promote and factors that inhibit clotting. Disruption of this equilibrium leads to either bleeding or thrombotic complications.

PATHOPHYSIOLOGY

The intact vascular endothelium provides a smooth surface that promotes the blood flow and inhibits coagulation. When the endothelial surface is disrupted, blood comes in contact with the subendothelial matrix, which activates the hemostatic system. The first step of the hemostatic process—formation of the platelet plug—consists of adherence of platelets to the margins of the injured vessel, followed by their activation and release of pro-coagulant substances. During this process, von Willebrand factor (vWFct) acts as a bridging protein between platelets and the vascular wall. The next step is the coagulation cascademis, a carefully regulated series of pro-coagulant events initiated by tissue factor released from the subendothelial matrix. Tissue factor along with factor VII activates factor X, which together with factor V forms the prothrombinase complex, which subsequently activates factor II (prothrombin) to generate thrombin. Thrombin is the enzyme that converts fibrinogen to fibrin. Fibrin polymerizes and crosslinks with the help of factor XIII to form a strong mesh that traps red cells, white cells, and more platelets to form the final clot. This pathway, known as the “extrinsic” pathway, feeds an auto-amplification loop to recruit the “intrinsic” coagulation cascade to further clot formation (Figure 92-1). To do so, thrombin activates factors IX and VIII, which in turn activate factor X to increase thrombin production several thousand-fold. The goal of the coagulation cascade is formation of a fibrin-based clot able to achieve hemostasis but to limit coagulation to interfere with normal blood flow. Once enough fibrin is generated, the coagulation cascade is terminated by anticoagulant factors including tissue factor pathway inhibitor (TFPI), activated protein C, and antithrombin. The fibrin clot will persist for a variable amount of time, allowing for the repair of the vascular wall before the clot is broken down by the fibrinolytic system. The main fibrinolytic enzyme is the plasmin, which in turn is kept in check by the inhibitory action of antiplasmin. Thus the coagulation cascade is a finely tuned system consisting of amplification steps limited by important checks to maintain the appropriate balance between clot formation and clot dissolution.

CLINICAL PRESENTATION

The main issues to consider in the clinical presentation of a patient with a suspected bleeding disorder are to determine whether the bleeding episodes are prolonged or unexpected, identify the pattern of bleeding, and clarify whether there are family members with similar manifestations.

Magnitude of the Bleed in Relation to the Causative Factor

Intense trauma will always cause vascular injury and bleeding. Patients with hemostatic defects have bleeds that are spontaneous or disproportionate to the inciting event, last longer than expected, or are recurrent. Inquire about hemostatic challenges such as surgeries, deliveries, dental extractions, intense traumatic events, or activities likely to involve trauma (contact sports).

Bleeding Pattern

Mucocutaneous bleeds manifested by purpurae, epistaxis, gastrointestinal (GI) bleeding, and menorrhagia suggest a defect of primary hemostasis involving platelets (i.e. diminished number or function), von Willebrand factor, or the vessel wall (e.g. inflammation, collagen defect). Deep-seated bleeds, on the other hand, such as muscular hematomas or hemarthroses, suggest a coagulopathy, most commonly caused by a deficit of factors VIII, IX, or XI. Generalized bleeding combining the two patterns is encountered in consumptive coagulopathies such as disseminated intravascular coagulation (DIC).

Family History

The majority of pediatric bleeding disorders are inherited. Hemophilia A and B have an X-linked pattern of inheritance (and therefore affect males predominantly), while von Willebrand disease (vWD) has an autosomal dominant inheritance with variable expressivity and penetrance.

DIAGNOSIS AND EVALUATION

Complete Blood Count

The number of circulating platelets is normally far greater than what is minimally needed for effective hemostasis. In fact, only when the platelet count is less than 50,000 to 70,000/fl does bleeding tendency increase. Severe thrombocytopenia, with platelet counts below 10,000 to 20,000/fl, puts the patient at risk for serious bleeds with minimal or no trauma. The approach to thrombocytopenia is discussed in Chapter 91, Thrombocytopenia.

