ACP medicine, 3rd Edition

Hematology

Coagulation Disorders

Lawrence L. K. Leung MD1

1Professor of Medicine and Chief, Division of Hematology, Department of MedicineM Stanford University School of Medicine

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

Recombinant factor VIIa has not been approved by the FDA for uses described in this chapter.

December 2005

Bleeding or bruising that is spontaneous or excessive after tissue injury may be caused by coagulation defects, fibrinolysis, abnormal platelet number or function, abnormal vascular integrity, or a combination of these abnormalities. This chapter addresses hemorrhagic disorders associated with abnormalities in coagulation. Hemorrhagic disorders associated with quantitative or qualitative platelet abnormalities and disorders associated with blood vessels are discussed elsewhere [see 5:XIII Platelet and Vascular Disorders].

Disorders of coagulation may be inherited or acquired. Congenital coagulation disorders are rare and are most frequently caused by defects in single coagulation proteins, with the two X-linked disorders—factor VIII and factor IX deficiencies—accounting for the majority of defects. Acquired coagulation disorders are more common than the inherited disorders and are more complex in their pathogenesis. The most common acquired hemorrhagic disorders are vitamin K deficiency, drug-induced hemorrhage, and disseminated intravascular coagulation (DIC).

Hereditary Coagulation Disorders

The coagulation disorders appear clinically as either spontaneous hemorrhage or excessive hemorrhage after trauma or surgery. The patient history usually indicates whether the disorder is congenital or acquired. The hereditary disorders are characterized by their appearance early in life and by the presence of a single abnormality that can account for the entire clinical picture.

VON WILLEBRAND DISEASE

Pathophysiology

von Willebrand disease (vWD), the most common hereditary bleeding disorder, is caused by a deficient or defective plasma von Willebrand factor (vWF). The gene encoding vWF is on chromosome 12. vWF has specific domains for binding clotting factor VIII, heparin, collagen, platelet GPIb, and platelet GPIIb-IIIa. These domains relate directly to the following functions of vWF: (1) its action as a carrier molecule for factor VIII:C, in which it protects the clotting factor from proteolysis and substantially prolongs its plasma half-life; (2) its promotion of primary platelet adhesion at high wall shear rates by linking platelets via their GPIb-IX-V receptor to subendothelial tissues at the wound site; and (3) its support of platelet aggregation by linking platelets via their GPIIb-IIIa receptors.1 The vWF circulates as multimers that range in size from 0.5 million daltons (the dimer) to 20 million daltons. Even larger noncirculating multimers are present in endothelial cells, where they are stored in the Weibel-Palade bodies. The ultralarge vWF multimers are normally processed by the ADAMTS13 metalloprotease into smaller multimers as they are released from the endothelial cells. The vWF is released either into the circulation or abluminally, where it attaches to subendothelial collagen. Platelet α-granules also contain vWF, which is released when platelets are activated. The vWF multimers that are 12 million daltons or larger are the most effective in supporting platelet adhesion.

Laboratory Evaluation

The many variant forms of vWD differ in their clinical manifestations, laboratory abnormalities, and required therapies. Because vWF is a carrier protein for factor VIII, the activated partial thromboplastin time (aPTT) is prolonged when the vWF level is low. The platelet count is usually, but not invariably, normal. Bleeding time is generally prolonged but not sufficiently reliable to be used for diagnosis. An automated platelet function test utilizing a platelet function analyzer (PFA-100) has been shown to be a better screening test for vWD than the bleeding time.2,3 In this assay, citrated whole blood is aspirated through a capillary tube under high shear rates onto a membrane coated with collagen in which a central aperture is made. Platelets are activated by either adenosine diphosphate (ADP) or epinephrine. The closure time is a measure of platelet-vWF interaction.

The diagnosis of vWD requires the determination of factor VIII and vWF levels. There are two caveats: (1) laboratory testing is notoriously variable and (2) the patient's blood group affects the vWF level—that is, patients with blood group O have lower vWF levels than those with blood group A, B, or AB, by as much as 30%.4 The vWF level is measured by either immunologic or functional methods. The former is reported as a percentage of normal vWF antigen. Because vWF circulates in physiologically important multimeric forms, it is sometimes helpful to determine the multimeric composition of the vWF in the patient's plasma. This is especially useful in identifying type 2 vWD (see below). The functional level of vWF is tested by the ristocetin-induced platelet aggregation test. Ristocetin is added to a patient's platelet-rich plasma, where it causes vWF to bind to platelets via the GPIb-IX-V receptor, leading to platelet activation and aggregation. In some laboratories, formalin-fixed platelets are used and, after the addition of ristocetin, agglutination of fixed platelets is measured.

Clinical Variants

The classification scheme for variants of vWD comprises three major groups: type 1 is a partial quantitative deficiency of vWF, type 2 is a qualitative abnormality of vWF, and type 3 is a severe and virtually total quantitative deficiency of vWF [see Table 1].5

Type 1

Type 1 vWD is the most common form of vWD, accounting for 75% of cases. It is generally an autosomal dominant trait that usually appears in the heterozygous form. In many cases, a mutation in the vWF protein occurs such that the mutant provWF monomers form dimers normally with the wild-type provWF monomers, but the resulting dimers are trapped in the endoplasmic reticulum and cannot be secreted.6Patients with classic type 1 vWD have a lifelong history of mild to moderate bleeding, typically from mucosal surfaces. They may be unaware of a bleeding disorder until they undergo surgery or experience trauma, when bleeding may be severe. vWF antigen, factor VIII, and the ristocetin cofactor levels are all decreased.

Type 2

Type 2 vWD is characterized by qualitative abnormalities of vWF and a variable decrease in vWF antigen, factor VIII, and ristocetin cofactor. In type 2A, the largest multimers are absent; in type 2B, multimers bind excessively to platelets because of a gain-of-function mutation; in type 2M, the abnormal vWF does not bind to GPIb-IX-V; and in type 2N, the binding site of vWF for factor VIII is mutated. All type 2 vWD variants, except for the rare type 2M, are characterized by a loss of the high-molecular-weight vWF multimers in the VWF polymer analysis.

Table 1 Classification and Differentiation of von Willebrand Disease

 

Type 1

Type 2A

Type 2B

Type 2M

Type 2N

Type 3

Pseudo-von Willebrand Disease

Inheritance

Autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal recessive

Autosomal dominant

Incidence

~75%

~20%

~5%

Rare

Rare

Uncommon

Uncommon

Cause

Deficiency of normal vWF

Abnormal vWF

Abnormal vWF

Abnormal vWF

Abnormal vWF

Severe deficiency of vWF

Abnormal platelet membrane

Template bleeding time

N or ↑

N or ↑

↑↑

N or ↑

Factor VIII assay

N or ↓

N or ↓

N or ↓

↓↓

↓↓

N or ↓

vWF antigen

Variable

Variable

Variable

N

↓↓

Variable

Ristocetin cofactor (RIPA)

N

↓↓

Plasma vWF multimer analysis

N

Only low-molecular-weight forms present

Only low- and intermediate-molecular-weight forms present.

N

N

Variable

Only low- and intermediate-molecular-weight forms present

N—normal   ↓—decreased   ↑—increased   vWF—von Willebrand factor

Type 3

The rare homozygous or double heterozygous form (type 3 vWD) is characterized by severe hemorrhage, a long aPTT, and factor VIII levels of less than 5%.

