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MD Consult: Books: Goldman: Cecil Medicine: Chapter 180 – HEMORRHAGIC DISORDERS: COAGULATION FACTOR DEFICIENCIES

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 180 – HEMORRHAGIC DISORDERS: COAGULATION FACTOR DEFICIENCIES

Craig M. Kessler

   COAGULATION DEFICIENCIES

Severe coagulation deficiencies, or coagulopathies, typically are characterized by the development of excessive bleeding or bruising that is unprovoked or, more commonly, is precipitated by trivial incidental or surgical trauma. Frequently, these hemorrhagic events result in life- and limb-threatening complications. Moderate and mild coagulopathies may remain clinically silent until they are detected serendipitously on routine laboratory screening assays for global coagulation (e.g., prothrombin time [PT] or activated partial thromboplastin time [aPTT]) or when these assays are ordered to evaluate the cause of abnormal bleeding or easy bruisability. Much of the morbidity of coagulopathies can be minimized or avoided altogether by advanced awareness and prophylactic replacement of the deficient clotting factor proteins. In contrast to the lifelong clinical manifestations of hereditary or congenital coagulopathies, acquired deficiencies usually appear acutely in previously asymptomatic individuals, may not be suspected immediately on examination, and may remit spontaneously or after eradication of an inciting disease state or the withdrawal of an offending medication. Acquired coagulation disorders often are associated with more severe bleeding than are those derived from congenital causes. Coagulopathies predominantly result from inadequate biosynthesis of coagulation factor proteins or from direct or indirect inhibition of activated clotting factor proteins by acquired antibodies or anticoagulant medications; however, qualitative defects, either congenital or acquired, also can result in bleeding.

   Hereditary Hemophilias

Definition

The hemophilias include hemophilia A, caused by a deficiency of clotting protein factor VIII (antihemophilic factor), and hemophilia B, caused by a deficiency of factor IX (also called antihemophilic factor B, plasma thromboplastin component, or Christmas factor, named after an individual with the disease). A deficiency of either of these two intrinsic coagulation pathway components results in inefficient and inadequate generation of thrombin.

Epidemiology

The sex-linked recessive disorders of hemophilia A and B are estimated to occur, respectively, in approximately 1 of every 5000 and 1 of every 30,000 male births. The higher incidence of hemophilia A may be due to the greater amount of DNA “at risk” for mutation in the factor VIII gene (186,000 base pairs) compared with the factor IX gene (34,000 base pairs). Hemophilia A and B are observed throughout all races and ethnic groups, and more than 25,000 individuals in the United States are recognized to have one of the hemophilias. Although carrier testing, genetic counseling, and prenatal diagnosis are widely available in the United States through the network of federally funded Hemophilia Treatment Centers, fecundity rates remain high, and few confirmed carriers elect to terminate their pregnancies even if an affected fetus is detected in utero. These decisions probably are influenced by the wide availability of efficacious and safe commercial coagulation factor replacement concentrates and by the prospect that gene therapy may eventually cure the hemophilias. The advent of highly active antiretroviral therapy ( Chapter 412 ), biological response modifiers such as pegylated interferon-α, and liver transplantation ( Chapter 158 ) has prolonged the survival of hemophiliacs with acquired immunodeficiency syndrome (AIDS) and chronic hepatitis. A substantial proportion (30%) of cases of hemophilia result from unanticipated new, spontaneous mutations. Overall, the hemophilias are much more common than the autosomal recessive coagulation disorders, which often affect progeny from consanguineous relationships and require the inheritance of two defective alleles for the bleeding manifestations to become evident.

Pathobiology

Genetics

As with other sex-linked recessive diseases, the genes for factor VIII and factor IX are located on the long arm of the X chromosome. Males with a defective allele on their single X chromosome do not transmit this gene to their sons, but all of their daughters become obligate carriers. Female carriers transmit the coagulation disorder to half of their sons, and half of their daughters become carriers. Female carriers can manifest hemophilia-like symptoms if the alleles on the X chromosome are unequally inactivated (lyonization); the defective hemophilic allele is expressed in preference to the normal allele, and a phenotypic hemophiliac is produced. Female hemophilia can arise as the result of mating between a hemophilic male and a female carrier (homozygous for the defective factor VIII or IX gene) or in carrier females who have the 45 XO karyotype (Turner’s syndrome) and are hemizygous for the defective hemophilia gene.

No single mutation is responsible for the hemophilias, and many missense and nonsense point mutations, deletions, and inversions have been described. Severe molecular defects predominate, with 40 to 50% of all cases of severe hemophilia A evolving from a unique inversion of intron 22 (the largest of the factor VIII introns). This inversion results from the recombination and translocation of DNA within intron 22 of the factor VIII gene, with areas of extragenic but homologous “nonfunctional” DNA located at a distance from intron 22. Other, less commonly encountered severe molecular defects include large gene deletions (5 to 10% of cases) and nonsense mutations (10 to 15% of cases). The encoded proteins resulting from these mutations are defective and do not express any factor VIII activity. Mild and moderate hemophilia A commonly are associated with point mutations and deletions. In contrast, factor IX mutations are more diverse, and severe hemophilia B more likely is caused by large deletions. Hemophilia B also may result from mutations that alter the γ-glutamyl residues of the factor IX protein, which normally become carboxylated through a vitamin K–dependent process and then assemble on a phospholipid surface for eventual activation. Mutated clotting factor genes responsible for the hemophilias may code for the production of defective nonfunctional proteins that circulate in the plasma and can be detected by immunoassays. Designated cross-reacting material, these proteins have no clinical relevance except that individuals without cross-reacting material may be more susceptible to alloantibody inhibitor formation.

Clinical Manifestations

The clinical pictures of hemophilia A and hemophilia B are indistinguishable from each other, with their clinical severity corresponding inversely to the circulating levels of plasma coagulant factor VIII or IX activity. Individuals with less than 1% of normal factor VIII or IX activity have severe disease characterized by frequent spontaneous bleeding events in joints (hemarthrosis) and soft tissues and by profuse hemorrhage with trauma or surgery. Spontaneous bleeds are uncommon with mild deficiencies (>5% normal activity); however, excessive bleeding still can occur with trauma or surgery. A moderate clinical course is associated with factor VIII or IX levels between 1 and 5%. Approximately 60% of all cases of hemophilia A are clinically severe, whereas only 20 to 45% of cases of hemophilia B are severe.

Severe hemophilia typically is suspected and diagnosed during infancy in the absence of a family history. Although the trauma of uncomplicated childbirth (vaginal or cesarean section) rarely produces intracranial hemorrhage, prolonged labor, forceps delivery, and the use of vacuum extraction are major risk factors. Circumcision within days after birth is accompanied by excessive bleeding in fewer than half of severely affected boys. The first spontaneous hemarthrosis in severely affected hemophiliacs usually occurs between 12 and 18 months of age, when ambulation begins, and in moderately affected individuals it occurs at about 2 to 5 years of age. The knees are the most prominent sites of spontaneous bleeds, followed by the elbows, ankles, shoulders, and hips; wrists are less commonly involved.

Acute hemarthroses ( Fig. 180-1 ) originate from the subsynovial venous plexus underlying the joint capsule and produce a tingling or burning sensation, followed by the onset of intense pain and swelling. On physical examination, the joint is swollen, hot, and tender to palpation, with erythema of the overlying skin. Joint mobility is compromised by pain and stiffness, and the joint usually is maintained in a flexed position. Replacement of the deficient clotting factor to normal hemostatic levels rapidly reverses the pain. Swelling and joint immobility improve as the intra-articular hematoma resolves. Intra-articular needle aspiration of fresh blood is not recommended because of the risk of introducing infection. Short courses of oral corticosteroids may be helpful to reduce the acute joint symptoms in children but rarely are used in adults.

FIGURE 180-1  Acute hemarthrosis of the knee is a common complication of hemophilia. It may be confused with acute infection unless the patient’s coagulation disorder is known, because the knee is hot, red, swollen, and painful.  (From Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003, with permission.)

Recurrent or untreated bleeds result in chronic synovial hypertrophy and eventually damage to the underlying cartilage, with subsequent subchondral bone cyst formation, bony erosion, and flexion contractures. The intra-articular iron deposited in hemarthroses may activate oncogenes, which subsequently stimulate synovial proliferation. Abnormal mechanical forces from weight bearing can produce subluxation, misalignment, loss of mobility, and permanent deformities of the lower extremities ( Fig. 180-2 ). These changes are accompanied by chronic pain, swelling, and arthritis. Plain radiographs and clinical examination of chronic hemarthroses often underestimate the extent of bone and joint damage; serial magnetic resonance imaging (MRI) appears to be the most sensitive and specific means of detecting and monitoring early and progressive disease.

FIGURE 180-2  Severe chronic arthritis in hemophilia. The knee is the most commonly affected joint. Both knees are severely deranged in this patient. Note that he is unable to stand with both feet flat on the floor.  (From Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003, with permission.)

Intramuscular hematomas account for about 30% of hemophilia-related bleeding events and are rarely life-threatening. They usually are precipitated by physical or iatrogenic trauma (i.e., after intramuscular injection of vaccines or medications) and can compromise sensory and motor function and arterial circulation if they entrap and compress vital structures in closed fascial compartments. Retroperitoneal hematomas may be confused clinically with appendicitis or hip bleeds. Unless these bleeding episodes are treated immediately and aggressively, permanent anatomic deformities, such as flexion contractures and pseudotumors (expanding hematomas that erode and destroy adjacent skeletal structures), may occur. Bleeding from mucous membranes is very common and may be exaggerated by the degradation of fibrin clots by proteolytic enzymes contained in secretions. Bleeding involving the tongue or the retropharyngeal space can rapidly produce life-threatening compromise of the airways. Gastrointestinal hemorrhages typically originate from anatomic lesions proximal to the ligament of Treitz and can be exacerbated by esophageal varices secondary to cirrhosis and portal hypertension or by the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of hemarthroses. Spontaneous bleeding in the genitourinary tract secondary to hemophilia is a diagnosis of exclusion after renal stones and infection are ruled out. Ureteral blood clots produce renal colic, which may be confused with nephrolithiasis and may be worsened by the use of antifibrinolytic agents. Ninety percent of hemophiliacs experience at least one episode of gross hematuria or hemospermia.

