Chapter 437. Acquired Coagulation Disorders

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. These conditions occur in disparate clinical situations ranging from otherwise healthy-appearing neonates to critically ill children with multiorgan failure. 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). Other conditions include acquired platelet dysfunction (see Chapter 439) and acquired inhibitors to specific coagulation proteins.

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).1 In 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which was found to be deficient in neonates suffering from HDN.2 Thus the term hemorrhagic disease of the newborn has been replaced by vitamin K deficiency bleeding, as this term is more specific and descriptive.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 anticonvulsant 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. In infants, it is again due to inadequate vitamin K content in breast milk and is thus found almost universally in those exclusively breast-fed. In older children (though often in infants as well), additional factors are necessary, which have in common reduced vitamin K intake and absorption. Some examples of conditions that lead to late-onset vitamin K deficiency are liver or pancreatic disease, both leading to an inability to absorb fat-soluble vitamins; gastrointestinal disorders that affect intestinal flora, because a secondary source of vitamin K is production by intestinal microorganisms; prolonged antibiotic use due to an alteration of intestinal flora; and ingestion (accidental or otherwise) of vitamin K antagonists that, while perhaps not technically causing vitamin K deficiency, can be overcome with vitamin K therapy (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. A recent comprehensive survey from Great Britain and Ireland demonstrated a rate of 0.14 per 100,000 live births in a population with a high rate of prophylactic vitamin K administration. The incidence of early- and late-onset VKDB is not known. Early-onset VKDB occurs in only a small proportion (probably < 5%) of at-risk births. The variety of conditions that lead to late-onset VKDB make defining the incidence challenging.

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. One can demonstrate conclusively the presence of vitamin K deficiency by assaying for non–γ-carboxylated proteins known as PIVKA (proteins induced by vitamin K absence). The lack of functional procoagulant proteins leads to reduction in thrombin generation (the key step in clot formation), increasing the risk for bleeding complications. The diminution of functional factors II, VII, IX, and X outweighs the reduced proteins C and S much in the same way that vitamin K antagonists lead to anticoagulation effects. 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. While so-called warning bleeds (bruising, epistaxis) may precede severe internal hemorrhage, they do not always occur. The incidence of intracranial hemorrhage in late-onset VKDB is 30% to 60%.

The differential diagnosis includes hemophilia and other congenital factor deficiencies, von Willebrand disease, platelet function abnormalities, and liver disease associated coagulopathy. 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 These deficiencies are autosomal recessive and extremely rare. A distinguishing feature in such patients is consanguinity. Such patients may report a history of having received vitamin K at birth (as this is nearly universal in industrialized societies). Ultimately, the lack of response to parenteral vitamin K administration may be the most important diagnostic clue. Confirmative enzyme or genetic assays are not readily available, but measuring levels of the involved factors in the parents may demonstrate borderline to slightly reduced values (Fig. 437-1).

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. The aPTT assesses the intrinsic pathway (factor VIII, factor IX, factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen) and the common pathway. In early or mild vitamin K deficiency, it is possible that only factor VII is reduced, due to its short half-life, thus leading to a prolonged PT but normal aPTT. In the typical scenario, the PT is prolonged out of proportion to the aPTT, for example, the PT being about 4 times the mean of the normal range versus an aPTT that is approximately twice normal.

With a prolonged PT and aPTT, the diagnosis can often be easily made based on clinical information. For example, a 5-day-old baby born at home and known not to have received vitamin K and who otherwise appears well requires no further laboratory testing. Administering vitamin K can be both diagnostic and therapeutic. 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). In older children presenting with VKDB due to one of the underlying disorders described above, the diagnosis may be more challenging, particularly in patients with liver dysfunction. Patients with obstructive liver disease are also at special risk for vitamin K deficiency due to reduced ability to absorb fat-soluble vitamins. In such situations, one must consider the contribution of liver dysfunction to the factor deficiencies. Complete correction of the PT and aPTT following administration of parenteral vitamin K strongly suggests that its deficiency is the cause of the bleeding, whereas no or only partial correction indicates that the liver dysfunction is also present.

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. There are several forms of vitamin K (vitamin K1, vitamin K2, and vitamin K3). 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. The very small risk of anaphylaxis with intravenous administration relates to older formulations of vitamin K.

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.

Once correction of vitamin K deficiency is achieved, its cause must be identified so that preventive actions can be instituted to prevent a recurrence. In early-onset vitamin K deficiency bleeding (VKDB), this may include cessation of breast-feeding if a mother is required to take medication that interferes with vitamin K metabolism that may be passed to the infant via breast milk. In classical-onset VKDB, additional vitamin K administration may be required if poor feeding is an ongoing problem or if a mother insists on exclusively breast-feeding. In late-onset VKDB, correction of the underlying disorder should be undertaken if possible, and continued vitamin K therapy (often parenterally) may be required.

