Rudolph's Pediatrics, 22nd Ed.

CHAPTER 437. Acquired Coagulation Disorders

Guy Young

Many hemorrhagic disorders in children are caused by genetic defects, but there are also a number of important acquired conditions that can lead to abnormal coagulation and subsequently bleeding complications. The most important of these conditions are vitamin K deficiency bleeding, coagulopathy of liver failure, and disseminated intravascular coagulation (a condition that can lead to both bleeding and thrombosis).

VITAMIN K DEFICIENCY BLEEDING

In 1894, Charles Townsend described 50 newborns who developed severe bleeding complications shortly after birth and coined the term hemorrhagic disease of the newborn” (HDN).1In 1936, Henrik Dam discovered a fat soluble “koagulation factor” (using the German spelling), which he named vitamin K and which was found to be deficient in neonates suffering from HDN.2 Thus the term hemorrhagic disease of the newborn has been replaced by vitamin K deficiency bleeding, as this term is more specific and descriptive. This discovery led to the use of prophylactic vitamin K, which has become routine in the immediate perinatal period and is very effective at preventing HDN.

CLASSIFICATION

Vitamin K deficiency bleeding (VKDB) is classified as early, classical, or late (see Table 437-1). Early onset occurs in the first 24 hours of life and is due to the cross-placental transfer of compounds that interfere with vitamin K metabolism or function, including some anti-convulsant drugs, antibiotics, antituberculous agents, and vitamin K antagonists. Classical VKDB as described by Townsend occurs in the first week of life and is due to a physiological deficiency in vitamin K at birth combined with a lack of vitamin K in breast milk or inadequate feeding. Vitamin K prophylaxis has its biggest impact in preventing this type of VKDB. Late onset VKDB can occur at any age, although it is classically described as occurring between 2 weeks and 6 months of age  (Table 437-1).

EPIDEMIOLOGY

Prior to the widespread use of vitamin K prophylaxis, the incidence of classical vitamin K deficiency bleeding (VKDB) was reported to be as high as 1.5%, but the condition is now considered rare.

PATHOPHYSIOLOGY

Vitamin K is a crucial cofactor in the production of the procoagulant proteins factors II, VII, IX, and X and is also required for the production of the natural coagulation inhibitors, proteins C and S. Vitamin K is essential for the γ-carboxylation necessary for the function of these clotting factors.  The reduction in functional coagulation factors can be easily measured by screening coagulation tests such as prothrombin time and activated partial thromboplastin time and by assaying the specific factors individually.

CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

The clinical features of vitamin K deficiency bleeding (VKDB) are similar to other coagulation disorders. The typical presenting symptoms are bruising (Fig. 437-1), mucous membrane bleeding, excessive bleeding associated with trauma or invasive procedures, or signs of internal hemorrhage such as abdominal pain, headache, or vomiting.

The most common disorder that can be mistaken for VKDB is liver disease–associated coagulopathy, as both result from deficiencies of some of the same clotting factors. The vitamin K–dependent factors II, VII, IX, and X are all synthesized in the liver and are deficient in both conditions. Thus, the prothrombin time, activated partial thromboplastin time, and specific measurement of these factors will not distinguish the 2 conditions. Moreover, the 2 conditions can coexist as liver dysfunction resulting from obstructed biliary flow, that can lead to vitamin K deficiency. Another condition that can be confused with VKDB is an inherited deficiency of all the vitamin K–dependent clotting factors due to 1 of several mutations in enzymes in the metabolic pathways involving the synthesis of the vitamin K–dependent factors.3,4 (Fig. 437-1).

Table 437-1. Classification of Vitamin K Deficiency Bleeding

DIAGNOSTIC EVALUATION

Patients suspected of having vitamin K deficiency bleeding (VKDB) should have a complete blood count (CBC) to assess the platelet count and prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests to screen for deficiencies of specific clotting factors. The PT is always prolonged, often to a very significant degree, and the aPTT is usually increased as well.

Simply repeating the PT and aPTT tests several hours after administration of parenteral vitamin K will demonstrate near or complete correction of both test results. Measuring factor levels (specifically factors II, VII, IX, and X) may assist in the diagnosis, but is not usually necessary and may delay instituting appropriate therapy (vitamin K replacement).

TREATMENT

Management of vitamin K deficiency bleeding is relatively straightforward, and often treatment will have begun prior to confirmation of the diagnosis. When therapy has not been instituted as part of the diagnostic evaluation, administration of vitamin K should be given immediately upon recognition of the disorder. Early intervention may prevent catastrophic hemorrhage.

Several aspects of therapy must be taken into consideration. These include the formulation of vitamin K and the route of administration. Currently, available treatment is generally with vitamin K1 (also known as phytonadione), which can be administered parenterally via intravenous, intramuscular, and subcutaneous injection or orally; intravenous administration is recommended in the acute setting. There is a clear advantage to parenteral administration since it results in a more rapid rise in factor levels than the oral route. Second, the enteral route is not entirely reliable, especially in late-onset vitamin K deficiency bleeding where poor absorption may have led to the condition in the first place.