Pseudo-von Willebrand disease

A platelet form of vWD, which is termed pseudo-von Willebrand disease (pseudo-vWD), has been described in which an abnormal GPIb is present on platelets, causing excessive binding of normal plasma vWF to unstimulated platelets.

The mean level of vWF antigen is 100 IU/dl, but the population distribution of vWF levels is very broad, with the 95% values encompassing 50 IU/dl to 200 IU/dl. The reasons for this broad distribution in vWF levels are not completely understood, but it makes the commonly used threshold (vWF level at 2 SD [standard deviation] below the mean) inadequate for diagnosis of type 1 vWD. This problem with diagnosis is compounded by the fact that mild bleeding symptoms are extremely common in the general population. A recent survey estimates that 25% of men and 46% of women would give a positive history of bleeding symptoms, such as frequent epistaxis, easy bruising, and postpartum bleeding.7 This suggests that type 1 vWD may be overdiagnosed, and it has been proposed that a more stringent diagnostic criterion be used—namely, limiting the diagnosis of type 1 vWD to patients with a vWF antigen level of less than 20 IU/dl.6 Patients with modestly reduced vWF antigen levels (i.e., between 30 and 50 IU/dl) usually do not have identifiable vWF gene mutations and rarely cosegregate with a family history of bleeding. Patients with modestly reduced vWF levels (and no history of family bleeding) may have a modestly increased risk of bleeding.

Treatment

Mild or moderate types 1 and 2

1-Desamino-8-D-arginine vasopressin (DDAVP or desmopressin) is effective in the management of traumatic bleeding and before surgery in some patients with mild or moderate type 1 and type 2A vWD. The intravenous administration of DDAVP at a dosage of 0.3 mg/kg over a 15- to 30-minute period causes the release of large amounts of vWF from endothelial cell stores. The peak response usually occurs in 30 to 60 minutes and persists for up to 4 to 6 hours. Repeated DDAVP administrations over a 24-hour period are ineffective; tachyphylaxis follows depletion of the endothelial vWF stores. A DDAVP nasal spray (300 µg) can be used in the ambulatory treatment of patients with vWD, both for the management of bleeding episodes and as preparation for minor surgery.8 The side effects of intravenous DDAVP are generally mild, including significant water retention and, rarely, thrombosis. Myocardial infarction has been reported. Because of the variability of response to DDAVP, a patient should be given a trial infusion of DDAVP before undergoing a planned procedure to determine whether the patient has an adequate response. Fibrinolysis inhibitor ε-aminocaproic acid (EACA), 3 g four times daily orally for 3 to 7 days, is also useful for dental procedures and minor bleeding events. Aspirin must be avoided.

Moderate and severe types 2 and 3

Patients with severe types 2A and 2B and with type 3 vWD generally require replacement therapy with Humate-P—a pasteurized intermediate-purity factor VIII concentrate that has a substantial amount of large vWF multimers—or with cryoprecipitate infusion containing vWF, factor VIII, and fibrinogen. Cryoprecipitate is generally not recommended. Transfusion of normal platelets can also be attempted on the grounds that platelet vWF can be hemostatically effective.9

Treatment during pregnancy

Treatment is generally not needed during pregnancy in women with vWD. The plasma vWF level rises during the second and third trimesters but falls rapidly after delivery. Late hemorrhage may occur 2 to 3 weeks post partum.10 DDAVP is not used before delivery because of the concern that it may initiate contractions. Patients with type 2B vWD may have worsening thrombocytopenia during pregnancy because of the increase of abnormal vWF in plasma.11

HEMOPHILIA A

Hemophilia A affects one in 10,000 males and is characterized by a deficient or defective clotting factor VIII. The factor VIII gene, which is located on chromosome X at Xq28, is among the largest known human genes, spanning 186 kb and containing 26 exons. It encodes a protein of about 300,000 daltons, which circulates in plasma at very low concentrations and is normally bound to and protected by vWF. The primary source of factor VIII production is likely the liver, because hemophilia A can be corrected by liver transplantation.

Because the gene for factor VIII coagulant activity is carried on the X chromosome, the disease is manifested in hemizygous males. All of the daughters of a hemophiliac male will be carriers, whereas half of the sons of a mother who carries the hemophilia trait will be hemophiliacs and half of her daughters will be carriers. Families appear to be affected to varying degrees, depending on the specific nature of the genetic defect.

The clinical severity of hemophilia A correlates well with the measured levels of factor VIII coagulant activity. In general, factor VIII levels below 1% are associated with severe hemorrhagic symptoms; levels between 1% and 5%, with moderate hemophilia; and levels between 5% and 25%, with mild hemophilia [see Table 2].

Approximately one third of hemophilia A cases represent new mutations and have a negative family history. More than 300 abnormal factor VIII genes have been found. The abnormalities, which include point mutations, gene insertions, and gene deletions, result in either deficient factor VIII production or the generation of a functionally defective factor VIII. An inversion within intron 22 of the factor VIII gene, which results in a truncated and unstable factor VIII protein, is found in approximately 45% of all severely affected hemophilia A patients (factor VIII levels below 1%).12

Diagnosis

Diagnosis is made on the basis of the clinical picture, family history (positive in two thirds of cases), and the factor VIII coagulant activity level. In most cases, the type of bleeding history and a classic family history rule out vWD (which, unlike hemophilia A, is autosomally transmitted). Accurate DNA analysis for the common intron 22 inversion is now available in DNA testing laboratories. This test provides molecular diagnosis in approximately 45% of patients with severe hemophilia. However, it should not be ordered in patients with mild or moderate hemophilia.

Table 2 Correlation of Factor VIII Coagulant Activity Level with Bleeding Patterns in Hemophilia

Plasma Factor VIII Level

Bleeding Pattern

< 1%

Severe, presentation in first year of life, bleeding with circumcision, spontaneous hemarthrosis and deep-tissue bleeding

1%–5%

Moderate, presentation in childhood, bleeding after trauma, spontaneous hemarthrosis rare

5%–25%

Mild; may be present in childhood; bleeding after trauma, surgery, or dental extraction

25%–50%

May be undetected, may present in adulthood with bleeding after major trauma or surgery

Treatment

General principles

The psychosocial aspects of hemophilia are complex. A child is often absent from school, is prone to crippling deformities, and runs a risk of drug addiction because of severe pain. Parents are understandably deeply concerned and sometimes troubled by guilt. Treatment should address these issues as well as the specific coagulation problem.

Factor VIII replacement

Factor VIII concentrates are effective in controlling spontaneous and traumatic hemorrhage. Currently available factor VIII products derived from plasma have been purified to varying degrees (e.g., Humate-P [intermediate purity], Koate-HP [high purity], and Monoclate [ultrapurity]) and have undergone viral inactivation. There are two forms of full-length recombinant factor VIII (Recombinate and Kogenate), and they are safe and efficacious.13,14 A second-generation, B-domain-deleted recombinant factor VIII (ReFacto) has also been developed and has been found to be effective and well tolerated.15 The new recombinant factor VIII has the advantage of considerably higher specific activity, and the final formulation is stable without added human serum albumin, thus further reducing the potential risk of transmission of human infectious agents.

Dental prophylaxis is critically important to reduce the need for dental surgery. Aspirin must be avoided. Revaccination against hepatitis B virus also should be considered.