Platelet Function Assay

The platelet function assay (PFA) simulates platelet adhesion in vitro by measuring response to collagen/epinephrine and collagen/ADP stimuli. The PFA is fairly sensitive for detecting vWD and severe platelet functional defects such as Glantzman thrombasthenia or Bernard Soulier disease. PFA sensitivity is lower for platelet secretion defects and storage pool defects. The PFA has high negative predictive value but poor specificity, since PFA closure times can be artifactually prolonged by anemia, thrombocytopenia, or various medications such as nonsteroidal anti-inflammatory drugs.

Platelet Aggregation Studies

Platelet aggregation studies evaluate platelet clumping in response to various agonists. The testing is relatively complex, time consuming, and requires large quantities of blood, making it impractical for young infants. A normal platelet aggregation study will exclude most qualitative platelet defects and all but the mildest forms of vWD.

Prothrombin Time

The prothrombin time (PT) is influenced by the activity of factors II, VII, IX, X, and fibrinogen. It thus explores the extrinsic and common coagulation pathways. It is commonly reported as the international normalized ratio (INR), in order to give comparable results across different laboratories. Isolated PT prolongation is suggestive of factor VII deficiency, which may be inherited or secondary to liver failure. An algorithm for the interpretation of coagulation test abnormalities is presented in Figure 92-2.

Activated Thromboplastin Time

The activated thromboplastin time (aPTT) evaluates the activities of coagulation factors of the intrinsic and common pathway: II, V, X, VIII, IX, XI, XII, prekallikrein, and bradykinin. It is important to note, however, that in general, levels of any given factor must decrease below 40% before PTT prolongation is noted. Furthermore, PTT is longer in the newborn and during infancy due to low levels of factor IX compared to the adult. Deficiency of factors VIII, IX, and XI may result in a clinically evident bleeding disorder, whereas deficiencies of factor XII, bradikinin, or prekallikrein are not associated with bleeding despite prolonging the aPTT.

Thrombin Time

The thrombin time measures the amount of time needed for conversion of fibrinogen to polymerized fibrin after addition of thrombin. It is prolonged in quantitative or qualitative fibrinogen abnormalities, as might be reflected by prolongation of both PT and aPTT, or if the specimen contains heparin.

Mixing Studies

Abnormal coagulation studies can be due to true deficiency of one or more clotting factors or to antibodies against clotting factors. To distinguish between these possibilities, mixing studies can be helpful. Mixing studies involve combining the patient’s plasma in equal proportion with normal plasma and determining the effect of the patient’s plasma on the PT and aPTT immediately and after 1 to 2 hours. If the patient’s prolonged PT or aPTT corrects after mixing with normal plasma, it suggests that the patient has a clotting factor deficiency (corrected by levels in the normal plasma); if, however, the test does not correct, it suggests the presence of an inhibitor such as lupus anticoagulant or an antiphospholipid antibody in the patient’s blood that interferes with the coagulation profile of normal plasma. Curiously, however, the presence of an inhibitor may not be clinically associated with a bleeding diathesis, despite influencing in vitro coagulation tests. In fact, lupus anticoagulants and antiphospholipid antibodies are more associated with thrombosis than with bleeding.

D-Dimers

D-dimers are the products of degradation of cross-linked fibrin, and their presence in the blood indicates the presence of a thrombus. An elevated D-dimer may be present in various conditions involving inflammation and activation of coagulation, including deep venous thrombosis (DVT) and pulmonary embolization. A normal D-dimer has a strong negative predictive value for venous thromboembolism in adults. In pediatrics, the negative predictive value of the D-dimer is weaker, as 13% to 40% of children with pulmonary embolization may have a normal D-dimer.

SPECIAL CONSIDERATIONS

Hemophilia

The term hemophilia refers to a group of bleeding disorders characterized by deep-seated bleeds (hematomas, hemarthroses) due to congenital deficiencies in factors VIII (hemophilia A), IX (hemophilia B), or XI (hemophilia C). Factor XI deficiency is uncommon in the general population, and the bleeding manifestations are generally milder.