Intracranial bleeds occur in 10% of patients, usually are induced by trauma, and are fatal in 30% of the cases. The risk of development of an intracranial hemorrhage is approximately 2% per year. Neuromuscular defects, seizure disorders, and intellectual deficits may ensue.

Diagnosis

The diagnosis of hemophilia in infancy is confirmed by detection of significantly reduced factor VIII or IX activities in the plasma of male babies born into families known to be affected by hemophilia or of male children who present with excessive bruising or bleeding at the time of circumcision, when intramuscular injections of immunizing vaccinations are administered, or after trauma during the toddler years. Hemarthrosis, the most common cause of morbidity in severe hemophilia, is not prevalent in pretoddler years. The diagnosis of mild hemophilia B in the neonate may be confounded by the fact that factor IX activity may be decreased substantially in normal infants owing to reduced hepatic synthesis of vitamin K–dependent proteins by an immature liver. Newborns without hemophilia have reduced levels of factor IX (to approximately 40% of normal), and there is a gradual rise during the first year of life into the low-normal adult range. Prematurity is associated with even lower factor IX levels due to the immaturity of the liver. Evaluation of suspected hemophilia in a female should exclude von Willebrand’s disease (vWD) and its variants (e.g., type 2 Normandy), as well as the rare occurrence of a normal male karyotype associated with testicular feminization. Molecular genetic testing may be useful to confirm suspected hemophilia in any patient with low circulating levels of factor VIII or factor IX.

Treatment

Reversal and prevention of acute bleeding events in hemophilia A and B are based on replacement of the missing or deficient clotting factor protein to restore adequate hemostasis ( Table 180-1 ). The morbidity, mortality, and overall cost of care for individuals with hemophilia are reduced significantly if care is provided by comprehensive hemophilia centers, where the multispecialty expertise, specialized coagulation laboratory, and diagnostic capabilities exist to coordinate and monitor specific patient needs.

Replacement guidelines ( Table 180-2 ) are intended to achieve plasma levels of factor VIII and IX activity of 25 to 30% for minor spontaneous or traumatic bleeds (e.g., hemarthroses, persistent hematuria), at least 50% clotting factor activity for the treatment or prevention of severe bleeds (e.g., major dental surgery, maintenance replacement therapy after major surgery or trauma), and 80 to 100% activity for any life-threatening or limb-threatening hemorrhagic event (e.g., major surgery, trauma). After major trauma or if visceral or intracranial bleeding is suspected, replacement therapy adequate to achieve 100% clotting factor activity should be administered before diagnostic procedures are initiated. Although replacement dosing is often empiric, plasma factor VIII activity increases about 2% (0.02 IU/mL) for each unit of factor VIII administered per kilogram of body weight, and factor IX activity increases about 1% (0.01 IU/mL) for each unit of factor IX administered per kilogram of body weight. The initial dose of factor IX diffuses into the extravascular space and binds to endothelial cell surfaces to a much greater degree than is observed with factor VIII. A 70-kg individual with severe hemophilia A or B (factor VIII or IX activity <1% of normal) who requires replacement to 100% activity for major surgery initially should receive 3500 IU of factor VIII or 7000 IU of factor IX concentrate. The circulating kinetics of factors VIII and IX require subsequent dosing every 8 to 12 hours and every 18 to 24 hours, respectively, and dosing should be individualized according to the peak recovery increment within 15 to 30 minutes after bolus infusion as well as trough activity levels. The frequency of repeat dosing also is determined by the rapidity of pain relief, recovery of joint function, and resolution of active bleeding. Replacement usually is maintained for 10 to 14 days after major surgery to allow for proper wound healing. Bolus dosing typically results in wide fluctuations in clotting factor activity levels and requires frequent laboratory monitoring to avoid suboptimal troughs. Continuous infusion regimens, consisting of 1 to 2 IU of factor VIII or IX concentrate per kilogram per hour after a bolus dose, maintain a plateau level without the necessity for frequent laboratory testing and reduce total concentrate consumption by 30 to 75% in surgical settings.

Because of the potential thrombogenicity associated with repeated administration of prothrombin complex concentrates for replacement of factor IX deficiency, high-purity, plasma-derived, or genetically engineered factor IX concentrates, which lack activated vitamin K–dependent clotting factors, are preferred therapies in hemophilia B.

Cryoprecipitate (the precipitate remaining after fresh-frozen plasma [FFP] is thawed at 4° C) and FFP contain factor VIII, but factor IX is contained only in FFP. However, they are not the optimal replacement products for either hemophilia A or hemophilia B because of their potential to transmit blood-borne pathogens. Plasma-derived clotting factor concentrates are manufactured from the plasma donations pooled from thousands of individual donors and are subjected to various types of viral inactivation techniques. Only lipid-enveloped viruses are susceptible to these procedures, which increases the risk that these products can transmit viruses such as parvovirus B19, hepatitis A, and prions, which have been implicated in variant Creutzfeldt-Jakob disease (vCJD) ( Chapter 442 ). The safety of these products has been enhanced by deferring the inclusion of first-time donor plasma collections from the plasma pool and by implementing more rigorous and specific viral surveillance of “minipools” (16 individual plasma donors) prior to manufacture. Nucleic acid amplification testing is used to detect hepatitis C, West Nile virus, and human immunodeficiency virus (HIV), and polymerase chain reaction (PCR) testing is used to detect parvovirus B19. Hepatitis B surface antigen is also measured. No assay is available to detect vCJD in plasma.

All clotting factor concentrates available in the United States (see Table 180-1 ), whether plasma derived or genetically engineered, are equally efficacious and are considered extremely safe; none has ever been implicated in the transmission of blood-borne viral pathogens or prions. Newer recombinant factor VIII and IX concentrates are manufactured free of added human or animal proteins in the culture medium or in the final formulation, to eliminate the theoretical risks of transmission of prions or murine viruses.


TABLE 180-1   — 
FDA-APPROVED CLOTTING FACTOR CONCENTRATES FOR HEMOPHILIA A AND B AVAILABLE IN THE UNITED STATES

Virucidal Technique Type/Name of Product (Manufacturer) Specific Activity (IU/mg Protein Discounting Albumin)
ULTRAPURE RECOMBINANT FACTOR VIII
First generation: Immunoaffinity; ion exchange chromatography Recombinate (Baxter); synthesized in CHO cell lines >4000
Second generation: Albumin-free final formulation; solvent detergent viral attenuation (TNBP/Triton X100); ion exchange chromatography; nanofiltration Refacto (Wyeth); B-domain–deleted molecule; synthesized in CHO cell lines; sucrose added as stabilizer 11,200–15,000
Second generation: Albumin-free final formulation; immunoaffinity and ion exchange chromatography; solvent detergent viral attenuation (TNBP/polysorbate 80); ultrafiltration Kogenate FS (Bayer, Inc.), Helixate FS (Bayer, Inc. for ZLB Behring, Inc.); both synthesized in baby hamster kidney cell lines; sucrose added as a stabilizer >4000
Third generation: No human or animal protein used in the culture medium or manufacturing process; immunoaffinity and ion exchange chromatography; solvent detergent viral attenuation (TNBP/polysorbate 80) Advate (Baxter); synthesized in CHO cell lines; trehalose added as a stabilizer >4000–10,000
ULTRAPURE HUMAN PLASMA–DERIVED FACTOR VIII
Immunoaffinity chromatography and pasteurization (60° C, 10 hr) Monoclate P (ZLB Behring, Inc.) >3000
Immunoaffinity chromatography, solvent detergent (TNBP/Octoxynol 9) Hemofil M (Baxter), Monarc M (Baxter, distributed by the American Red Cross, which also provides the donor plasma) >3000
INTERMEDIATE-PURITY AND HIGH-PURITY HUMAN PLASMA–DERIVED FACTOR VIII
Affinity chromatography, solvent detergent (TNBP and polysorbate 80), and terminal dry heating (80° C, 72 hr) Alphanate SD (Grifols, Inc.); contains functional vWF protein 50–100 (>400 when corrected for vWF protein content)
Solvent detergent; terminal dry heating (80° C, 72 hr) Koate-DVI (Bayer, Inc.); contains functional vWF protein 50–100
Pasteurization (heating in solution, 60° C, 10 hr) Humate-P (ZLB-Behring, Inc.); used predominantly for von Willebrand’s disease 1–10
INTERMEDIATE-PURITY PORCINE PLASMA–DERIVED FACTOR VIII
(TNBP/polysorbate 80) Hyate-C (Ibsen/Biomeasure, Inc.); porcine plasma–derived factor VIII used for patients with alloantibody or autoantibody factor VIII inhibitor >50 (available in limited quantities)
ULTRAPURE RECOMBINANT FACTOR IX
Affinity chromatography and ultrafiltration BeneFix (Wyeth); CHO cell lines maintained in fetal calf serum-free medium >200 (albumin free)
VERY HIGHLY PURIFIED PLASMA-DERIVED FACTOR IX
Dual-affinity chromatography, solvent detergent (TNBP/polysorbate 80), and nanofiltration (viral filter) AlphaNine SD (Grifols, Inc.) >200
Monoclonal antibody immunoaffinity chromatography, solvent detergent (sodium thiocyanate), and ultrafiltration Mononine (ZLB-Behring, Inc.) >160 (albumin free)
LOW-PURITY PLASMA-DERIVED FACTOR IX COMPLEX CONCENTRATES
Solvent detergent (TNBP/polysorbate 80) Profilnine SD (Grifols, Inc.) <50
Vapor heat (10 hr, 60° C, 1190 mbar pressure plus 1 hr 80° C, 1375 mbar) Bebulin VH (Baxter) <50
ACTIVATED PLASMA–DERIVED FACTOR IX COMPLEX CONCENTRATE (RESERVED PRIMARILY FOR PATIENTS WITH ALLOANTIBODY AND AUTOANTIBODY FACTOR VIII AND IX INHIBITOR)
Vapor heat (10 hr, 60° C, 1190 mbar plus 1 hr, 80° C, 1375 mbar) FEIBA VH (Baxter) <50
RECOMBINANT FACTOR VIIa (INDICATED FOR PATIENTS WITH ALLOANTIBODY AND AUTOANTIBODY FACTOR VIII AND IX INHIBITOR)
Affinity chromatography; solvent detergent (TNBP/polysorbate 80) NovoSeven (Novo Nordisk, Inc.); synthesized in baby hamster kidney cells; solvent (bovine calf serum used in culture medium); albumin-free formulation 50,000 IU/mg