Genetic counseling should be part of the management program. Because of the difficult life severe hemophiliacs lead, a woman may opt to terminate pregnancy if she is certain of her carrier status or if she knows that her fetus is affected. There are several strategies for detecting carriers. In women who are carriers, factor VIII levels are typically about half of normal, whereas vWF levels are normal. The ratio of factor VIII to vWF for carriers is thus 0.516; however, the error rate for this test is 10% to 17%. A more accurate genetic diagnosis for carriers can be made by a linkage approach. This approach is based on restriction fragment length polymorphisms (RFLPs) within the factor VIII gene. Analysis of the affected male will establish the pattern for the X chromosome carrying the hemophilia allele, without knowledge of the precise mutation. There are a large number of intragenic polymorphisms that allow the two copies of factor VIII genes in a female potential carrier to be distinguished, identifying her carrier state with high accuracy.

These molecular probes for RFLPs are now being used to determine the status of the fetus. Tissue can be obtained by amniocentesis or chorionic villus sampling.

Management of acute hemorrhage

Deep tissue bleeding, hemarthrosis, and hematuria are the common forms of clinical bleeding in hemophilia A. Acute threats to life are posed by retroperitoneal hemorrhage; bleeding of the mouth, tongue, or neck that impairs the airway; and intracranial hemorrhage. Both ultrasonography and computed tomography can be used to identify retroperitoneal and intramuscular hematomas.

Principles of replacement therapy

A plasma procoagulant level of 100% means that there is one unit of procoagulant per milliliter of plasma. Most persons have 40 ml of plasma per kilogram of body weight. Thus, from a determination of a patient's plasma volume and procoagulant level, the required amount of factor VIII replacement can be calculated. For example, in the case of a 60 kg boy who has an uncomplicated hemarthrosis of the knee and a baseline factor VIII of less than 1%, raising the factor VIII level to about 25% (0.25 U/ml) for 2 to 3 days should suffice. This patient has a plasma volume of 60 kg × 40 ml/kg, or 2,400 ml; he will need 0.25 U/ml × 2,400 ml, or 600 U of factor VIII, as an initial bolus. Another method of estimation is based on the following effect: the infusion of 1 U of factor VIII per kilogram increases factor VIII levels by 2%. Thus, dividing the desired level of factor VIII increase by 2 will give the number of U/kg required. In the example cited, 25% of factor VIII will require 12.5 U/kg, or 750 U, of factor VIII replacement.

The biologic half-life of factor VIII is approximately 12 hours; the dose can be repeated every 12 to 24 hours as long as needed to control the hemorrhage. In patients with hemarthrosis, the factor VIII level should be maintained for 2 to 3 days.

Elective surgery and dental extraction

Dental work should be performed by a dentist who is experienced in the treatment of hemophiliacs. Before dental extraction, factor VIII is administered to raise the level to approximately 50%. The fibrinolytic inhibitor EACA is started the night before surgery at a loading dose of 3 g orally and continued at 2 to 3 g three or four times daily for 7 to 10 days after the dental work has been completed. Usually, further administration of factor VIII is not required.

Before elective surgery, the factor VIII level should be raised to 50% to 100% (0.5 to 1.0 U/ml) and then maintained above 50% for the next 10 to 14 days. Maintaining a higher concentration of factor VIII does not reduce the frequency of hemorrhage.17

DDAVP can be used to treat acute traumatic hemorrhage in patients with mild to moderate hemophilia and even to prepare such patients for minor surgery. DDAVP, which causes the release of vWF from endothelial cell stores, cannot be used repeatedly over many days, because such stores become depleted. DDAVP is infused at a dosage of 0.3 µg/kg in 50 ml of saline over 15 to 30 minutes and produces a prompt increase in factor VIII. The biologic half-life of the released factor VIII is 11 to 12 hours.

Management of an inhibitor

Inhibitors tend to occur in more severely affected patients, who tend to receive the greatest number of factor VIII concentrates. In a recent single-center study of 431 patients over 3 decades, approximately 10% of patients with severe hemophilia A had an inhibitor (about a third were children younger than 10 years).18 Not all inhibitors produce clinical problems. Assays for factor VIII inhibitors should be performed at regular intervals in all patients who have severe hemophilia.

Hemorrhage in a patient with an inhibitor can be life threatening. In a patient who has an inhibitor titer of less than 5 Bethesda units and who is not a vigorous antibody responder, a large amount of factor VIII concentrate should be administered in an attempt to overwhelm the antibody. Alternative therapies are porcine factor VIII (Hyate:C), prothrombin complex concentrates (e.g., Konyne and Proplex) to circumvent the factor VIII deficiency,19,20 and activated prothrombin complex concentrates, such as Autoplex-T and FEIBA.

Recombinant activated factor VII (rFVIIa) has been found to be safe and efficacious in 70% to 85% of more than 1,500 bleeding episodes in hemophilia patients with inhibitors.21,22 Recombinant factor VIIa may compete against the normal plasma unactivated factor VII for tissue factor binding and thus enhance thrombin generation at the bleeding site.23 In addition, high-dose rFVIIa may bind to activated platelets and activate factors IX and X on the platelet surface in the absence of tissue factor.24

High-dose intravenous IgG has been used to treat nonhemophiliacs with acquired factor VIII inhibitors, but it is usually not efficacious in hemophiliacs with inhibitors (alloantibodies).

OTHER HEREDITARY HEMORRHAGIC DISORDERS

Factor IX Deficiency (Hemophilia B)

Factor IX deficiency (hemophilia B, or Christmas disease) is an X-linked disorder that is clinically indistinguishable from hemophilia A. The factor IX gene is on the X chromosome and produces a clotting factor that, like other vitamin K-dependent factors, has a region rich in γ-carboxylated glutamic acids. Calcium ion bridges link this region to the activated platelet cell surface, where factor IXa interacts with factor VIIIa to form a membrane-associated complex that efficiently converts factor X to factor Xa (intrinsic tenase) [see 5:XII Hemostasis and Its Regulation]. A large number of insertions, rearrangements, and deletions have been detected in the factor IX gene, and the hemophilia B syndrome is very heterogeneous.25

Diagnosis

Diagnosis of hemophilia B requires a factor IX assay. The management principles are the same as those for hemophilia A. A plasma-derived pasteurized factor IX concentrate preparation (Mononine) displays excellent specific activity and a desirable biologic half-life of 18 to 34 hours. Recombinant factor IX is also commercially available.

Treatment

The level of factor IX that is needed to control hemostasis in patients with hemophilia B is somewhat lower than the level of factor VIII required for the treatment of hemophilia A—about 15% to 20% for the former and 30% to 50% for the latter. Factor IX is a smaller molecule than factor VIII and is distributed in the albumin space. In making replacement calculations, it is assumed that administration of 1 U/kg of factor IX will increase the plasma level by 1%. Factor IX has a biphasic half-life, and plasma levels of this factor can be maintained by infusing the concentrate every 24 hours. Molecular biology techniques can now detect the factor IX deficiency carrier state and permit accurate genetic counseling. Sustained correction of a bleeding disorder in hemophilia B mice has been demonstrated by the gene therapy approach,26 and clinical trials of factor IX in hemophilia B patients have been initiated.27

Factor XI Deficiency

Patients with factor XI deficiency frequently come to medical attention when a prolonged aPTT is detected in preoperative screening. It is most frequently observed in Ashkenazi Jews, although sporadic cases have been described in people of different ethnic origins. Factor XI deficiency is inherited as an autosomal recessive trait, and heterozygous deficiency is not associated with any clinical bleeding. Homozygous or compound heterozygous deficient patients generally have factor XI levels of less than 15%, and most bleeding manifestations in these patients are related to trauma or surgery, especially at sites of high fibrinolytic activity (e.g., the urinary tract, tonsils, and tooth sockets).28 Factor XI plays a supportive role in the clotting cascade. It is activated by thrombin and then functions in a positive feedback manner to augment thrombin generation and clot stabilization [see 5:XII Hemostasis and Its Regulation]. Thus, factor XI is primarily required in situations in which there is a significant hemostatic challenge; this explains the mild bleeding diathesis in factor XI deficiency.