Although the effect of parenteral vitamin K is rapid, it is not instantaneous, and it takes several hours to correct the factor deficiencies. Thus, in a patient with severe hemorrhage, additional therapy aimed at immediate correction of these factor deficiencies is required using a plasma-derived product known as a prothrombin complex concentrate (PCC). PCCs contain factors II, VII, IX, and X, and immediately following infusion will correct these factor deficiencies. Such treatment is not in lieu of vitamin K but only to provide immediate replacement of the deficient factors. If PCCs are not available, fresh-frozen plasma is an alternative; because repeated administration is necessary, volume overload is a risk, and fresh-frozen plasma requires some processing time, including thawing. Administration of recombinant activated factor VII can be considered in cases of life-threatening bleeding.

FIGURE 437-1. Significant bruising in a child with late-onset vitamin K deficiency bleeding.

Once correction of vitamin K deficiency is achieved, its cause must be identified so that preventive actions can be instituted to prevent a recurrence.

COMPLICATIONS

VKDB may resolve with no sequelae or be catastrophic (intracranial hemorrhage with permanent neurologic impairment). Unfortunately, intracranial hemorrhage may be the presenting manifestation, especially in late-onset VKDB.5,6

PROGNOSIS AND OUTCOMES

The prognosis of vitamin K deficiency bleeding (VKDB) is generally excellent. The early and the classical forms do not recur if corrective actions are taken. For patients with underlying disorders that lead to the late-onset form, such as cystic fibrosis, ongoing vitamin K therapy is necessary.

PREVENTION

There is no question that vitamin K prophylaxis is effective at reducing the risk for VKDB in infants, but controversies exist regarding the route of administration and, to some extent, the dosing.7-10 The advantage of intramuscular prophylaxis, which is widely used in the United States, is its long duration of action, presumably from a depot effect.  Oral vitamin K prophylaxis is the preferred method in parts of Europe and Japan. Dosing regimens vary based on local practice and guidelines. Regardless of the chosen method, it is vital that prophylaxis be given to all infants. In particular, babies born at home or other non-hospital settings are at higher risk for not receiving prophylaxis, so parents should be questioned about this at first contact with the pediatrician.

DISSEMINATED INTRAVASCULAR COAGULATION

Disseminated intravascular coagulation (DIC) is a disorder characterized by consumption of procoagulant, anticoagulant, and fibrinolytic proteins as well as consumption of platelets.11 Patients thus develop hemorrhagic and/or thrombotic complications. In some patients, hemorrhage may predominant, and in others thrombosis is the main feature—occasionally they may occur simultaneously. DIC is always caused by an underlying disorder. In children, the most common etiology is sepsis (see Table 437-2).

PATHOPHYSIOLOGY

The pathophysiology of DIC is complex and not completely understood (see reference 11 for details). Briefly, an inciting event, such as sepsis, triggers the release of proinflammatory cytokines, in particular interleukin-6 and tumor necrosis factor-α. Interleukin-6 leads to tissue factor–mediated activation of the coagulation system that in turn leads to enhanced fibrin formation in the microvasculature.

CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

The predominant clinical features are hemorrhage and organ dysfunction as a result of microvascular thrombosis. Bleeding can occur at any site, including venipuncture and intravenous or intra-arterial catheter insertion sites. Signs of thrombosis may be obvious, as in skin necrosis, or more subtle and manifest as renal or hepatic insufficiency. Children with DIC are often critically ill, have central venous and/or arterial catheters, suffer from infection, and are immobilized. Thus, it is not unusual for large vessel thrombosis to occur in children with DIC.

DIAGNOSTIC EVALUATION

No specific laboratory findings confirm disseminated intravascular coagulation (DIC), so its diagnosis is based on the clinical features, with laboratory abnormalities providing supportive evidence. The typical laboratory alterations in DIC are the result of fibrin formation and degradation as well as consumption of coagulation proteins. Routine laboratory tests such as complete blood count, prothrombin time, activated partial thromboplastin time, and fibrinogen are often abnormal. Thrombocytopenia is usually present, and depending on the underlying cause, leukocytosis, leukopenia, or anemia may be present. When DIC is suspected, measurement of fibrin degradation products is useful, and while an abnormal result is not confirmatory, it is strongly suggestive of DIC.

TREATMENT

The single most important treatment for DIC is controlling the underlying condition responsible for the DIC. Attempts at correcting the coagulopathy will be futile if the primary disorder cannot be controlled. However, once DIC begins, it may continue, even if the primary disorder is appropriately treated. Since DIC affects all aspects of the coagulation system, therapies aimed at correcting them may be effective. The use of fresh-frozen plasma is one approach. While fresh-frozen plasma contains all of the coagulation proteins, large volumes are required, often repeatedly; this may result in fluid overload, particularly in patients with renal and/or liver insufficiency. Similarly, platelet transfusions are indicated for patients with significant thrombocytopenia who are bleeding.