Baxter = Baxter/Immuno, Inc.; CHO = Chinese hamster ovary; FDA = U.S. Food and Drug Administration; TNBP = tri(n-butyl)phosphate; vWF = von Willebrand’s factor; Wyeth = Wyeth-Ayerst/Genetics Institute.


TABLE 180-2   — 
FDA-APPROVED COAGULATION PROTEINS AND REPLACEMENT THERAPIES AVAILABLE IN THE UNITED STATES

Coagulation Protein Deficiency Inheritance Pattern Prevalence Minimum Hemostatic Level Replacement Sources
Factor I (fibrinogen):     50–100 mg/dL Cryoprecipitate/FFP
Afibrinogenemia Autosomal recessive Rare (<300 families)    
Dysfibrogenemia Autosomal dominant or recessive Rare (>300 variants)    
Factor II (prothrombin) Autosomal dominant or recessive Rare (25 kindreds) 30% of normal FFP, factor IX complex concentrates
Factor V (labile factor) Autosomal recessive 1 per 1 million births 25% of normal FFP
Factor VII Autosomal recessive 1 per 500,000 births 25% of normal Recombinant factor VIIa (20–30 μg/kg), FFP, factor IX complex concentrates
Factor VIII (antihemophilic factor) X-linked recessive 1 per 5000 male births 80–100% for surgery/life-threatening bleeds, 50% for serious bleeds, 25–30% for minor bleeds Factor VIII concentrates (see Table 180-1 )
von Willebrand’s disease:     >50% vWF antigen and ristocetin cofactor activity DDAVP for mild to moderate disease (except type 2B; variable response to 2A); cryoprecipitate and FFP (not preferred except in emergencies); factor VIII concentrates, viral attenuated, intermediate purity (preferred for disease unresponsive to DDAVP and for type 3) (see Table 180-1 )
Type 1 and 2 variants Usually autosomal dominant 1% prevalence
Type 3 Autosomal recessive 1 per 1 million births
Factor IX (Christmas factor) X-linked recessive 1 per 30,000 male births 25–50% of normal, depending on extent of bleeding and surgery Factor IX concentrates; FFP not preferred except in dire emergencies (see Table 180-1 )
Factor X (Stuart-Prower factor) Autosomal recessive 1 per 500,000 births 10–25% of normal FFP or factor IX complex concentrates
Factor XI (hemophilia C) Autosomal dominant; severe type is recessive 4% Ashkenazi Jews; 1 per 1 million general population 20–40% of normal FFP or factor XI concentrate
Factor XII (Hageman factor), prekallikrein, high-molecular-weight kininogen Autosomal recessive Not available No treatment necessary
Factor XIII (fibrin stabilizing factor) Autosomal recessive 1 per 3 million births 5% of normal FFP, cryoprecipitate, or viral-attenuated factor XIII concentrate

DDAVP = desmopressin; FDA = U.S. Food and Drug Administration; FFP = fresh-frozen plasma; vWF = von Willebrand’s factor.

Hemarthroses

The moderate or severe levels of pain that accompany acute hemarthroses respond to immediate analgesic relief, temporary immobilization, restraint from weight bearing, and clotting factor replacement. Narcotic analgesics, such as codeine (30 to 60 mg up to four times daily) or synthetic derivatives of codeine, should be prescribed alone or combined with doses of acetaminophen that are low enough (<10 g) to avoid hepatic toxicity in patients with chronic hepatitis. Although these medications do not possess significant anti-inflammatory activity, they are preferable to NSAIDs or aspirin, which can exacerbate bleeding complications through their antiplatelet aggregatory effects. Despite its possible arterial hypercoagulable side effects when used in high doses, the cyclooxygenase 2 inhibitor, celecoxib, when used judiciously (100 to 200 mg once or twice daily in patients without sulfonamide allergy, a dose that does not antagonize platelet function in vitro), often provides safe and effective pain relief for the chronic arthritis produced by recurrent hemarthroses. Alternative approaches to analgesia include acupuncture, transdermal nerve stimulation, and hypnosis ( Chapter 36 ); these modalities may reduce narcotic consumption.

Strategies intended to prevent end-stage joint destruction should be initiated at an early age. Synovectomy through open surgery or arthroscopy removes the inflamed tissue and should result in substantially decreased pain and recurrent bleeding. Nonsurgical synovectomy (synoviorthosis), which involves the intra-articular administration of a radioisotope, is particularly useful for high-risk patients and for patients with alloantibody inhibitors against factor VIII or factor IX. Neither synovectomy nor synoviorthosis reverses joint damage, but both procedures may delay its progression. Non–weight-bearing exercises, such as swimming and isometrics, are important to periarticular muscle development and maintenance of joint stability for ambulation. Intractable pain and severe joint destruction secondary to repeated hemorrhage require prosthetic replacement. Chronic ankle pain responds best to open surgical or arthroscopic fixation and fusion (arthrodesis).

The ultimate strategy to minimize or eliminate progressive joint destruction by recurrent hemarthroses is predicated on the concept of primary prophylaxis—the scheduled administration of clotting factor concentrates two (for factor IX products) or three (for factor VIII replacement) times weekly at doses adequate to maintain trough clotting factor activity levels greater than 1% to 2% of normal. The first and only prospective, randomized clinical trial of primary prophylaxis in young children with severe hemophilia A compared a regimen of every-other-day infusions of factor VIII at 25 IU/kg to prevent hemorrhage (primary prophylaxis) with intensive therapy using more than 3 infusions, totaling more than 80 IU/kg of factor VIII, at the time of each acute joint hemorrhage (on-demand therapy) to minimize joint damage, reverse bleeding, and relieve acute pain. Primary prophylaxis reduced the total number of total bleeds and hemarthroses by up to 90% compared with intensive on-demand therapy.[1] Long-term compliance with primary prophylaxis prevented the development or progression of bone and cartilage damage, as observed by serial MRI studies, and preserved overall joint function. An alternative and potentially more cost-effective approach to primary prophylaxis individualizes the dose of factor VIII replacement therapy and dosing intervals based on the variability of the individual’s bleeding pattern. One schema initiates primary prophylaxis with factor VIII at 50 IU/kg weekly and escalates to 30 IU/kg twice weekly if the frequency of bleeding is unacceptable (i.e., four joint/soft tissue bleeds) or if a target joint develops (three bleeds into a single joint over a consecutive 3-month period). If breakthrough bleeding continues, a third escalation dose to 25 IU/kg every other day can be implemented. Primary prophylaxis is facilitated by the placement of a central venous access device.

As obligate recipients of clotting factor replacement products, virtually all hemophiliacs treated before 1985, when techniques for elimination of lipid-enveloped viruses were introduced, have been exposed to hepatitis C virus (HCV), often with multiple genotypes ( Chapter 151 ). Hepatitis G, observed in 15% to 25% of hemophiliacs, is susceptible to current viral attenuation procedures. Hepatitis B virus, also lipid enveloped, is a rare problem for hemophiliacs now because vaccination at an early age is the standard of care. Hepatitis A virus is not lipid coated and was transmitted to a small but significant number of patients through solvent detergent–treated factor VIII and factor IX concentrates in the past; hepatitis A vaccination now should eliminate this risk. Parvovirus B19 seroprevalence approaches 80% in older adult hemophiliacs exposed to plasma-derived products. Hepatitis A and parvovirus B19 have unclear long-term clinical consequences. Nevertheless, their transmission in plasma-derived concentrates symbolizes the vulnerability of hemophiliacs to blood-borne pathogens that escape viral attenuation processes. Cadaver and living-donor liver transplantation ( Chapter 158 ) has improved the survival of hemophiliacs with chronic hepatitis-induced liver failure and cured the coagulopathy, suggesting that the liver is the predominant source of normal synthesis of factors VIII and IX. Liver transplantation may be performed successfully in HIV/HCV-coinfected individuals who have an undetectable HIV viral titer while receiving highly active antiretroviral therapy.

Ancillary and Other Therapies

Ancillary treatment strategies for hemophilias include the use of antifibrinolytic agents, such as ε-aminocaproic acid (1 to 2 g PO up to four times daily) or tranexamic acid (3 or 4 g PO daily in divided doses), to minimize mucous membrane bleeding and the application of fibrin glues to bleeding sites. Desmopressin (DDAVP [Stimate] may be administered by nasal insufflation 2 hours before a scheduled surgical procedure (one spray per nostril, to provide a total dose of 300 μg; or, in patients weighing less than 50 kg, 150 μg administered as a single spray); or DDAVP may be administered intravenously (dissolved in 50 mL normal saline) over 20 minutes at a dose of 0.3 μg/kg. DDAVP is useful in patients with mild hemophilia A, inasmuch as an adequate incremental rise in factor VIII activity can circumvent the use of clotting factor concentrates. Repeated administration of DDAVP (intravenously or by intranasal spray) can be complicated by tachyphylaxis, hyponatremic seizures, and angina.