For patients with severe factor XI deficiency (< 15%) who require surgery, fresh frozen plasma should be used to replenish the plasma level to more than 50%. EACA given orally at a dosage of 3 g three or four times daily is also effective for minor surgical or dental procedures. In a recent retrospective study of 62 women with severe factor XI deficiency, about 70% of the women did not have any postpartum hemorrhage. Of the 30% who did have postpartum hemorrhage, some had a history of recurrent clinical bleeding. Postpartum hemorrhage had no relationship with the particular abnormal factor XI genotype or with the level of factor XI.29

Fibrinolytic Abnormalities

Two uncommon congenital hemorrhagic disorders have been ascribed to abnormalities of fibrinolysis. Deficiency of α2-antiplasmin, the major plasmin inhibitor, has led to uncontrolled plasmin activity with consequent hemorrhage. Enhanced fibrinolytic activity with occasional clinical bleeding has also been linked to deficiency of plasminogen activator inhibitor-1 (PAI-1), the physiologic inhibitor of tissue plasminogen activator (t-PA) and urokinase.30 Treatment of both types of fibrinolytic abnormalities consists of the antifibrinolytic agents, tranexamic acid, or EACA, all of which block the binding of plasminogen and plasmin to fibrin.

Acquired Hemorrhagic Disorders

In addition to the hereditary coagulation disorders, several acquired disorders have been identified that can lead to generalized hemorrhage.

VITAMIN K DEFICIENCY

A vitamin K-dependent carboxylase in the liver synthesizes γ-carboxyglutamic acid, which is required for the biologic function of prothrombin and factors VII, IX, and X. In the absence of vitamin K, an abnormal prothrombin that lacks γ-carboxyglutamic residues is synthesized. Specific immunoassays performed in patients with vitamin K deficiency reveal a sharp decrease in normal prothrombin levels and a concomitant increased level of the abnormal des-γ-carboxyprothrombin. The same molecular derangement occurs with factors VII, IX, and X.31

Clinical Features and Diagnosis

Deficiency of vitamin K, which decreases levels of prothrombin and factors VII, IX, and X, occurs in cases of severe malnutrition, intestinal malabsorption, and obstructive jaundice. In patients with obstructive jaundice, bile salts, which are necessary for the emulsification and absorption of the fat-soluble vitamins (vitamins A, D, E, and K), cannot enter the intestine. Long-term ingestion of oral antibiotics suppresses vitamin K production by intestinal organisms. The effect is especially marked in patients who, because of their illness, are unable to consume a full, nourishing diet. Mucosal bleeding and ecchymoses occur if the procoagulant levels fall below 10% to 15% of normal.

Treatment

Therapy with vitamin K1 (phytonadione), 10 to 25 mg/day orally for 2 or 3 days—or parenteral vitamin K1 in cases of obstructive jaundice—usually reverses the abnormality in about 6 to 24 hours. If there is severe bleeding, fresh frozen plasma (approximately 3 units) restores procoagulant levels rapidly [see Principles of Replacement Therapy, above].

DRUG-INDUCED HEMORRHAGE

Warfarin-Induced Hemorrhage

Warfarin overdose or potentiation of its action by other drugs can cause very severe bleeding. The prothrombin time (PT) is prolonged, and mucosal bleeding, gastrointestinal bleeding, or ecchymosis is the usual pattern. If hemorrhage is significant, treatment to restore procoagulant levels to 30% of normal must be started with fresh frozen plasma. If there is no urgency, oral vitamin K1 may be given. Generally, 1 to 2.5 mg of vitamin K1 will be sufficient to return anticoagulation (defined as the international normalized ratio [INR]) to therapeutic levels after 16 hours. High doses of vitamin K1 (10 mg or more) should be avoided because they may cause warfarin resistance for up to a week. Surreptitious warfarin use can be identified by a serum warfarin assay, which is available at special laboratories. Factitious or accidental ingestion of some of the long-acting vitamin K antagonists that are used as rodenticides (superwarfarins) may lead to prolonged bleeding symptoms. The synthesis of vitamin K-dependent clotting factors can be impaired for months after the initial exposure. Repeated administration of fresh frozen plasma, supplemented by massive doses of oral vitamin K1 (100 to 150 mg/day), may be required to control bleeding symptoms.

Heparin-Induced Hemorrhage

Heparin overdose may not be obvious. It causes subcutaneous hemorrhages and deep tissue hematomas. The aPTT, PT, and thrombin time (TT) are vastly prolonged, but the reptilase time (RT) is normal. Intravenous protamine administration at a dosage of 1 mg/100 U of administered heparin terminates the overdose response. Because the half-life of protamine is shorter than that of heparin, a heparin rebound may occur, necessitating a second administration of protamine. Low-molecular-weight heparin (LMWH) preparations cause as much bleeding as standard unfractionated heparin. The ability of protamine to reverse the actions of LMWH is incomplete. Protamine (1 mg/100 U of anti-factor Xa) can be tried; if protamine treatment is unsuccessful, recombinant factor VIIa should be considered.

Hemorrhage Caused by Thrombolytic Therapy

Thrombolytic therapy is now used for acute myocardial infarction and for some cases of pulmonary embolism. The complications of thrombolytic therapy are essentially all hemorrhagic. In general, bleeding has been confined to relatively trivial oozing at vascular invasion sites, but subdural hematomas, cerebral infarction, and intracranial bleeding have also occurred. The thrombolytic agents, even those designed to be relatively fibrin specific, occasionally cause a significant systemic lytic state, with low levels of fibrinogen, factor V, and factor VIII. Furthermore, the generation of fibrinogen degradation products in turn interferes with the formation of a firm clot and with platelet function.

If thrombolytic therapy is suspected as the cause of bleeding in a particular patient, blood should be drawn quickly for an aPTT, a TT, an RT, and a fibrinogen level. If thrombolytic therapy is the cause, the aPTT is prolonged, the fibrinogen level is usually below 50 mg/dl, and the TT and RT are both prolonged (as a result of the fibrin degradation products and decreased plasma fibrinogen).

Table 3 Causes of Disseminated Intravascular Coagulation (DIC)

Events that initiate DIC
  Septicemia
  Cancer procoagulants (Trousseau syndrome)
  Acute promyelocytic leukemia
  Crush injury, complicated surgery
  Severe intracranial hemorrhage
  Retained conception products, abruptio placentae, amniotic fluid embolism
  Eclampsia, preeclampsia
  Major ABO blood mismatch, hemolytic transfusion reaction
  Burn injuries
  Heatstroke
  Malignant hypertension
  Extensive pump-oxygenation (repair of aortic aneurysm)
  Giant hemangioma (Kasabach-Merritt syndrome)
  Severe vasculitis
Events that complicate and propagate DIC
  Shock
  Complement pathway activation

The disorder is treated with cryoprecipitate (to raise the fibrinogen level to approximately 100 mg/dl), fresh frozen plasma, and platelet concentrates. If these measures do not stop the bleeding, the use of a specific antifibrinolytic agent such as EACA should be considered. EACA is given as a 5 g bolus I.V. over 30 to 60 minutes and then in a dosage of 1 g/hr by continuous I.V. infusion.32

DYSPROTEINEMIAS

The abnormal proteins associated with myeloma and macroglobulinemia can interfere with platelet function and cause clinical bleeding. These proteins can cause abnormalities in the coagulation tests as well. Both IgG and IgA myeloma proteins can cause prolonged TTs by interfering with the fibrin polymerization process. Less commonly, they may interact with specific clotting factors. Management is directed at the primary disease. Generally, these paraproteins do not cause clinically significant bleeding. If bleeding occurs, plasmapheresis rapidly corrects the defects by abruptly lowering the level of abnormal protein.

