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2384 Part XXI ◆ Diseases of the Blood

Chapter 476

Hereditary Clotting

Factor Deficiencies(Bleeding Disorders)J. Paul Scott and Veronica H. Flood

Hemophilia A (factor VIII deficiency) and hemophilia B (factor IXdeficiency) are the most common and serious congenital coagulationfactor deficiencies. Te clinical findings in hemophilia A and hemo-philia B are virtually identical. Hemophilia C is the bleeding disorderassociated with reduced levels of factor XI (see Chapter 476.2). Reducedlevels of the contact factors (factor XII, high-molecular-weight kinino-

gen, and prekallikrein) are associated with significant prolongation ofactivated partial thromboplastin time (aP; also referred to as PTT ),but are not associated with hemorrhage, as discussed in Chapter 476.3.Other coagulation factor deficiencies that are less common are brieflydiscussed in subsequent subchapters.

476.1 Factor VIII or Factor IX Deficiency(Hemophilia A or B)J. Paul Scott

Deficiencies of factors VIII and IX are the most common severe inher-ited bleeding disorders. Recombinant factor VIII and factor IX con-centrates are available to treat patients with hemophilia and thereby

avoid the infectious risk of plasma-derived transfusion-transmitteddiseases.

PATHOPHYSIOLOGY Factors VIII and IX participate in a complex required for the activationof factor X. ogether with phospholipid and calcium, they form the“tenase,” or factor X–activating, complex. Figure 475-1 in Chapter 475shows the clotting process as it occurs in the test tube, with factor Xbeing activated by either the complex of factors VIII and IX or thecomplex of tissue factor and factor VII. In vivo, the complex of factorVIIa and tissue factor activates factor IX to initiate clotting. In thelaboratory, prothrombin time (P) measures the activation of factor Xby factor VII and is therefore normal in patients with factor VIII orfactor IX deficiency.

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Chapter 476 ◆ Hereditary Clotting Factor Deficiencies (Bleeding Disorders) 238

specific mention. A patient may lose large volumes of blood into tiliopsoas muscle, verging on hypovolemic shock, with only a vagarea of referred pain in the groin. Te hip is held in a flexed, internarotated position owing to irritation of the iliopsoas. Te diagnosismade clinically from the inability to extend the hip but must be cofirmed with ultrasonography or C (Fig. 476-1). Life-threatenibleeding in the patient with hemophilia is caused by bleeding into vistructures (central nervous system, upper airway) or by exsanguintion (external trauma, gastrointestinal or iliopsoas hemorrhagPrompt treatment with clotting factor concentrate for these lithreatening hemorrhages is imperative. If head trauma is of sufficie

concern to suggest radiologic evaluation, factor replacement shouprecede radiologic evaluation. Simply put: “reat first, image secondLife-threatening hemorrhages require replacement therapy to achiea level equal to that of normal plasma (100 IU/dL, or 100%).

Patients with mild hemophilia who have factor VIII or factor levels >5 IU/dL usually do not have spontaneous hemorrhages. Teindividuals may experience prolonged bleeding aer dental wosurgery, or injuries from moderate trauma and may not be diagnosuntil they are older.

LABORATORY FINDINGS AND DIAGNOSISTe laboratory screening test that is affected by a reduced level of factVIII or factor IX is P. In severe hemophilia, the P value is usua2-3 times the upper limit of normal. Results of the other screening teof the hemostatic mechanism (platelet count, bleeding time, prothro

bin time, and thrombin time) are normal. Unless the patient has inhibitor to factor VIII or IX, the mixing of normal plasma with patieplasma results in correction of P value. Te specific assay for factoVIII and IX will confirm the diagnosis of hemophilia. If correctidoes not occur on mixing, an inhibitor may be present. In 25-35% patients with hemophilia who receive infusions of factor VIII or factIX, a factor-specific antibody may develop. Tese antibodies adirected against the active clotting site and are termed inhibitors. such patients, the quantitative Bethesda assay for inhibitors should performed to measure the antibody titer.

DIFFERENTIAL DIAGNOSISIn young infants with severe bleeding manifestations, the differentdiagnosis includes severe thrombocytopenia; severe platelet functi

Aer injury, the initial hemostatic event is formation of the plateletplug, together with the generation of the fibrin clot that prevents furtherhemorrhage. In hemophilia A or B, clot formation is delayed and is notrobust. Inadequate thrombin generation leads to failure to form atightly crosslinked fibrin clot to support the platelet plug. Patients withhemophilia slowly form a so, friable clot. When untreated bleedingoccurs in a closed space, such as a joint, cessation of bleeding may bethe result of tamponade. With open wounds, in which tamponadecannot occur, profuse bleeding may result in significant blood loss. Teclot that is formed may be friable, and rebleeding occurs during thephysiologic lysis of clots or with minimal new trauma.