PROGNOSIS AND OUTCOMES

Patients who develop DIC may succumb to the underlying disorder or to the complications of bleeding and thrombosis, but it is not possible to quantify this. For patients who survive, the long-term outcomes vary from complete recovery with no sequelae to severe and permanent disability, such as intracranial hemorrhage or loss of limbs or digits.

LIVER DISEASE

The liver is the synthetic site for most of the procoagulant and anticoagulant proteins, so hepatic insufficiency often leads to coagulopathy. The clinical manifestations are similar to those of vitamin K deficiency (since all vitamin K–dependent coagulation factors are synthesized in the liver), although the patient population at risk differs.

PATHOPHYSIOLOGY

While both procoagulant (fibrinogen, factors II, V, VII, VIII, IX, X, and XI) and anticoagulant (antithrombin, protein C, protein S) proteins are made in the liver, the hemostatic balance in liver disease is tilted toward bleeding. The loss of procoagulant proteins leads to inability to generate thrombin and form fibrin clots at sites of vascular injury. In addition to reduced synthesis of coagulation proteins, other mechanisms that contribute to the coagulopathy include activation of the coagulation and fibrinolytic system, poor clearance of activated clotting factors, thrombocytopenia, platelet dysfunction, and vitamin K deficiency.

Table 437-2. Clinical Conditions Most Commonly Associated with Disseminated Intravascular Coagulation

Sepsis

Malignancy (particularly acute myelogenous leukemia)

Trauma

Major hemorrhage

Cardiopulmonary bypass surgery

Other surgery

Severe hemolysis

CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

The clinical features of liver disease are similar to those described for vitamin K deficiency  (see discussion in vitamin K deficiency bleeding section above).

DIAGNOSTIC EVALUATION

In patients with liver disease and bleeding, both the prothrombin time and activated partial thromboplastin time are prolonged and, depending on the degree of hepatic dysfunction, the fibrinogen level is also reduced.

TREATMENT

The ideal treatment for coagulopathy of liver disease is correction of the hepatic dysfunction. Yet, this is often not possible. Several different hemostatic therapies can be used to manage bleeding. Fresh-frozen plasma contains all clotting factors, but large volumes are required.14

COMPLICATIONS

The complications in patients with liver disease– associated coagulopathy are the same as in vitamin K deficiency bleeding, that is, severe sequelae when bleeding leads to permanent organ damage. One potentially significant complication of therapy with either prothrombin complex concentrates (PCC) or rfactor VIIa is thrombosis.

PROGNOSIS AND OUTCOMES

As with DIC, the prognosis is largely dependent on the treatment of the underlying disease. For patients with transient liver disease or who are successful recipients of a liver transplant, the outcome should be complete recovery.

PREVENTION

There is no standard approach to preventing bleeding in patients with hepatic coagulopathy. Generally, treatment is aimed at controlling bleeding rather than preventing it.

ACQUIRED FACTOR DEFICIENCIES

Acquired deficiencies of individual coagulation factors are uncommon in the pediatric population. They are generally the result of autoanti-bodies or alloantibodies against specific factors. Diagnosis may be delayed due to the rarity of the condition and due to confusing an acquired deficiency with a congenital deficiency. This may lead to delays in instituting proper therapy. It is not unusual for patients with acquired inhibitors to develop severe bleeding complications. The acquired disorders encountered most frequently include deficiencies of factors II (prothrombin), V, and VII, and acquired von Willebrand syndrome. Each of disorder occurs in selected populations. Acquired hypoprothrombinemia (factor II) may accompany the antiphospholipid antibody syndrome and thus most commonly affects older children (> 10 years of age) and females. It may also be encountered secondary to a systemic autoimmune disease.17-22 Acquired factor V (and rarely factor VIII) deficiency occurs mostly in patients exposed to topical bovine thrombin, a hemostatic agent sometimes used in cardiovascular and orthopedic surgery.23 Acquired factor VIII deficiency can also result from the use of topical bovine thrombin that is contaminated with bovine factor VIII. In addition, it is also possible to develop autoantibodies to factor VIII, a condition sometimes referred to as acquired hemophilia.24 In children the condition is exceedingly rare. Acquired von Willebrand syndrome in children has been associated with systemic lupus erythematosus, Wilms tumor, and congenital heart disease.

The main mechanism underlying development of acquired factor deficiencies is antibody formation against the specific factors.  The pathophysiology of the acquired von Willebrand syndrome is heterogeneous and depends on the associated condition. Mechanisms include antibody formation, decreased production, proteolysis, and adsorption of von Willebrand factor to malignant cells.

The differential diagnoses are essentially the congenital forms of these same factor deficiencies.

In hypoprothrombinemia, bleeding can best be treated with prothrombin complex concentrates as previously described. The only other option for increasing the prothrombin level is fresh-frozen plasma. Elimination of the antibody is best achieved with a short course of corticosteroids or another immunosuppressive agent.22 Treatment of bleeding due to acquired factor VIII deficiency is similar to the treatment of an inhibitor in patients with congenital factor VIII deficiency (see Chapter 436) by use of so-called bypassing agents (activated prothrombin complex concentrates and factor VIIa).