DISSEMINATED INTRAVASCULAR COAGULATION

Pathophysiology

Many different circumstances can cause DIC [see Table 3]. In each case, massive activation of the clotting cascade overwhelms the natural antithrombotic mechanisms, giving rise to uncontrolled thrombin generation. This condition results in thromboses in the arterial and venous beds, leading to ischemic infarction and necrosis that intensify the damage, release tissue factor, and further activate the clotting cascade. Massive coagulation depletes clotting factors and platelets, giving rise to consumption coagulopathy and bleeding. Tissue damage and the deposition of fibrin result in the release and activation of plasminogen activators and the generation of plasmin in amounts that overwhelm its inhibitor, α2-antiplasmin. Plasmin degrades fibrinogen, prothrombin, and factors V and VIII and produces fibrin-fibrinogen degradation products. These substances interfere with normal fibrin polymerization and impair platelet function by binding to the platelet surface GPIIb-IIIa fibrinogen receptor. These fibrin-fibrinogen degradation products thus function as circulating anticoagulant and antiplatelet agents, exacerbating the consumption coagulopathy, and play a significant role in the bleeding diathesis [see Figure 1].

 

Figure 1. In compensated disseminated intravascular coagulation (DIC), such as that which occurs in Trousseau syndrome, thrombotic manifestations predominate in the clinical presentation. In decompensated DIC, however, fibrin-fibrinogen degradation products exacerbate the consumption coagulopathy and play a significant role in the bleeding diathesis.

Endotoxin released during gram-negative septicemia enhances the expression of tissue factor, thereby accelerating procoagulant activation while suppressing thrombomodulin expression. These actions downregulate the protein C/protein S system, further promoting the tendency to DIC.33 Experimental-endotoxemia models also showed marked suppression of fibrinolysis activity caused by a sustained increase in plasma PAI-1.34 In patients with solitary or multiple hemangiomas associated with thrombocytopenia (Kasabach-Merritt syndrome), DIC is presumably initiated by prolonged contact of abnormal endothelial surface with blood in areas of vascular stasis. Platelets and fibrinogen are consumed in these hemangiomas, where fibrinolysis appears to be enhanced,35 and such consumption can lead to hemorrhage. Certain snakebites can also produce DIC; several mechanisms have been identified. For example, Russell viper venom contains a protease that directly activates factor X and can produce almost instantaneous defibrination.

Clinical Consequences

The consequences of DIC depend on its cause and the rapidity with which the initiating event is propagated. If the activation occurs slowly, an excess of procoagulants is produced, predisposing to thrombosis. At the same time, as long as the liver can compensate for the consumption of clotting factors and the bone marrow maintains an adequate platelet output, the bleeding diathesis will not be clinically apparent. The clinical situation consists of primarily thrombotic manifestations, which can be both venous thrombosis and arterial thrombosis [see 5:XIV Thrombotic Disorders]. Venous thromboses commonly involve deep vein thrombosis in the extremities or superficial migratory thrombophlebitis. Patients can also experience arterial thrombosis, leading to digital ischemia, renal infarction, or stroke. Arterial ischemia can in part be the result of emboli that originate from fibrin clots in the mitral valve, a condition termed nonbacterial thrombotic endocarditis, or marantic endocarditis. This condition is sometimes known as compensated, or chronic, DIC and accounts for Trousseau syndrome36 (a chronic DIC caused by an underlying malignancy, most frequently pancreatic or other gastrointestinal cancer). The cancer cells may produce either tissue factor or another procoagulant that activates the clotting system.

If the reaction is brisk and explosive, the clinical picture is dominated by intravascular coagulation; depletion of platelets, fibrinogen, prothrombin, and factors V and VIII; and the production, by plasmin action, of fibrin degradation products, which further interfere with hemostasis. The clinical consequence is a profound systemic bleeding diathesis, with blood oozing from wound sites, intravenous lines, and catheters, as well as bleeding into deep tissues. The intravascular fibrin strands produce microangiopathic hemolytic anemia.

Diagnosis

Microangiopathic red blood cells on smear and a moderate to severe thrombocytopenia suggest the diagnosis. A number of laboratory abnormalities are present in DIC, depending on the stage of the DIC. Because of clotting factor depletion, the aPTT and PT are prolonged and the fibrinogen level is low. Because fibrin degradation products interfere with fibrin polymerization, the TT and RT are also prolonged. The level of fibrin degradation products, as measured by the D-dimer level, is elevated. Plasma plasminogen, protein C, and α2-antiplasmin levels are also low because of consumption; however, these measurements are generally not required. In the case of compensated DIC, most of these parameters can be normal except for the elevation of the D-dimer level, which indicates the presence of intravascular cross-linked fibrin deposition and fibrinolysis. Sometimes, the fibrinogen level can even be high because fibrinogen is an acute-phase reactant. When the DIC becomes decompensated, consumption coagulation predominates and the other laboratory abnormalities listed are present (see above). Repetition at regular intervals of specific coagulation tests (see above), especially the platelet count, fibrinogen level, and D-dimer level, is critical. These tests provide a kinetic parameter that greatly aids in the assessment of the severity of the DIC and the choice of appropriate management.

Treatment

Currently, management must be directed at the primary disease to switch off the initiating event. This approach may involve chemotherapeutic treatment of an underlying tumor, administration of antibiotics and surgical drainage of an abscess, or emptying the uterus when complications of pregnancy have been the inciting cause. Hemodynamic support is essential. The use of antifibrinolytic agents such as EACA or aprotinin is contraindicated. Despite its bleeding complications, DIC is a severe hypercoagulable state, and these agents block the fibrinolytic system and may exacerbate its thrombotic complications. The administration of blood products, such as platelets, fresh frozen plasma, or cryoprecipitate, may add fuel to the fire and worsen the consumption coagulopathy. However, if clinical bleeding becomes significant, it is prudent to give vigorous blood product support.

The use of heparin in cases of acute DIC has not been established. Although heparin, by activating antithrombin (AT), is effective in inhibiting thrombin and therefore should be efficacious in the treatment of DIC, its use is generally limited to situations of chronic or compensated DIC. Heparin, given subcutaneously, is effective in the treatment of venous thrombosis in patients with Trousseau syndrome. In the case of decompensated DIC, in which bleeding is the major clinical manifestation, heparin may significantly exacerbate the bleeding and is therefore generally not indicated. The use of high-dose AT infusion has been advocated in this situation, but its efficacy has not been established by randomized studies.37,38

Recombinant human activated protein C (APC, or drotrecogin alfa [activated]) has been shown to significantly reduce mortality in patients with severe sepsis (mortality was 24.7% in patients given APC versus 30.8% in patients given placebo).39 Although it is associated with a slightly increased risk of bleeding, APC appears to be an effective agent in the treatment of severe DIC in patients with sepsis, even for patients with normal protein C levels.40 In large randomized trials, neither recombinant tissue factor pathway inhibitor (TFPI) nor AT concentrate reduced mortality in septic patients.41,42 In cases of DIC associated with solitary or multiple hemangiomas, the hemangiomas can be excised when they are localized, and they occasionally show a good response to local irradiation. Attempts to control DIC associated with hemangiomas by the administration of heparin, corticosteroids, aspirin, and estrogens have not been successful. The key to successful management of DIC associated with certain snakebites is identification of the type of snake and prompt administration of appropriate antivenin.