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

Parenteral (specifically intramuscular) vitamin K prophylaxis in the immediate newborn period was once reported to be associated with an increased risk of childhood cancer, but several studies have failed to confirm the initial reports. Aside from this, the only confirmed complications associated with vitamin K therapy are anaphylaxis and hemolysis, both of which have been reported with intravenous administration but currently are rare.

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

Classical VKDB makes an excellent case history for the triumph of prophylaxis. Following recognition of the cause of VKDB, institution of widespread prophylaxis reduced the occurrence to 1.4 per 1 million live births in the British and Irish survey.3

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. Newborns receiving intramuscular prophylaxis have increased levels of vitamin K for at least 4 weeks compared with infants receiving no prophylaxis. The disadvantages are discomfort, poor acceptance by some parents, and, rarely, intramuscular hematomas, local abscesses, and the potential of local nerve and vessel damage. Finally, extremely high levels of vitamin K are achieved following intramuscular injection, and it remains unknown whether this could be harmful. Oral vitamin K prophylaxis is the preferred method in parts of Europe and Japan. Dosing regimens vary based on local practice and guidelines. In addition to avoidance of extraordinarily high levels of vitamin K, the oral route is also more acceptable to parents. Its principal disadvantage is that administration must continue after discharge from the hospital, leading to an increased pool of at-risk infants due to poor compliance. Regardless of the chosen method, it is vital that prophylaxis be given to all infants. In particular, babies born at home or other nonhospital 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 (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).

Epidemiology and Population at Risk

There is essentially no information on the incidence of DIC in children. The at-risk populations include neonates whose physiological deficiencies in many procoagulant and anticoagulant proteins make them prone to develop both bleeding and thrombosis when conditions associated with DIC occur. Other vulnerable populations include patients who do not have a spleen either congenitally or due to splenectomy and children with sickle cell disease who are functionally asplenic.

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. Tumor necrosis factor-α leads to inhibition of the natural anticoagulants (antithrombin and proteins C and S) and inhibits fibrinolysis. The sum of these effects is microvascular thrombosis, which causes organ dysfunction and consumption of procoagulant proteins and platelets resulting hemorrhage. Furthermore, acquired platelet dysfunction results from fibrin degradation and renal insufficiency.

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.

When a patient with an underlying disorder associated with DIC presents with hemorrhage or thrombosis, there is often little doubt regarding the diagnosis. However, the presentation can be insidious, with few findings on the physical examination and laboratory tests that are minimally abnormal (see laboratory discussion below). Since DIC is sometimes included among a group of disorders known as microangiopathic hemolytic anemias, the differential diagnosis may include other conditions that lead to microangiopathic hemolytic anemia, such as Kasabach-Merritt syndrome, thrombotic thrombocytopenic purpura, and atypical hemolytic-uremic syndrome. Another condition that can present with features similar to DIC is the antiphospholipid antibody syndrome.

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. A scoring system has been developed by the International Society on Thrombosis and Haemostasis that incorporates the results of the above assays.12 Measurement of specific coagulation proteins is not required for diagnosis or treatment but may be helpful both diagnostically and therapeutically. The levels of most procoagulant and natural anticoagulant factors are reduced to varying degrees, with the exception of factor VIII, which may be elevated as it is an acute phase reactant.

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. In one study in neonates with DIC, fresh-frozen plasma did not have an impact on resolution of DIC or survival.13,14 Importantly, fresh-frozen plasma should not be given only to correct laboratory abnormalities such as the prothrombin time or activated partial thromboplastin time, but should be considered primarily in patients with bleeding. Similarly, platelet transfusions are indicated for patients with significant thrombocytopenia who are bleeding.

There are several novel approaches for restoring the anticoagulant proteins, antithrombin, and protein C, that could downregulate thrombin generation and microvascular thrombosis.15 Several large, international trials using antithrombin replacement conducted in adults have demonstrated benefit in patients with DIC due to sepsis. Another potentially effective treatment in DIC secondary to sepsis is activated protein C.16 Its positive effect may be due to inhibition of thrombin generation, downregulation of proinflammatory cytokines, or both.

There are no studies in adults or children with DIC that demonstrate a survival benefit with the use of anticoagulation. However, similar to the approach with fresh-frozen plasma and platelet transfusion for bleeding, anticoagulation with heparin is indicated for patients experiencing large vessel thrombosis or purpura fulminans.