Alloantibody Inhibitors to Factors VIII and IX

Alloantibodies usually are detected in childhood after a median of 9 to 12 consecutive days of exposure to clotting factor. These inhibitors occur with an increased incidence in sibships; they are more common in individuals with large, multidomain factor VIII and factor IX gene deletions; and they manifest a racial predilection. The incidence of factor VIII alloantibodies is 24 to 52%, with an increased frequency in blacks and Hispanics. Factor IX alloantibodies are observed with a 1.5% to 3% incidence and predominate among Scandinavians. Patients with factor IX inhibitor seem to be susceptible to anaphylaxis and the development of nephrotic syndrome with subsequent exposure to sources of factor IX.

Alloantibody inhibitors arise predominantly in individuals with severe congenital deficiencies of factor VIII or IX, and they are suspected when replacement therapy does not provide the usual immediate relief in bleeding symptoms. These immunoglobulin G (IgG) antibodies, usually IgG4 subclass, completely neutralize clotting factor activity; no or reduced increments in factor VIII or IX levels are observed after the administration of bolus doses of concentrate. These inhibitors are time and temperature dependent. The strength of the inhibitor is quantitated in Bethesda units (BU); 1 BU is defined arbitrarily as the amount of inhibitor that neutralizes 50% of the specific clotting factor activity in normal plasma. Patients with high-titer inhibitor, or “high responders,” have greater than 5 BU, and an anamnestic antibody enhancement usually develops 5 to 7 days after subsequent exposure to the antigenic clotting factor protein. Patients with low-titer inhibitor (i.e., ≤5 BU) are “low responders” and do not manifest anamnesis. Low-titer inhibitors, in contrast to the high-titer situation, can be overwhelmed easily by large amounts of human factor VIII or factor IX concentrate, usually three to four times the usual dose.

Treatment of patients with high-titer inhibitors against factor VIII or factor IX is complicated by the observation that no single approach is uniformly successful. Bypassing agents are available to treat bleeding episodes (see Table 180-1 ); specifically, the activated prothrombin complex concentrate FEIBA VH (50 to 100 IU/kg every 8 hours) and recombinant factor VIIa (rFVIIa; 90 μ/kg every 3 hours) may be administered as indicated until bleeding is controlled. In congenital hemophilia A patients with inhibitors, one dose of FEIBA VH or two doses of rFVIIa controlled hemarthrosis episodes 81 and 79% of the time, respectively, in patients with congenital hemophilia A and alloantibody inhibitors.[1] The activated and unactivated prothrombin complex concentrates contain activated vitamin K–dependent clotting factors that “bypass” the intrinsic pathway inhibitor. As a result, repeated administration over a short time frame is complicated by potential thrombogenicity, and the aPTT and clotting factor assays are useless monitors of adequate hemostasis. The availability of porcine plasma–derived factor VIII concentrate is severely limited, but at doses between 50 and 100 U/kg it has an 80% excellent or good response rate. Factor VIII activity can be measured after its administration and provides objective laboratory evidence of hemostasis. This product is nonthrombogenic, but anamnestic immune responses can result in increased antibody titers against porcine and human factor VIII. A recombinant form of porcine factor VIII concentrate is currently in clinical trials and may supplant the plasma formulation in the future. Recombinant factor VIIa is an additional effective therapy in patients with high-titer inhibitors, particularly those who have factor IX alloantibodies and who experience anaphylactic reactions or the nephrotic syndrome after exposure to factor IX–containing replacement products or FFP.

Immune tolerance induction regimens are often useful to eradicate alloantibody inhibitors. Consisting of daily administration of factor VIII or IX concentrates, this regimen is essentially a desensitization process with a 68% success rate. Young age, low-titer inhibitor, and immediate initiation after detection of the inhibitor increase the likelihood of success. After tolerance has been achieved, maintenance prophylaxis with factor VIII or IX concentrate administered two to three times weekly (20 to 30 IU/kg) is necessary.

Prevention

Carrier Detection and Prenatal Diagnosis

Carrier detection and prenatal diagnosis have become technically feasible, very sensitive, and widely available, but their application is influenced by ethical, cultural, religious, economic, educational, and personal considerations. For instance, carrier detection is particularly useful to identify women who themselves may be at risk for hemorrhagic complications during the delivery process, and it can identify male offspring who will be particularly vulnerable to develop intracerebral bleeds at birth. Alternatively, these techniques can provide important information for making difficult reproductive decisions. Patients may decide to accept the 50% likelihood that any male child of a confirmed carrier of hemophilia A or B will be affected; to abstain from pregnancy and/or to adopt; to determine the sex of the fetus and terminate pregnancy if an affected male child is identified; or to embark on in vitro fertilization with subsequent uterine transfer of only harvested female embryos (as confirmed by fluorescent in situ hybridization) or genetically unaffected male and female embryos (as determined by PCR-based techniques for specific hemophilia gene mutations). Genetic counseling and testing have not resulted in increased rates of termination of pregnancy for hemophilia in developed countries, where the availability of safe and effective replacement products is ubiquitous and offers the potential of an almost normal lifespan with greatly reduced disability. In economically developing nations with limited health resources, however, hemophiliacs do not receive timely or adequate treatment and often die in childhood.

The phenotypic identification of obligate female carriers of hemophilia, who are related to affected males, can be accomplished with 90% accuracy by measuring low levels of factor IX activity or relatively low factor VIII coagulant activity compared with levels of von Willebrand’s factor antigen (vWF : Ag). Coagulation activity assays used for the phenotypic identification of carriers or affected males lose their sensitivity when large populations are screened for random mutations and cannot be applied easily to fetal blood specimens or amniotic fluid, which are usually contaminated by thromboplastic materials that provide spuriously high clotting factor activity results. In addition, in the case of hemophilia B, the presence of cross-reactive factor IX antigen may confound the ability to predict carrier status or fetal involvement. Genotypic analysis for specific mutations is the most accurate and reliable means of prenatal detection and carrier testing for the hemophilias. More than 150 heterogeneous point mutations of the factor VIII gene (comprising 186 kb with 26 exons) have been associated with development of hemophilia A, necessitating linkage analysis employing DNA polymorphic markers in assays based on restriction fragment length polymorphism. Increased accuracy is achieved if the specific gene defect is known and genetic material is available from the propositus and the carrier. PCR amplification of DNA and denaturing gradient gel electrophoresis analysis are useful for detection of the intron 22 inversion, which is associated with half of the cases of severe hemophilia A. The molecular basis of hemophilia B is even more heterogeneous than that of hemophilia A, with several hundred causative mutations, predominantly single nucleotide polymorphisms with ethnic variation but no frequent mutation type, reported in this considerably smaller gene comprising 34 kb, 8 exons, and 7 introns. A listing of the mutations that have been characterized to cause the hemophilias can be accessed via the Human Gene Mutation Database (www.hgmd.org), through HAMSTeRS (The Haemophilia A Mutation, Structure, Test, and Resource Site) at http://europium.csc.mrc.ac.uk, and the Haemophilia B Mutation Database at www.kcl.ac.uk/ip/petergreen/haemBdatabase.html (all accessed August 24, 2006).

Prognosis

The life expectancy of severe hemophiliacs approaches 65 years when HIV-related issues are excluded. The age-matched death rate of hemophiliacs who are HIV seropositive is 5 times greater than that of the normal population, 33 times greater for hemophiliacs with frank AIDS, and 2.4 times greater for those coinfected with hepatitis C. HIV is currently responsible for more than 55% of all hemophilia-related deaths. In contrast, the lifetime risk of intracranial hemorrhage is 2 to 8%. Approximately one third of all hemophiliacs between the ages of 21 and 60 years are HIV infected, with infection more common among those with hemophilia A. The availability of anti-HIV protease inhibitors ( Chapter 412 ) has prolonged the HIV disease-free survival time of infected hemophiliacs. Those coinfected with hepatitis C have a poorer prognosis, however, despite the initiation of pegylated interferon-α and ribavirin therapy ( Chapter 152 ). The progression of hepatitis C can be exacerbated by alcohol and by hepatotoxic medications prescribed for prophylaxis of opportunistic infections and chronic pain (e.g., large doses of acetaminophen). Life expectancy is related to the severity of hemophilia, with the mortality rate of severely affected patients being four to six times greater than that of patients with mild deficiencies. With timely treatment, there is no increased mortality associated with the presence of alloantibody inhibitors. Problems with growth and development are exaggerated in HIV-infected boys, with increased cortical atrophy on magnetic resonance imaging (15% in HIV-positive vs. 6.5% in HIV-negative boys) and delayed growth velocity in adolescence. IQ does not seem to be affected by either HIV or hemophilia.

Future Directions

Gene Therapy for Hemophilia A and B

The hereditary hemophilias are model diseases for gene therapy, because they are caused by specific, well-defined gene mutations; a small incremental rise in clotting factor synthesis can lead to substantially improved treatment and quality of life; and inadvertent overexpression by successful gene transfer would not be detrimental. Successful gene transfer techniques have been developed to provide long-term therapeutic benefits in hemophilic mice and dog models, but not thus far in humans, probably because current gene delivery systems and their viral vectors have induced antibodies that suppress long-term expression of clotting factor activity.

   Acquired Hemophilias

Epidemiology and Pathobiology

Autoantibody inhibitors can occur spontaneously in individuals with previously normal hemostasis (nonhemophiliacs). Although approximately 50% of patients have no obvious underlying cause, the remainder of cases are associated with autoimmune diseases, lymphoproliferative disorders, idiosyncratic drug associations, and pregnancy.