ACQUIRED HEMOPHILIA AND OTHER DISORDERS OF CIRCULATING INHIBITORS

In addition to the hemorrhage caused by the circulating alloantibody inhibitors in severe hemophilias A and B, clinical hem- orrhage is occasionally caused by circulating inhibitors directed against specific clotting factors, which seem to appear spontaneously. Because acquired autoantibody to factor VIII, which gives rise to the clinical picture of acquired hemophilia, is the most common of these circulating inhibitors, it will be described here in some detail, but many of the same principles apply to other inhibitors.

Autoantibodies to factor VIII are usually IgGa and, frequently, IgG4 and thus do not fix complement. They are usually directed against the functionally important A2 and C2 domains43 on factor VIII. About half of the patients with an acquired factor VIII inhibitor have no identifiable associated disorder, but many disease states have been identified in the other patients, including autoimmune disorders such as systemic lupus erythematosus, lymphoproliferative disorders, plasma cell malignancies, drug reactions (e.g., reaction to penicillin), the postpartum state, and skin disorders.44

Diagnosis

Patients with an acquired factor VIII inhibitor commonly present with new-onset mucosal hemorrhages, hematomas, and ecchymoses but have a negative bleeding history. Typically, the clinical picture of acquired hemophilia caused by factor VIII inhibitor occurs in an elderly patient or in a young woman during pregnancy or in the postpartum period. The laboratory hallmark of an acquired inhibitor to a clotting factor is a prolonged clotting time that is not corrected by mixing equal parts of the patient's plasma with normal plasma. In the case of factor VIII inhibitor, the PTT is prolonged and the PT and TT are normal. The antibody binds to factor VIII with complex kinetics such that the inhibitory effect becomes apparent only after prolonged incubation. Therefore, if an acquired factor VIII inhibitor is suspected, mixing studies should be performed after 5-minute and 60-minute incubations. The diagnosis can be confirmed by demonstration of a very low factor VIII level when other clotting factor levels are normal. Determination of the titer of the factor VIII inhibitor (expressed in Bethesda units [BU] per milliliter, with 1 BU/ml indicating a sufficient number of inhibitors to cause the complete inhibition of factor VIII in 1 ml of blood) is useful in choosing the appropriate therapy.

Treatment

The hemorrhage caused by circulating inhibitors may be clinically life threatening. Attempts at factor replacement are usually not successful, because the inhibitor inactivates the exogenous factor VIII. Occasionally, if the inhibitor has a low titer (e.g., < 2 to 3 BU/ml), massive factor VIII replacement can overwhelm the inhibitor. However, this treatment may trigger a significant anamnestic response resulting in increased levels of antibody, which complicates further management. Immunosuppressive therapy with a combination of cyclophosphamide (given either as a monthly intravenous pulse therapy or orally on a daily basis) and prednisone has been successful in most cases.45,46 The inhibitor usually becomes undetectable after three or four monthly cycles of chemotherapy. In the case of severe or life-threatening hemorrhage in which there is insufficient time to reduce the level of inhibitor, porcine factor VIII can be administered, because the antibody usually displays low cross-reactivity.

Another alternative therapy for acute bleeding is the administration of procoagulant complexes, which may bypass the inhibitor block by providing large amounts of factor X and factor VII.47 Still other therapeutic options include plasmapheresis and high-dose intravenous IgG, although the response rate for intravenous immune globulin (IVIg) appears to be quite low.48 Recombinant activated factor VII (90 µg/kg given as an I.V. bolus every 2 to 3 hours) has been used successfully in patients with this condition. There is growing evidence that rituximab, given intravenously at 375 mg/m2 once weekly for 4 weeks, is effective.49,50 In patients with a very high titer inhibitor (>100 BU/ml), a combination of rituximab and cyclophosphamide may be required.

ACQUIRED VON WILLEBRAND DISEASE

Diagnosis

Patients with acquired von Willebrand disease, who are generally in their 50s and 60s and do not have a personal or family history of a bleeding disorder, present with mucocutaneous-type bleeding.51 The workup is the same as that for vWD. The acquired form of the disease frequently occurs in the setting of underlying lymphoproliferative, myeloproliferative, or cardiovascular disease. A study showed that acquired vWD is quite common in patients with severe aortic stenosis. vWF abnormalities are directly related to the severity of aortic stenosis and improve after valve replacement.52 Acquired vWD is also occasionally associated with angiodysplasia in patients with recurrent gastrointestinal bleeding. Frequently, a small monoclonal gammopathy is found on serum protein electrophoresis. The plasma antibody to vWF is functional in a minority of cases, as demonstrated by inhibition of vWF in a functional assay by mixing studies.53 However, most cases involve nonneutralizing antibodies to vWF, which can be demonstrated by enzyme-linked immunosorbent assay (ELISA). Presumably, the antibody binds to vWF and causes its rapid clearance, leading to a low plasma vWF level. Nonimmune mechanisms (e.g., adsorption of vWF onto tumor cells) have also been described. Multimeric analysis of plasma vWF typically shows a decrease in the high-molecular-weight multimers, resembling type 2A vWD.

Treatment

DDAVP is useful in correcting the bleeding diathesis in about one third of cases of acquired vWD. High-dose intravenous IgG (1 g/kg I.V. daily for 1 to 2 days) generally garners a good temporary response, with an increase in the vWF level and a shortening of the aPTT, lasting from a few days to 2 weeks. If the patient has a defined lymphoproliferative, myeloproliferative, or autoimmune disease, the underlying disease should be treated. However, the response of acquired vWD to immunosuppressive therapy with cyclophosphamide and prednisone is generally not as favorable as the response in the case of acquired factor VIII inhibitor.

HEMORRHAGE CAUSED BY SEVERE LIVER DISEASE

Patients with severe liver disease may suffer life-threatening hemorrhages. The most frequent types are esophageal and gastrointestinal hemorrhages related to varices, gastritis, or peptic ulcer. There may also be bleeding from biopsy sites and during and after surgery. Mucosal and soft tissue bleeding may occur, but generally, this is not the dominant bleeding problem.