Prognosis and Outcomes

It is difficult to determine prognosis in a child with disseminated intravascular coagulation (DIC). This is due to the fact that there are many underlying disorders that lead to DIC, and the course of DIC once established is difficult to predict. 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.

Prevention

Since DIC is caused by underlying disorders, the prevention of DIC is entirely dependent on prevention of the triggering conditions. An example is vaccination against infectious organisms that can lead to DIC, such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae. Likewise, prevention of the other conditions or complications listed in Table 437-2 may prevent DIC.

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.

Epidemiology and Population at Risk

The population at risk includes patients with congenital or acquired hepatic disorders. The incidence of hepatic coagulopathy depends upon the specific type and severity of liver impairment.

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.

Clinical Features and Differential Diagnosis

The clinical features of liver disease are similar to those described for vitamin K deficiency. Bleeding can occur anywhere and range from minor (bruising, oral mucosa) to catastrophic (intracranial hemorrhage). The degree of hepatic insufficiency required to induce the coagulopathy is such that the liver dysfunction is generally obvious. Occasionally, it may be difficult to distinguish hepatic coagulopathy from vitamin K deficiency, and both may be present simultaneously (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. Additional laboratory assays are rarely needed to confirm the diagnosis but may help guide therapy. While one can measure all the coagulation factors listed above, aside from fibrinogen, those of greatest interest are factors II, VII, IX, and X, since specific therapies are available to correct these deficiencies. In addition, it is important to monitor the platelet count as thrombocytopenia can exacerbate bleeding due to factor deficiencies.

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 Another approach to therapy is to identify which factors are deficient by assaying them individually and then correcting those that are most reduced. Generally, patients with significant hepatic dysfunction will be deficient in fibrinogen, potentially corrected with cryoprecipitate infusions, and factors II, VII, IX, and X, which can be treated with prothrombin complex concentrates as discussed previously for vitamin K deficiency.

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. Major complications of therapy are volume overload from fresh-frozen plasma and thrombosis due to PCCs. The liver is responsible for removing excess activated clotting factors from the circulation that can accumulate with the use of PCCs.

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. In some instances, however, when there is no prospect for recovery of liver function, yet profoundly abnormal coagulation test results exist, it is reasonable to consider prophylactic approaches while awaiting liver transplantation.

Acquired deficiencies of individual coagulation factors are uncommon in the pediatric population. They are generally the result of autoantibodies 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. With hypoprothrombinemia, antiprothrombin antibodies may lead to bleeding. In acquired factor V deficiency, the offending anti-bovine antibody cross-reacts with human factor V, resulting in severe bleeding. Topical bovine thrombin is known to contain trace amounts of other clotting proteins, including factor V and factor VIII. In addition, children can rarely develop idiopathic autoantibodies to factor VIII, leading to depletion of factor VIII with severe bleeding. 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. This distinction is important as it impacts on the treatment. Since inherited factor V deficiency is quite rare, when factor V deficiency occurs after known topical thrombin exposure, the etiology is almost always acquired antibodies. Congenital can be distinguished from acquired hemophilia or von Willebrand disease by the family history.

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 If hypoprothrombinemia is secondary to a systemic autoimmune disease, treatment should be directed at the underlying disorder. Treatment of bleeding complications associated with acquired factor V deficiency can be very challenging for a number of reasons. First, no concentrated products are available that contain factor V, necessitating the infusion of large volumes of fresh-frozen plasma. Second, since this is an antibody-mediated disorder, the infused factor V is rapidly eliminated. Third, ongoing bleeding leads to consumption of the infused factor V. Another potential approach is to transfuse platelets, since they contain factor V and can deliver it to the site of bleeding.25-27 The antibodies will resolve over time, but removal has been reported with intravenous immunoglobulin treatment.28 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). Eradication of the antibodies requires corticosteroids and other immunomodulatory agents such as intravenous immune globulin, cyclophosphamide, or rituximab, an anti-CD20 monoclonal antibody.29 Treatment for the bleeding associated with the acquired von Willebrand syndrome is the same as that for congenital von Willebrand disease (see Chapter 436). Antifibrinolytic agents such as aminocaproic acid are excellent adjunctive therapies.

As most of these conditions are either self-resolving or treatable by correction of the underlying disorder, the prognosis in general is excellent.

Most of these conditions described in this chapter cannot be prevented. The exception is the factor V or factor VIII deficiency that occurs secondary to exposure to topical bovine thrombin. A recently approved product is recombinant human thrombin, which in laboratory studies is of low immunogenicity and free of contaminants such as other clotting proteins.