Clinical Manifestations and Diagnosis

Patients typically have massive hemorrhagic events, usually much more severe than events produced by alloantibodies in patients with congenital hemophilia. The laboratory expression of autoantibodies is similar to that of alloantibodies, except that clotting factor activity is not completely neutralized. Residual clotting factor activities between 3% and 20% of normal frequently are observed in patients with autoantibodies.

Treatment

The same principles of replacement therapy for alloantibodies also apply to these acquired autoantibody inhibitors. Porcine factor VIII concentrate is particularly useful in acquired hemophilia A, because little cross-reactivity usually occurs even with extremely high titers of anti–human factor VIII antibodies. Because of its limited availability, clinical studies are underway with genetically engineered forms of this protein. Immunosuppressive therapy with corticosteroids (prednisone, 1 mg/kg PO daily for 3 weeks) or cytotoxic agents (such as cyclophosphamide, 150 mg daily PO or 500 to 750 mg/m2 IV bolus every 3 to 4 weeks, with dose titration or delays depending on the development of cytopenias), is typically required to suppress the inhibitor and is usually continued until the autoantibody inhibitor has disappeared. Whether addition of cytotoxic agents improves outcome at 2 years, however, is unclear. Administration of anti-CD20 antibody (rituximab, 375 mg/m2 IV weekly for 4 weeks) appears promising for the long-term eradication of autoantibody inhibitors, although no randomized controlled studies have been performed. There are also anecdotal cases of successful rituximab eradication of alloantibody inhibitors. High-dose intravenous gamma globulin may be a useful adjunctive therapy. Immune tolerance induction regimens that combine alkylating agents, daily administration of clotting factor concentrate, and high-dose corticosteroids have been successful in eradicating autoantibody inhibitors. If inhibitor-related hemorrhage is refractory to administration of the bypassing clotting factor agents, the initiation of intense extracorporeal plasmapheresis over a staphylococcal protein A column may remove enough neutralizing IgG alloantibody or autoantibody to facilitate successful hemostasis after replacement therapy.

Prognosis

Several large series of patients with acquired hemophilia have revealed a substantial mortality rate, ranging from 15 to 25%, which is considerably higher than that observed with alloantibody factor VIII inhibitors. A large meta-analysis indicated that overall survival in acquired hemophilia was influenced primarily by achievement of a complete remission; age younger than 65 years at diagnosis; and related diseases (malignancy versus postpartum versus others). Fifteen percent of the deaths were associated with sepsis, and 71% of these patients had developed cyclophosphamide-induced neutropenia. Hemorrhagic complications, which were the primary cause of death, could be reduced if the inhibitor could be eradicated. Of note, complete remission was observed in 89% of cyclophosphamide-treated individuals, compared with 70% of those treated with corticosteroids alone and 41% of those who received no treatment.

   Hereditary von Willebrand’s Disease

Definition

The most common bleeding disorder is vWD, an autosomal dominantly inherited hemorrhagic disease that affects both sexes, with a prevalence of 1 to 3% of the population and no ethnic predominance. Homozygous patients are rare and carry a recessive mutant gene.

Pathobiology

Normal vWF is a large, multimeric glycoprotein product of the vWF gene, located on chromosome 12. The protein consists of 220,000-D monomeric subunits, and the fully processed protein may reach a total molecular weight of 20 million D, with its platelet agglutination properties mediated predominantly by the highest-molecular-weight multimers. The phenotypic classification of vWD recognizes three major types of the disease based on the multimeric structure and function of the vWF protein ( Table 180-3 ).


TABLE 180-3   — 
PATTERNS OF VON WILLEBRAND’S DISEASE

Type vWF:AG/vWF:RCOF RIPA RIPA–Low Dose Multimeric Pattern
1 (classic) ↓/↓ ±↓ Absent Uniform ↓ in all multimers
2 (variant)
  2A ↓/↓↓↓ ↓↓ Absent ↓ in large and intermediate multimers
2B ±↓/±↓ Normal Increased ↓ in large multimers
2N (Normandy) Normal/normal Normal Normal
Platelet type ±↓/±↓ ±↑ Increased with cryoprecipitate ↓in large multimers
3 (Homozygote or compound heterozygote) Absent/absent Absent Absent Absent

↓, reduced; ±↓, more or less reduced; ↓↓↓, greatly reduced; RIPA = ristocetin-induced platelet aggregation; vWF:Ag = von Willebrand’s factor antigen; vWF:RCoF = von Willebrand’s factor ristocetin cofactor activity.

Type 1 vWD accounts for 75 to 80% of patients and is inherited predominantly via an autosomal dominant mode; a qualitative defect is present in which the vWF structure is normal but vWF:Ag and activity are reduced. Defects in synthesis or secretion from the endothelial cell or megakaryocyte or increased intravascular clearance, probably independent of proteolysis by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin, also known as von Willebrand factor cleaving protease), induce the type 1 vWD phenotype. However, several vWF gene mutations produce increased intracellular retention (i.e., decreased secretion) or enhanced plasma clearance without altering the structure of vWF.

Type 2 vWD includes approximately 20% of vWD patients, is inherited in either a dominant or a recessive pattern, and is characterized by qualitative and quantitative abnormalities in the vWF protein. Further subclassification is based on multimeric structure and responses in the ristocetin-induced platelet aggregation (RIPA) assay. Defects in vWF multimeric assembly and/or enhanced ADAMTS-13–mediated proteolytic degradation of vWF account for many of these qualitatively abnormal molecules. Up to 30 variants have been described, each with unique aberrations in vWF multimer structure. In type 2A, the most common variant, there is loss of the largest and intermediate-sized multimers, whereas type 2B lacks only the largest vWF multimers. The multimeric patterns in type 2A may result from defective synthesis of the vWF protein or increased susceptibility of vWF to proteolysis in vivo. In type 2B, the highest-molecular-weight multimers of vWF are adsorbed preferentially and with abnormally high affinity to the glycoprotein Ib receptor binding site on the platelet membrane surface. Alternatively, a structural defect in the glycoprotein Ib platelet receptor binding site for vWF can produce a multimeric pattern similar to that of type 2B by virtue of its preferential adsorption of the highest-molecular-weight multimers from normal vWF in the circulation. This latter variant is designated platelet-type pseudo-vWD. Type 2N (Normandy) is an unusual variant that resembles hemophilia A, although it is inherited in an autosomal dominant pattern. The defective vWF protein is normal from functional and multimeric perspectives but lacks an intact binding site for factor VIII. Unbound factor VIII is cleared from the circulation with a short half-life.

Type 3 vWD is an exceedingly rare variant that occurs in 1 of every 1 million individuals. It is characterized by almost complete absence of circulating vWF.

Clinical Manifestations

Most patients with vWD have mild disease that may go undiagnosed until trauma or surgery occurs. Symptomatic individuals manifest easy bruisability and mucosal surface bleeding, including epistaxis and gastrointestinal hemorrhage. Menorrhagia affects 50 to 75% of affected women and may be the initial symptom. These symptoms are consistent with platelet-based defects and reflect the crucial role of vWF protein in mediating platelet-platelet and platelet–subendothelial matrix interactions in the process of vascular plug formation and primary hemostasis. The use of aspirin or NSAIDs with anti–platelet aggregation effects may exacerbate the symptoms. Deep subcutaneous and intramuscular bleeds, hemarthroses, and intracranial hemorrhages are unusual in vWD except in the rare type 3 variant. The factor VIII deficiency is caused by to the absence of vWF protein, which normally complexes with factor VIII, delivers it to sites of ongoing coagulation, and prevents its clearance from the circulation.

Diagnosis

Because the physical examination usually reveals nonspecific evidence of easy bruising and bleeding, the diagnosis of vWD depends in large part on laboratory findings that measure the bleeding time, factor VIII activity, vWF:Ag level, and vWF activity or ristocetin cofactor activity (vWF:RCoF).

The bleeding time in patients with vWD is variably prolonged and may be influenced by the thrombocytopenia associated with vWD type 2B. The test is labor intensive and performer dependent. Although it is used to diagnose vWD, it is less useful as a predictor of adequate hemostasis after replacement therapy. The platelet function analyzer (PFA-100; Dade-Behring, Liederbach, Germany) provides a global perspective of vWF and platelet function and may substitute for bleeding time in the diagnosis of vWD; however, both bleeding time and the PFA-100 results are relatively insensitive for the diagnosis of vWD, particularly in the absence of other, more specific assays and a significant medical history, and they do not always correlate with bleeding propensity after replacement therapy. The aPTT is also variably prolonged because of concurrent factor VIII deficiency, but a normal aPTT does not exclude the diagnosis of vWD.

The vWF activity assay or vWF:RCoF is the most specific and sensitive test for vWF function but may be only slightly decreased in mild vWD. The vWF:Ag assay measures the immunologic expression of vWF and usually is performed via electroimmunoassay or enzyme-linked immunosorbent assay (ELISA). It is reduced slightly in mild vWD and its variants and is virtually absent in type 3. Because these assays are sensitive to the molecular mass of vWF, vWF:RCoF activity is discordantly low as a result of a low-normal or slightly reduced vWF:Ag level in the type 2 variants of vWD. Both vWF:RCoF and vWF:Ag are acute phase reactants; they are increased by exercise, stress, pregnancy, oral contraceptives, and liver disease and are decreased with hypothyroidism and in the presence of blood group O. vWD subtypes can be analyzed by in vitro platelet aggregation assays in which the patient’s platelet-rich plasma is activated by the addition of standard and low concentrations of ristocetin or cryoprecipitate. Types 1 and 3 vWF show mild or marked hyporesponsiveness to the standard concentration of ristocetin, whereas type 2B shows hyperaggregation with half-standard concentrations of ristocetin. Platelet-type pseudo-vWD can be differentiated from type 2B by observing spontaneous platelet agglutination after the addition of cryoprecipitate.