The coagulopathy of severe liver disease is complex and not well delineated. Because the liver is the major site of synthesis for all the clotting factors, decreased levels of multiple clotting factors are observed, including fibrinogen, prothrombin, factor V, and factor VII; factor VIII is excepted, presumably because it is an acute-phase reactant. An increased level of abnormal fibrinogen with reduced clotting capability is also observed in patients with cirrhosis.54 In addition, there is reduced clearance of activated clotting factors by the liver. DIC appears to occur commonly in patients with cirrhosis55 (presumably because of triggering of the clotting cascade by hepatic tissue damage), but its precise role in both acute fulminant hepatitis and chronic liver disease has not been firmly established. Moderate thrombocytopenia is common, resulting from a combination of decreased platelet production (from relative deficiency of thrombopoietin [TPO], because the liver is the major site of TPO synthesis) and increased platelet destruction from hypersplenism. Platelet function is generally maintained. There is also evidence of hyperfibrinolysis, but its contribution to the overall hemostatic defect is uncertain. The liver also synthesizes most of the natural anticoagulant proteins. AT, protein C, and protein S levels are decreased. The best screening tests for this disorder include the PT, aPTT, platelet count, fibrinogen level, and D-dimer level. Specific assays that may guide therapy include factor V, factor VII, and AT. Replacement for active bleeding is accomplished by administering fresh frozen plasma, cryoprecipitates, and platelets as required. Prothrombin-complex concentrates are not recommended, because they do not replenish all the deficient clotting factors and may exacerbate the DIC. In general, although the multiple hemostatic defects contribute to the bleeding diathesis in severe liver disease, hemodynamic and anatomic factors are the primary determinants in this situation.

PRIMARY FIBRINOLYSIS

Cases of generalized primary fibrinolysis are rare. Many of the early reports of primary fibrinolysis probably represented secondary fibrinolysis associated with DIC. Postprostatectomy hematuria may constitute a true example of hemorrhage caused by localized fibrinolysis. The high concentration of urokinase in the urine in this condition causes plasminogen to be converted to plasmin with resulting clot lysis. If other causes of persistent postoperative hematuria can be ruled out, the condition can be treated with oral or intravenous EACA. Local instillation of EACA by urethral catheter is also effective.

BLEEDING AFTER CARDIOPULMONARY BYPASS

A mild thrombocytopenia (approximately 100,000/µl) commonly occurs in patients after cardiopulmonary bypass surgery.56 A significant acquired platelet function disorder develops in some patients, probably caused by contact between the platelets and the oxygenator apparatus, which in turn leads to partial platelet degranulation.57 In addition to the release of platelet granule contents, activation of fibrinolysis may occur together with modest clotting factor depletion.58 The hemorrhage in such cases generally responds to platelet transfusions. The use of DDAVP in this setting has been reported to reduce postoperative blood loss; however, a meta-analysis of 17 clinical trials showed only a modest beneficial effect.59

The bovine protease inhibitor aprotinin has been shown to reduce bleeding and transfusion requirements in patients undergoing cardiopulmonary bypass.60 Aprotinin inhibits plasmin and may also attenuate the systemic inflammatory response by inhibition of the proinflammatory mediator kallikrein.61 It reduces plasmin-mediated proteolysis of platelet membrane proteins and preserves platelet function.62 Randomized clinical trials showed that the two antifibrinolytic agents EACA and tranexamic acid are equally efficacious as aprotinin in this setting.63,64 Aprotonin should be reserved for patients who are likely to require blood transfusion, especially those undergoing second operations and those with preexisting hemostatic defects. Preoperative testing of hemostasis appears not to be useful.

Table 4 Differential Diagnosis of Postoperative Hemorrhage

Dilutional thrombocytopenia caused by massive transfusion
Acquired platelet function defect after cardiopulmonary bypass
Inadequate heparin neutralization
Disseminated intravascular coagulation
Coagulopathy caused by shock liver
Acquired antithrombin and anti-factor V inhibitors after exposure to fibrin glue
Heparin-induced thrombocytopenia
Thrombocytopenia caused by GPIIb-IIIa inhibitors (e.g., abciximab)
Hyperfibrinolysis after prostate surgery
Undiagnosed von Willebrand disease or hemophilia
Thrombocytopenia caused by posttransfusion purpura
False abnormalities in coagulation test results

During bypass surgery, patients are sometimes exposed to topical thrombin (fibrin glue), which is used for local hemostasis control. Generally, bovine thrombin and trace amounts of other clotting factors to which patients may develop antibodies are used in these preparations. The antibodies against bovine thrombin cause a prolongation of the TT but are innocuous in themselves. However, potentially serious complications arise when the antibodies cross-react with human thrombin. Some patients develop antibodies against bovine factor V that cross-react with human factor V and may lead to clinical bleeding.65,66 A review of reported cases found that bovine thrombin-associated factor V antibodies developed in 40% to 66% of cardiac surgery patients and in 20% of neurosurgery patients, and clinical bleeding complications occurred in about one third of these cases.67 Mixing studies utilizing the patient's plasma and normal plasma will reveal the presence of the inhibitors, and the measurement of the appropriate factor levels will allow the correct diagnosis to be made. Sometimes, plasmapheresis is required to control the acute bleeding.

EVALUATION OF POSTOPERATIVE BLEEDING

Serious hemorrhage during or after surgery is a complicated clinical problem requiring rapid diagnosis and prompt intervention. The first question is whether the bleeding has a local anatomic cause (e.g., unligated vessel) or is the result of a systemic hemostatic failure. If the patient is bleeding only in the operative area, it would suggest a local anatomic cause, such as an unligated bleeding vessel. The patient's bleeding history, especially with the results of prior surgical procedures, is extremely useful, but the available history may be inadequate or incomplete. A revealing clue to a systemic malfunction is bleeding at multiple sites, particularly areas other than that of the surgical wound. Bleeding around a catheter, from venipuncture sites, and from venous cutdowns is highly indicative of a hemorrhagic disorder.

Rapid assessment of the total clinical setting is imperative. The following questions should be addressed:

  • Does the patient have underlying renal, hepatic, or malignant disease?
  • Has the surgery required pump bypass techniques or the induction of hypothermia, or has the patient been in shock or been hypothermic?
  • How many units of blood and blood products have been given and over what period of time?
  • Were baseline screening procoagulant tests obtained before surgery, and is the patient's frozen plasma still available?

The differential diagnosis of postoperative hemorrhage should include a number of bleeding disorders [see Table 4].

Prompt resolution of postoperative bleeding requires a panel of coagulation tests—including aPTT, PT, TT, fibrinogen assay, and D-dimer—a platelet count, and a well-stained blood smear for evaluation of platelet and red cell morphology. This battery of tests should be performed immediately. More specialized studies can be obtained if there is evidence of a specific disorder.