The incidence of hemophilia is about 1:5000 males; about 85% have factor VIII deficiency and 15% have factor IX deficiency. Inheritance for both factor VIII and factor IX deficiency is X-linked; therefore males are affected and females are generally asymptomatic carriers. About one-third of factor VIII mutations are spontaneous, thus there may be no family history of a bleeding disorder.

Clinical Presentation

The clinical manifestations of hemophilia A and B correlate with factor VIII or IX activity and levels. Individuals with a factor activity of <1% are deemed severe; they may develop joint bleeds and hematomas during routine daily activities with no or minimal trauma. Patients who have factor levels between 1% and 5% (moderate severity) develop joint bleeds with mild to moderate trauma and have significant bleeds with surgical or dental procedures. Subjects who have factor levels between 5% and 30% have a mild clinical course, they rarely bleed, only with moderate to severe trauma or with surgical or dental procedures.

Musculoskeletal bleeds are common in severe hemophilia. Hemarthroses typically affect the large joints (ankles, knees, elbows) and usually start when the infant starts to crawl and walk and continue throughout childhood. In the absence of factor replacement therapy, a patient may have several joint bleeds per month. The first sign of a hemarthrosis is pain, especially with weight bearing or moving of the joint, followed by enlargement of the joint, warmth, and reduction in the range of motion. Repeated or persistent joint bleeds lead to synovial proliferation, damage of the cartilage, and ultimately to chronic hemophilic arthropathy manifested through pain, repeat bleeds, and limitation of range of motion.

Muscle bleeds are also common in hemophilia. They present with pain, point tenderness, swelling, and ecchymosis of the overlying skin. Large muscle bleeds, occurring in locations where the muscle is surrounded by a tight fascia such as the forearm or the lower leg may increase the pressure in that compartment and compromise the blood circulation in what is referred to as compartment syndrome. The clinical presentation of compartment syndrome includes changes in the color and temperature of the skin, paresthesia, weakness, and decreased pulse amplitude. Iliopsoas muscle bleeds are sometimes subtle, presenting with vague abdominal pain, and pain with the flexion of the thigh or antalgic position, with the affected leg flexed on the abdomen and internally rotated. Sometimes the symptoms may mimic a hip hemarthrosis; a hip ultrasound may be a useful test to differentiate between the two. Ileopsoas bleeds may result in significant blood loss and may lead to hemorrhagic shock. Bleeding in hemophilia may be life threatening if it occurs in the vicinity of the airway, if it is intracranial, or if it is large enough to cause exsanguination.

Treatment

The treatment of an acute bleed includes:

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  Correcting the coagulopathy with clotting factor replacement and antifibrinolytic therapy

  
  
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  Decreasing the blood flow to the site of bleeding and reducing local inflammation through limb elevation, pressure, and ice packs

  
  
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  Rest of the affected joint or muscle until the pain subsides

  
  
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  Pain management

Timely intervention and effective management are essential for the treatment of acute bleeds in hemophiliacs. The primary goal is to correct the clotting activity as soon as possible, even before the full evaluation of the patient is complete, and a pediatric hematologist familiar with the case should be involved early in the decision-making process. Clotting factor concentrates are either plasma derived or artificially produced by recombinant technology. Risk of transmitting a severe infection such as HIV or hepatitis through the use of clotting factor concentrates is extremely low, with no documented transmissions for decades. The dose of factor concentrate and the length of therapy are based on the type of hemophilia, baseline factor activity, and severity of the bleed (Table 92-1). For factor VIII concentrates, 1 IU/kg raises the factor activity by 2% and the half-life is approximately 12 hours. Regarding factor IX concentrates, 1 IU/kg raises factor activity by 1% (0.7% to 0.8% for recombinant factor IX [Benefix]) and the half-life is approximately 18 hours.