Gene-based assays are the most specific means of diagnosing vWF variants via restriction enzyme mapping of the vWF gene. These assays are available predominantly through research laboratories and should be obtained if the routine laboratory tests for vWF activity are equivocal. Type 3 vWF exhibits large deletions, whereas the other types are caused by variable point mutation defects. Type 2N has defects in the functional domain coding for vWF binding to factor VIII.

Treatment

The goals of therapy for vWD consist of correcting the deficiencies in vWF protein activity to greater than 50% of normal and in factor VIII activity to levels appropriate for the clinical situation. Although cryoprecipitate is licensed by the U.S. Food and Drug Administration (FDA) for prophylaxis or treatment of vWD-related bleeding complications, the lack of viral safety relegates its use exclusively to emergency circumstances when no other options are readily available. Replacement therapy with viral-attenuated, intermediate-purity or high-purity factor VIII concentrates containing an incomplete complement of high-molecular-weight multimers of vWF (e.g., Humate-P, Koate-DVI, Alphanate SD) is preferred and should be reserved for patients with type 1 and 2A variants unresponsive to DDAVP and for those with type 2B and type 3 diseases. These products also are indicated for the 2N variant and provide a source of normal vWF to complex with the normal intrinsic factor VIII. Dosing of these concentrates for vWD is calculated according to ristocetin cofactor units. On-demand IV bolus administration (60 RCoF U/kg) and continuous infusion regimens have been used successfully. An ultra-high-purity, plasma-derived vWF concentrate, which is virtually devoid of FVIII:C, is available in France and corrects deficient vWF:Ag and vWF:RCoF activity as efficiently as do products that contain FVIII:C; however, there is a 6- to 10-hour delay in the recovery of endogenous FVIII:C activity levels to adequate hemostatic ranges. This product has limited value to treat acute severe bleeds or to provide hemostasis for emergent surgery in patients with type 3 vWD, who require concurrent additional therapy with sources of factor VIII:C. The proportion of high-molecular-weight multimers, which are restored after the administration of these replacement products, is variable and correlates poorly with clinical efficacy. Excellent to good hemostatic responses are achieved in more than 90% of surgeries and bleeding episodes after administration of one or two doses of any of these products.

Any of these plasma-derived concentrates may precipitate thrombotic complications or exacerbate the thrombocytopenia in patients with vWD variant 2B or platelet-type pseudo-vWD. These individuals should receive transfusions with normal platelets that possess glycoprotein Ib/IX complexes with normal vWF affinity. Otherwise, DDAVP (0.3 μg/kg in 50 mL of normal saline infused over 20 minutes or intranasally at 150 μg per nostril for adults) is the recommended treatment and eliminates potential exposure to blood-borne pathogens.

The adjunctive use of antifibrinolytic agents, such as ε-aminocaproic acid (1 to 2 g PO up to four times daily) or tranexamic acid (3 or 4 grams PO daily in divided doses), is helpful after DDAVP therapy for bleeds. These agents should not be used routinely for renal bleeds or menorrhagia.

The following important caveats for vWD treatment should be considered: (1) A prolonged bleeding time does not need to be normalized to achieve adequate hemostasis after replacement therapy. Correction of vWF and factor VIII activity suffices and correlates closely with the clinical risk of bleeding. (2) DDAVP administration should be avoided in most individuals with type 2B variant vWD. Their thrombocytopenia may worsen, because DDAVP induces the release of abnormal vWF into the circulation, with additional in vivo platelet agglutination/aggregation. (3) Individuals with variant type 2N may not manifest a sustained factor VIII response to DDAVP, because the vWF released cannot complex with the simultaneously released factor VIII and prevent its clearance from the circulation. (4) Individuals who respond adequately to intravenously administered DDAVP may not respond adequately to the intranasal DDAVP preparation. Ideally, patients should be tested for their responses before treatment is needed for surgery. (5) Pregnant women with type 2B variant vWD may experience an exacerbation of thrombocytopenia as pregnancy progresses. Levels of the abnormal vWF increase as estrogen levels increase. (6) Free water intake, whether intravenous or by mouth, should be severely restricted for 4 to 6 hours after DDAVP administration to minimize the risk of hyponatremia and seizures. (7) vWD is associated clinically with Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), so gastrointestinal bleeding may occur. (8) Replacement therapy in type 3 vWD occasionally may precipitate the formation of alloantibody inhibitors that neutralize vWF activity. Recombinant factor VIIa concentrate is an effective alternative replacement product for vWF patients with alloantibody inhibitor.

Prognosis

In Western countries, the mortality rate for vWD approaches zero because of the ability to diagnose the disease and to treat it safely and effectively with a variety of replacement products.

   Acquired von Willebrand’s Disease

Acquired vWD is a rare condition that usually occurs as a complication of autoimmune, myeloproliferative, or lymphoproliferative disorders. The acquired vWD associated with neuroblastoma is secondary to proteolysis of vWF by tumor-secreted hyaluronidase. Abnormal vWF multimeric composition is a hallmark of these syndromes. vWF replacement regimens in this condition are similar to those for congenital vWD, but responses are unpredictable. In some patients with refractory bleeding, intravenous gamma globulin (IVIG, 1 g/kg), recombinant activated factor VII concentrate (90 μg/kg), plasmapheresis with albumin exchange, corticosteroids (1 mg/kg/day), alkylating agents, and rituximab (375 mg/m2 weekly for 4 doses) have been initiated to enhance recovery of adequate hemostasis.

   Factor XI Deficiency (Hemophilia C)

Epidemiology

Factor XI deficiency occurs at a prevalence of 1 per 1 million in the general population and 1 per 500 births in Ashkenazi Jewish families. Factor XI is the only component of the contact phase system (factor XII, prekallikrein, and high-molecular-weight kininogen) of the intrinsic pathway of coagulation that is associated with excessive bleeding complications when a deficient state exists.

Pathobiology

Factor XI deficiency is predominantly an autosomal recessive trait, although some mutations may have a dominant transmission pattern. The factor XI gene (FXI) is located on chromosome 4, and the Glu117stop mutation in FXI is the most common cause of factor XI deficiency, secondary to poor secretion/stability of the truncated protein or decreased levels of messenger RNA. To date, 65 mutations of FXI have been identified in factor XI–deficient patients (see www.FactorXI.org), but close correlation between hemorrhagic phenotype and genotype is lacking. In Ashkenazi Jewish individuals, two predominant gene mutations occur with equal frequency and are designated type II (a stop codon in exon 5) and type III (a single base defect in exon 9). The most severe clinical disease is observed in patients homozygous for type II, who usually have less than 1% factor XI activity. Homozygous type III individuals also manifest severe symptoms, but typically less severe than those of type II patients, and have slightly higher factor XI levels of about 10 to 20%. Compound heterozygotes, type II/III, make up the bulk of factor XI–deficient patients; they have clinically mild disease, with factor XI levels between 30 and 50%. Genotypic identification of affected patients is determined practically by measuring factor XI levels rather than by defining the specific gene defect.

Clinical Manifestations

The clinical bleeding tendencies in factor XI deficiency are less severe than those observed in severe hemophilia A or B and are not correlated with the extent of the deficiency. Most individuals with less than 20% of normal factor XI activity experience excessive bleeding after trauma or surgery; however, a few do not bleed. In contrast, bleeding has been observed in approximately 35 to 50% of mildly affected patients with factor XI levels between 20 and 50% of normal. Spontaneous hemorrhagic episodes, hemarthroses, and intramuscular and intracerebral bleeds are unusual; traumatic and surgical bleeds typically involve the mucous membranes. Patients undergoing tonsillectomy, prostatectomy, or dental extraction are at highest risk for bleeding unless replacement therapy is administered. Women may experience significant menorrhagia. Patients with mild factor XI deficiency and coincident mild vWD have an increased risk of bleeding.

Diagnosis

Factor XI deficiency is diagnosed in the laboratory by a prolonged aPTT, normal PT, and decreased factor XI activity ascertained in a specific quantitative clotting assay (normal range, 60 to 130%).

Treatment

FFP remains the mainstay for factor XI replacement (15 to 20 mL/kg); however, it is not viral inactivated. A minimum factor XI level of 40% is essential for major bleeds and major surgery. A viral-inactivated factor XI concentrate is not available in the United States, but such products have been used in Europe for more than 15 years (Factor XI, Bio Products Laboratory, Elstree, United Kingdom; Hemoleven, LFB, Les Ulis, France). Hypercoagulability (e.g., fatal disseminated intravascular coagulation, myocardial infarction, acute cerebrovascular events) occurs in approximately 10% of patients, particularly in older individuals with preexisting cardiovascular disease and malignancy. Replacement dosing levels should never exceed 70% factor XI activity. Repeat dosing with FFP or factor XI concentrate should be in the context of the long (60- to 80-hour) biologic half-life of factor XI in vivo.

The decision to treat heterozygotes with factor XI at levels greater than 20% is empiric and should be based on the individual’s prior history of bleeding after trauma or surgery. Alternatively, the family medical history of previous bleeding complications can be considered. For symptomatic patients, the preoperative or post-trauma use of FFP and pooled plasma products can be minimized or avoided by administering DDAVP, 0.3 μg/kg intravenously. Because hemorrhagic complications originate most commonly from mucosal membrane surfaces, antifibrinolytic agents such as ε-aminocaproic acid or tranexamic acid are frequently helpful as adjunctive therapy.

Alloantibody inhibitors, which neutralize the hemostatic effects of exogenously administered factor XI replacement, can develop in patients who have factor XI levels lower than 1 IU/dL and who have been exposed to plasma or factor XI concentrate. Recombinant factor VIIa can prevent bleeding during or after surgery in these patients.