References

  1. Clemetson KJ: Platelet GPIb-V-IX complex. Thromb Haemost 78:266, 1997
  2. Fressinaud E, Veyradier A, Truchaud F, et al: Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases. Blood 91:1325, 1998
  3. Posan E, McBane RD, Grill DE, et al: Comparison of PFA-100 testing and bleeding time for detecting platelet hypofunction and von Willebrand disease in clinical practice. Thromb Haemost 90:482, 2003
  4. Triplett DA: Laboratory diagnosis of von Willebrand's disease. Mayo Clin Proc 66:832, 1991
  5. Sadler JE, Gralnick HR: A new classification for von Willebrand's disease. Blood 84:676, 1994
  6. Sadler JE: New concepts in von Willebrand disease. Annu Rev Med 56:173, 2005
  7. Sadler JE: Von Willebrand disease type I: a diagnosis in search of a disease. Blood 101:2089, 2003
  8. Rose EH, Aledort LM: Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med 114:563, 1991
  9. Castillo R, Monteagudo J, Escolar G, et al: Hemostatic effects of normal platelet transfusion in severe von Willebrand's disease patients. Blood 77:1901, 1991
  10. Ito M, Yoshimura K, Toyoda N, et al: Pregnancy and delivery in patients with von Willebrand's disease. J Obstet Gynaecol Res 23:37, 1997
  11. Rick ME, Williams SB, Sacher RA, et al: Thrombocytopenia associated with pregnancy in a patient with type IIb von Willebrand's disease. Blood 69:786, 1987
  12. Antonarakis SE, Rossiter JP, Young M, et al: Factor VIII inversions in severe hemophilia A: results of an international consortium study. Blood 86:2206, 1995
  13. Bray GL, Gomperts ED, Courter S, et al: The Recombinate Study Group: a multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 83:2428, 1994
  14. Seremetis S, Lusher JM, Abildgaard CF, et al: Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group. Haemophilia 5:9, 1999
  15. Courter SG, Bedrosian CL: Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Semin Hematol 38(suppl 4):52, 2001
  16. Green PP, Mannucci PM, Briet E, et al: Carrier detection in hemophilia A: a cooperative international study: II. The efficacy of a universal discriminant. Blood 67:1560, 1986
  17. Rochat C, McFadyen ML, Schwyzer R, et al: Continuous infusion of intermediate-purity factor VIII in haemophilia A patients undergoing elective surgery. Haemophilia 5:181, 1999
  18. Yee TT, Pasi KJ, Lilley PA, et al: Factor VIII inhibitors in haemophiliacs: a single-center experience over 34 years, 1964–97. Br J Haematol 104:909, 1999
  19. Hough RE, Hampton KK, Preston FE, et al: Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors. Br J Haematol 111:974, 2000
  20. Lusher JM: Controlled clinical trials with prothrombin complex concentrates. Prog Clin Biol Res 150:277, 1984
  21. Hedner U, Glazer S, Falch J: Recombinant activated factor VII in the treatment of bleeding episodes in patients with inherited and acquired bleeding disorders. Transfusion Med Rev 7:78, 1993
  22. Negrier C, Lienhart A: Overall experience with NovoSeven. Blood Coagul Fibrinolysis 11 (suppl 1):S19, 2000
  23. van't Veer C, Golden NJ, Mann KG: Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa. Blood 95:1330, 2000
  24. Monroe DM, Hoffman M, Allen GA, et al: The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia. Semin Thromb Hemost 26:373, 2000
  25. Roberts HR, Eberst ME: Current management of hemophilia B. Hematol Oncol Clin North Am 7:1269, 1993
  26. Wang L, Takabe K, Bidlingmaier SM, et al: Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. Proc Natl Acad Sci USA 30:3906, 1999
  27. White GC II: Gene therapy in hemophilia: clinical trials update. Thromb Haemost 86:172, 2001
  28. Salomon O, Seligsohn U: New observation on factor XI deficiency. Haemophilia 10(suppl 4):184, 2004
  29. Salomon O, Steinberg DM, Tamarin I, et al: Plasma replacement therapy during labor is not mandatory for women with severe factor XI deficiency. Blood Coagul Fibrinolysis 16:37, 2005
  30. Fay WP, Parker AC, Condrey LR, et al: Human plasminogen activator inhibitor-1 (PAI-I) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 90:204, 1997
  31. Furie B, Furie BC: Molecular and cellular biology of blood coagulation. N Engl J Med 326:800, 1992
  32. Sane DC, Califf RM, Topol EJ, et al: Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management. Ann Intern Med 111:1010, 1989
  33. Esmon CT, Fukudome K, Mather T, et al: Inflammation, sepsis, and coagulation. Haematologica 84:254, 1999
  34. Levi M: Disseminated intravascular coagulation: what's new? Crit Care Clin 21:449, 2005
  35. Hall GW: Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 112:851, 2001
  36. Rickles FR, Levine MN, Edwards RL: Hemostatic alterations in cancer patients. Cancer Metastasis Rev 11:237, 1992
  37. Jochum M: Influence of high-dose antithrombin concentrate therapy on the release of cellular proteases, cytokines, and soluble adhesion molecules in acute inflammation. Semin Hematol 32:14, 1995
  38. Fourrier F, Chopin C, Huart JJ, et al: Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 104:882, 1993
  39. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699, 2001
  40. Dhainaut JF, Yan SB, Joyce DE, et al: Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravasular coagulation. J Thromb Haemost 2:1924, 2004
  41. Abraham E, Reinhart K, Opal S, et al: Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238, 2003
  42. Warren BL, Eid A, Singer P, et al: Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869, 2001
  43. Scandella DH, Nakai H, Felch M, et al: In hemophilia A and autoantibody inhibitor patients: the factor VII A2 domain and light chain are most immunogenic. Thromb Res 101:377, 2001
  44. Ludlam CA, Morrison AE, Kessler C: Treatment of acquired hemophilia. Sem Hematol 31:16, 1994
  45. Lian C-Y, Larcada AF, Chiu AY-Z: Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med 110:774, 1989
  46. Shaffer LG, Phillips MD: Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med 127:206, 1997
  47. Morrison AE, Ludlam CA, Kessler C: Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 81:1513, 1993
  48. Crenier L, Ducobu J, des Grottes JM, et al: Low response to high-dose intravenous immunoglobulin in the treatment of acquired factor VIII inhibitor. Br J Haematol 95:750, 1996
  49. Wiestner A, Cho HJ, Asch AS, et al: Rituximab in the treatment of acquired factor VIII inhibitors. Blood 100:3426, 2002
  50. Stasi R, Brunetti M, Stipa E, et al: Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia. Blood 103:4424, 2004
  51. Federici AB, Rand JH, Bucciarelli P: Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 84:345, 2000
  52. Vincentelli A, Susen S, Le Tourneau T, et al: Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 349:343, 2003
  53. Mohri H, Motomura S, Kanamori H, et al: Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 91:3623, 1998
  54. Francis JL, Armstrong DJ: Acquired dysfibrinogenemia in liver disease. J Clin Pathol 35:667, 1982
  55. Stein SF, Harker LA: Kinetic and functional studies of platelets, fibrinogen, and plasminogen in patients with hepatic cirrhosis. J Lab Clin Med 99:217, 1986
  56. Pouplard C, May MA, Regina S, et al: Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin-dependent antibodies. Br J Haematol 128:837, 2005
  57. Kestin AS, Valeri CR, Khuri SF, et al: The platelet function defect of cardiopulmonary bypass. Blood 82:107, 1993
  58. Bolan CD, Alving BM: Pharmacologic agents in the management of bleeding disorders. Transfusion 30:541, 1990
  59. Cattaneo M, Harris AS, Stromberg U, et al: The effect of desmopressin on reducing blood loss in cardiac surgery: a meta-analysis of double-blind, placebo-controlled trials. Thromb Haemost 74:1064, 1995
  60. Lemmer JH, Dilling WE, Morton JR, et al: Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 62:1659, 1996
  61. Khan MM, Gikakis N, Miyamoto S, et al: Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass. Ann Thorac Surg 68:473, 1999
  62. Day JR, Punjabi PP, Randi AM, et al: Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 110:2597, 2004
  63. Greilich PE, Brouse CF, Whitten CW, et al: Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin. J Thorac Cardiovasc Surg 126:1498, 2003
  64. Hekmat K, Zimmermann T, Kampe S, et al: Impact of tranexamic acid vs. aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: a prospective, randomised, double-blind trial. Curr Med Res Opin 20:121, 2004
  65. Zehnder JL, Leung LL: Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood 76:2011, 1990
  66. Berruyer M, Amiral J, French P, et al: Immunization by bovine thrombin used with fibrin glue during cardiovascular operations. J Thorac Cardiovasc Surg 105:892, 1993
  67. Streiff MB, Ness PM: Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion 42:18, 2002

Editors: Dale, David C.; Federman, Daniel D.