   Contact Activation Factors

Although factor XI is important for activating factor IX in the intrinsic pathway generation of thrombin, it is only one of the four components of the contact phase of coagulation. Deficiencies in any of the other three factors (factor XII, prekallikrein, and high-molecular-weight kininogen) produce in vitro laboratory abnormalities.

Patients have no clinical bleeding. Counterintuitively, 8 to 10% of individuals with severe factor XII deficiency (<1% activity) have experienced premature venous thromboembolic events, occasionally fatal in nature. This finding has led to speculation that factor XII deficiency may lead to hypercoagulability through defective participation of the contact phase proteins in the activation of fibrinolysis.

Autoantibody inhibitors and antiphospholipid antibodies have been associated with decreased levels of factor XII. No clinical sequelae have been associated.

Diagnosis

Deficiencies of each of these factors prolong the aPTT, which may normalize after prolonged incubation of the patient’s plasma at 37° C with a negatively charged activator of the aPTT assay (i.e., kaolin or Celite). Specific assays are also available to quantitate each of the contact factors.

Treatment

No therapy is indicated. Routine anticoagulation regimens are used to treat the thrombogenic events ( Chapter 178 ).

   Factor XIII (Fibrin-Stabilizing Factor) Deficiency

Factor XIII is a transglutaminase that is activated by thrombin and subsequently cross-links fibrin to protect it from lysis by plasmin. It also is involved in wound healing and tissue repair and seems to be crucial for maintaining a viable pregnancy. Homozygous severe deficiency states are rare and are inherited in an autosomal recessive manner with a prevalence of 1 per 3 million births. Consanguinity is common.

Clinical Manifestations

Typically, patients are first seen shortly after birth with persistent bleeding around the umbilical stump. Intracranial bleeding events, usually precipitated by minimal trauma, occur commonly enough in infants to justify initiation of a primary prophylaxis regimen of replacement therapy. Delayed bleeding after surgery and trauma is the hallmark of the disease; however, easy bruisability, poor wound healing with defective scar formation and dehiscence, and hemarthroses are characteristic. Spontaneous abortions are increased in severely affected women.

Diagnosis

The diagnosis usually is suspected on clinical grounds, inasmuch as factor XIII deficiency is not detected by the conventional screening coagulation assays (i.e., the aPTT or the PT). Most laboratories use a rapid screening assay that assesses the ability of a fibrin clot to remain intact with incubation in 5 mol/L of urea or 1% monochloroacetic acid. With factor XIII levels less than 1% of normal, the clot dissolves within 2 to 3 hours.

Treatment

Replacement therapy for prophylaxis or treatment of acute bleeds can be accomplished by administering cryoprecipitate, FFP, or, preferably, plasma-derived factor XIII concentrate (Fibrogammin P, which is pasteurized for viral safety and is available in the United States via compassionate investigational new drug [IND] use through ZLB-Behring, Inc., Marburg, Germany, and King of Prussia, PA). Clinical studies are in progress to evaluate a placentally derived product. Normal hemostasis is achieved with a factor XIII level of only 5% of normal. The circulating half-life of factor XIII is 10 days, so prophylactic replacement can be scheduled every 3 to 4 weeks. Acquired alloantibody inhibitors can develop in severely affected individuals. Autoantibodies also occur, usually in association with systemic lupus erythematosus (SLE).

   Dysfibrinogenemia and Afibrinogenemia

Approximately 300 abnormal fibrinogens have been described, but few cause symptoms. Abnormal fibrinogens are rare, autosomally inherited proteins. Their characterization has provided valuable information on the structure and function of fibrinogen and better understanding of wound healing and fibrinolysis.

Clinical Manifestations

More than 50% of the dysfibrinogenemias are asymptomatic, 25% are associated with a mild hemorrhagic tendency (commonly caused by defective release of fibrinopeptide A), and 20% predispose individuals to thrombophilia (usually caused by impaired fibrinolysis). Concurrent bleeding and thrombosis also may occur. The prevalence of dysfibrinogenemia in patients with a history of thromboembolic episodes approaches 0.8%, typically occurring in late adolescence and early adulthood. Women experience a high incidence of pregnancy-related complications, such as spontaneous abortion and postpartum thromboembolic events. Thrombin times and reptilase times (plasma-based clotting times with substitution of reptilase snake venom for thrombin) are not helpful in predicting whether an abnormal fibrinogen will be prothrombotic, prohemorrhagic, or asymptomatic, but clinical history, fibrinopeptide release studies, and fibrin polymerization studies may be useful. Clinically insignificant dysfibrinogenemias may be acquired in association with hepatocellular carcinoma.

In contrast to the hepatic synthesis of a qualitatively abnormal protein in dysfibrinogenemia, congenital afibrinogenemia, an autosomal recessive disorder, represents the markedly deficient production of a normal protein. Severe life-threatening hemorrhagic complications can occur at any site, beginning at birth with umbilical bleeding. Intracranial hemorrhage is a frequent cause of death. Poor wound healing is characteristic. All coagulation-based assays that depend on the detection of a fibrin clot end point are markedly prolonged. Afibrinogenemia is usually detectable by specific functional or immunologic assays. Platelet dysfunction may accompany afibrinogenemia and exacerbate bleeding.

Diagnosis

Abnormalities usually are detected incidentally when routine coagulation screening assays reveal decreased fibrinogen concentrations and prolonged thrombin clotting times. On further evaluation, discordance between functional and immunologic fibrinogen levels (>50 mg/dL more antigenic than functional) is observed; clotting times using snake venom (reptilase or ancrod) are variably prolonged.

Treatment

Deficiencies of fibrinogen may be corrected by the administration of FFP or cryoprecipitate; however, viral safety remains an issue. Viral-attenuated (pasteurized), plasma-derived fibrinogen concentrates (not available in the United States but licensed in France, Japan, Scotland, and China) or solvent detergent—or psoralen-treated FFP (when licensed by the FDA) will be preferable alternatives. The replacement goal is 100 mg/dL of fibrinogen. With a circulating biologic half-life of at least 96 hours, treatment every 3 to 4 days is adequate. Primary prophylaxis regimens may be useful in afibrinogenemia; on-demand or prophylactic replacement for trauma or surgery is recommended for prohemorrhagic dysfibrinogenemias. Individuals with thrombophilic manifestations should receive anticoagulation indefinitely.

   Deficiency of Factor V (Proaccelerin, Labile Factor)

Factor V is a component of the prothrombinase complex that assembles factors Va and Xa on the phospholipid membrane of the platelet for prothrombin (factor II) activation to thrombin.

   Congenital Factor V Deficiency

Deficiency of factor V is a rare, autosomal recessive disorder (1 per 1 million births). The factor V Leiden protein, which is responsible for resistance to activated protein C and thrombophilia, does not affect factor V coagulant activity ( Chapter 182 ). The severity of the plasma factor V reduction correlates less well with the risk of clinical bleeding than does the platelet factor V content in the α-granule. This observation illustrates the crucial role of the platelet in promoting adequate hemostasis at bleeding sites and explains why transfusions of normal platelets may be preferred over FFP for the treatment of hemorrhagic episodes secondary to congenital or acquired factor V deficiency. Hemostasis can be maintained without correcting plasma factor V activity (>25% of normal).

   Combined Deficiencies of Factors V and VIII

Factors V and VIII are structurally homologous proteins, and combined deficiencies of these factors occur as an autosomal recessive disorder with a prevalence of 1 per 100,000 births among Jews of Sephardic origin. The severity of bleeding is determined by the levels of these factors, which usually range from 5% to 30% of normal. Replacement therapy should be aimed at normalizing both clotting protein activities.

   Acquired Factor V Deficiency

Acquired factor V deficiency has been described in individuals exposed to bovine factor V, which contaminates the thrombin preparations used topically to control bleeding during cardiovascular surgery. This abnormality probably represents the development of anti–bovine factor V antibodies that cross-react with the human factor V protein. Profuse bleeding accompanies this complication.

   Deficiencies of Vitamin K–Dependent Coagulation

   Deficiencies of Factors II, VII, and X

Pathobiology and Clinical Manifestations

Congenital deficiencies of factors II, VII, and X are rare, autosomally inherited disorders. Heterozygotes (with factor levels approximately 20% of normal) are typically asymptomatic except in the immediate newborn period, when physiologic vitamin K deficiency exacerbates the underlying clotting factor deficiency. Homozygotes with clotting factor levels lower than 10% of normal manifest variable symptoms. As with other coagulopathies, these deficiencies usually are suspected after the onset of neonatal umbilical stump bleeding. Thereafter, unless replacement or prophylactic therapy is provided, these patients are subject to mucosal bleeding from epistaxis, menorrhagia, and dental extractions; to hemarthroses and intramuscular hematomas; and to bleeding after surgery or trauma.

The genetic factor II variant resulting from a glycine-to-alanine (G-to-A) mutation at nucleoside 20210 is associated with elevated prothrombin levels and an increased risk of venous and arterial thrombosis ( Chapter 182 ). The PT and aPTT are not affected.

Acquired factor VII deficiency has been associated with Dubin-Johnson and Gilbert syndromes ( Chapter 150 ).

Acquired factor IX deficiency has been associated with Gaucher’s disease, because factor IX binds to glucocerebroside ( Chapter 223 ). Factor IX deficiency also may accompany Noonan’s syndrome, an autosomal dominant disease complex characterized by congenital heart disease, abnormal facies, and excessive bleeding or bruising.

Diagnosis

In the coagulation laboratory, factor VII deficiency is associated with a prolonged PT and a normal aPTT. This pattern localizes the deficiency to the extrinsic pathway. In contrast, deficiencies of factors II and X prolong the PT and the aPTT, with the defects localized to the common pathway of coagulation. A Russel viper venom–based clotting assay can differentiate between these two deficiencies, because, as a direct activator of factor X, the assay is prolonged with factor X but not factor II deficiency. Mixing patient plasma with normal plasma shows correction of these assays, and specific clotting assays using plasma that is deficient in the coagulation protein to be studied confirm the diagnosis.

Treatment

Replacement therapy is indicated for acute symptomatic bleeds and for prophylaxis before surgery. In addition to FFP, which has the potential to transmit blood-borne viruses, factor IX complex concentrates can be administered to achieve hemostatic levels of any of these vitamin K–dependent factors (25 to 30% of normal).

Bleeding complications caused by acquired IgG autoantibodies directed against any coagulation factor protein may be reversed rapidly, albeit temporarily, by extracorporeal immunoadsorption over a Sepharose-bound polyclonal antihuman IgG or staphylococcal A column with concomitant replacement therapy and initiation of immunosuppression.

   Factor Deficiency in Amyloidosis

Acquired severe deficiency of factor X, often accompanied by deficiencies of other vitamin K–dependent factors, occasionally occurs in individuals with systemic amyloidosis ( Chapter 296 ). Because amyloid fibrils in the reticuloendothelial system bind endogenous and exogenous sources of factor X, replacement therapy with FFP or factor IX complex concentrates, even in large quantities, may not always be sufficient. Recombinant factor VIIa concentrate has been used to reverse acute bleeding. Splenectomy may ameliorate recurrent bleeding complications.

   Other Acquired Coagulation Deficiencies

   Lupus Anticoagulants and the Antiphospholipid Syndrome

Epidemiology

The lupus anticoagulant may be discovered incidentally when routine coagulation assays reveal prolongations in the PT, the aPTT, or both; when young women experience recurrent spontaneous miscarriages or pregnancy-related thromboembolic events; when young women and elderly men are detected with cerebral arterial thromboses; when patients are affected by SLE (20 to 40%; see Chapter 287 ) or other autoimmune diseases or lymphoproliferative malignancies; and when patients have been receiving long-term therapy with psychotropic medications (e.g., chlorpromazine; see Chapter 420 ). Lupus anticoagulant also can occur with the active opportunistic infections and malignancies associated with AIDS.

Pathobiology

The lupus anticoagulant is the functional expression of an IgG or IgM antiphospholipid autoantibody, which prolongs coagulation in in vitro assays but typically does not produce bleeding complications in vivo. The immunologic expression of the antiphospholipid autoantibodies can be measured by anticardiolipin antibody ELISA. The antiphospholipid antibodies are not directed specifically against the anionic phospholipids that function as templates for activation of the prothrombinase complex but in actuality appear to interact with plasma proteins (β2-glycoprotein I or apolipoprotein H), which in turn bind to anionic phospholipids. β2-Glycoprotein I modulates the normal coagulation process by binding to phospholipid membranes; there is impaired thrombin generation in a β2-glycoprotein I knockout mice model. However, when so-called antiphospholipid antibodies complex with β2-glycoprotein in vivo, the modulatory function for β2-glycoprotein I is negated, thereby resulting in increased risks for recurrent venous thromboembolism, fetal wastage, and arterial thrombotic episodes, including stroke. There is evidence that the antiphospholipid antibodies inhibit protein C activation, interfere with antithrombin III activity, disrupt the annexin V “shield,” and interfere with normal fibrinolysis. All of these phenomena are prothrombotic events.

Clinical Manifestations

The lupus anticoagulant can precipitate clinical bleeding complications when antiphospholipid/anticardiolipin antibodies complex with factor II (prothrombin) and produce an acquired prothrombin deficiency, probably because of accelerated clearance of lupus anticoagulant-prothrombin complexes from the circulation. Bleeding tendencies also arise when the lupus anticoagulant targets platelet membranes and produces quantitative and/or qualitative platelet abnormalities.

Nonpregnant individuals with thrombotic manifestations of lupus anticoagulant or antiphospholipid antibody have a 50% risk of experiencing recurrent events over a 5-year period. Typically, recurrent hypercoagulable episodes occur in a pattern consistent with the initial findings (i.e., venous recurrence follows an initial deep venous thrombosis).

Diagnosis

The in vitro anticoagulant properties of the antiphospholipid antibodies are detected when mixing studies of the patient’s plasma with normal plasma reveal immediate inhibition of the aPTT or the PT at baseline with no additional prolongation after a 2-hour incubation (in contrast to the findings with factor VIII autoantibody). Confirmatory assays include the kaolin clotting time (the most sensitive test), the dilute Russell’s viper venom time, the dilute tissue thromboplastin inhibition assay, the textarin:ecarin venom clotting time ratio, and the platelet neutralization assay. All of these laboratory tests depend on the presence of phospholipid; antiphospholipid antibodies block the binding of coagulation factors and the modulators of coagulation (protein S and activated protein C) to their phospholipid assembly surface template.

Treatment

The approach to the management of lupus anticoagulant or antiphospholipid antibody varies according to the severity of symptoms and the clinical circumstances. In the setting of idiopathic fetal loss, there is a 15 to 20% association with the antiphospholipid syndrome, with 75% of the pregnancy losses occurring in the first trimester. Treatment with low-dose unfractionated heparin (5000 U subcutaneously every 8 hours) and daily aspirin (81 mg) has resulted in 80% fetal survival. The use of corticosteroids is controversial and is not recommended because of attendant diabetes and hypertension. Supplemental calcium and vitamin D ( Chapter 264 ) should be administered to minimize the risks of osteoporosis from prolonged heparin use. Clinical trials with preparations of low-molecular-weight heparin (LMWH) and immunosuppressive agents such as intravenous gamma globulin are in progress. An FDA-mandated advisory suggested that the use of LMWHs may be associated with a low incidence of teratogenicity and possibly with thrombogenicity; although these complications have not been observed in meta-analyses of LMWH in pregnancy; controlled studies are needed to confirm any potential risk.

Individuals who experienced venous thromboembolism associated with antiphospholipid antibodies should be treated for at least 6 months with oral anticoagulation with warfarin to maintain a target international normalized ratio (INR) of 2.0 to 3.0. For patients with recurrent noncardioembolic stroke and antiphospholipid antibodies, oral anticoagulation with warfarin at a target INR of 2.0 to 3.0 is preferred, rather than use of antiplatelet agents.

The nonvirilizing androgen preparations danazol and stanozolol may be helpful in raising depressed factor II levels into the hemostatic range. Asymptomatic individuals may benefit from prophylactic aspirin therapy 81 mg/day, which has a favorable risk-to-benefit profile.

   Coagulopathies Secondary to Anticoagulation

The most common acquired clinical coagulopathies occur secondary to anticoagulation with warfarin and other coumarin analogues and to the use of heparin.

Warfarin

Vitamin K–dependent clotting factors II, VII, IX, and X are functionally defective after warfarin use because post-translational carboxylation of their γ-glutamyl residues cannot be accomplished. The risks for life-threatening bleeding increase proportionally with the intensity of anticoagulation and INRs rising to greater than 6.0. Warfarin effects can be exaggerated by potentiating medications, excessive ethanol use, and simultaneous dietary vitamin K deficiency. Bleeding may be severe or occult and may unmask the presence of pathologic lesions, such as gastrointestinal or genitourinary carcinomas.

Treatment

For acute and profuse bleeding events caused by warfarin with any INR, vitamin K1, 1 to 5 mg, should be administered subcutaneously or intravenously in conjunction with FFP (10 to 20 mL/kg) or small amounts of factor IX complex concentrate (25 to 50 IU/kg). Recombinant factor VIIa concentrate (20 to 30 μg/kg) also has been reported to be a useful salvage therapy to reverse refractory hemorrhage caused by overanticoagulation with warfarin. For minor bleeding or markedly increased INRs without bleeding, warfarin should be withheld for 1 to 2 days and vitamin K1 administered (1 to 2 mg subcutaneously or intravenously). A single dose of oral vitamin K1 (1 mg) also has been used successfully in this scenario, but the INR may not correct significantly for about 48 hours. Administration of FFP may be considered for INRs greater than 9.0 to facilitate reduction of the INR and to minimize potential bleeding in high-risk patients. These maneuvers allow for easy reinitiation of warfarin with appropriate dose adjustment. The frequency of major hemorrhage, the mortality rate, and the incidence of recurrent thromboembolic complications all are reduced greatly when anticoagulated patients receiving long-term warfarin therapy are managed in anticoagulation clinics.

Heparin

Heparin anticoagulation also can induce life-threatening hemorrhagic complications. The aPTT and thrombin times are prolonged even with minimal amounts of heparin in the circulation or with contaminating indwelling catheters from which blood specimens are obtained. The reptilase time can be used to distinguish heparin from other causes of thrombin time prolongation (e.g., fibrin degradation products, abnormal fibrinogens). The PT may be prolonged in the presence of large concentrations of heparin. Heparin functions as a circulating inhibitor, so that mixing studies of patient plasma with normal plasma do not result in correction of the aPTT. LMWH preparations do not affect the aPTT but may affect the thrombin time, depending on the thrombin concentration used in the assay ( Chapter 35 ). The anticoagulant properties of LMWHs can be monitored by the anti-factor Xa assay.

Treatment

Acute and profuse bleeding episodes secondary to heparin can be reversed by administration of protamine sulfate (1 mg/100 U of residual heparin). Overdosing with protamine sulfate can produce its own coagulopathy. Otherwise, the circulating survival time of standard heparin in plasma is short enough (2 to 4 hours) to allow the anticoagulant state to dissipate on its own. The half-life of LMWH is longer, but bleeding is uncommon unless the patient has renal dysfunction. The anticoagulation effects of LMWH may be reversed with protamine sulfate, although the response can be marginal and unpredictable. Recombinant factor VIIa (30 to 90 μg/kg) has been used anecdotally to reverse refractory bleeding associated with LMWH.

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