CLINICAL MANIFESTATIONSNeither factor VIII nor factor IX crosses the placenta; bleeding symp-toms may be present from birth or may occur in the fetus. Only 2% ofneonates with hemophilia sustain intracranial hemorrhages, and 30%of male infants with hemophilia bleed with circumcision. Tus, in theabsence of a positive family history (hemophilia has a high rate ofspontaneous mutation), hemophilia may go undiagnosed in thenewborn. Obvious symptoms such as easy bruising, intramuscularhematomas, and hemarthroses begin when the child begins to cruise.Bleeding from minor traumatic lacerations of the mouth (a torn frenu-lum) may persist for hours or days and may cause the parents to seekmedical evaluation. Even in patients with severe hemophilia, only 90%have evidence of increased bleeding by 1 yr of age. Although bleedingmay occur in any area of the body, the hallmark of hemophilic bleeding

is hemarthrosis. Bleeding into the joints may be induced by minortrauma; many hemarthroses are spontaneous. Te earliest joint hemor-rhages appear most commonly in the ankle. In the older child andadolescent, hemarthroses of the knees and elbows are also common.Whereas the child’s early joint hemorrhages are recognized only aermajor swelling and fluid accumulation in the joint space, older childrenare frequently able to recognize bleeding before the physician does.Tey complain of a warm, tingling sensation in the joint as the firstsign of an early joint hemorrhage. Repeated bleeding episodes into thesame joint in a patient with severe hemophilia may become a “target” joint. Recurrent bleeding may then become spontaneous because ofthe underlying pathologic changes in the joint.

Although most muscular hemorrhages are clinically evident owingto localized pain or swelling, bleeding into the iliopsoas muscle requires

Figure 476-1 Massive hematoma into the iliopsoas muscle in a patient with hemophilia B. A 38 yr old man with severe deficiency of factor (hemophilia B) was admitted for right lower abdominal pain of progressively increasing severity and tenderness. He had had a common cold wsevere cough and loss of appetite for approximately 1 wk. A, Abdominal radiograph shows presence of the psoas sign on the right side and leshifted colon gas. B, CT scan shows massive hematoma in the right iliopsoas muscle, resulting in anterior translocation of the right kidneC, Reconstructed 3-dimensional image shows more clearly the kidney translocation and the extended, but intact, large vessels. These are useffindings for the diagnostic procedures, because progressive right lower abdominal pain may closely simulate acute appendicitis. The hemorrhawas successfully managed by replacement of factor IX for 1 wk without any recurrence. The patient did not have any inhibitors to factor IX. (Fro

Miyazaki K, Higashihara M: Massive hemorrhage into the iliopsoas muscle, Intern Med 44:158, 2005.)

A B C



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Calculation of the dose of recombinant factor VIII (FVIII) or recom-binant factor IX (FIX) is as follows:

Dose of rFVIII IU

desired rise in rFVIII Body weight kg

( )

% ( ) ( ) .= × × 0 5

Dose of rFIX IUdesired rise in plasma FIX Body weight kg

( )% ( ) ( ) .= × ×1 44

For factor VIII, the correction factor is based on the volume ofdistribution of factor VIII. For factor IX, the correction factor is basedon the volume of distribution and the observed rise in plasma levelaer infusion of recombinant factor IX.

able 476-1 summarizes the treatment of some common types ofhemorrhage in a patient with hemophilia.

With the availability of recombinant replacement products, prophy-laxis is the standard of care for most children with severe hemophilia,to prevent spontaneous bleeding and early joint deformities. In addi-tion to currently available recombinant factors, products are beingdeveloped to increase the plasma half-life and reduce the immunoge-nicity of hemostatic factors. A study comparing prophylaxis withaggressive episodic treatment provides evidence for the superiority ofprophylaxis in preventing debilitating joint disease. If target jointsdevelop, “secondary” prophylaxis is oen initiated.

With mild factor VIII hemophilia, the patient’s endogenously pro-duced factor VIII can be released by the administration of desmopres-

sin acetate. In patients with moderate or severe factor VIII deficiency,the stored levels of factor VIII in the body are inadequate, and desmo-pressin treatment is ineffective. Te risk of exposing the patient withmild hemophilia to transfusion-transmitted diseases and the cost ofrecombinant products warrant the use of desmopressin, if it is effective.A concentrated intranasal form of desmopressin acetate, not theenuresis or pituitary replacement dose, can also be used to treatpatients with mild hemophilia A. Te dose is 150 g (1 puff) for chil-dren weighing 50 kg. Most centers administer a trial of desmopres-sin to determine the level of factor VIII achieved aer its infusion.Desmopressin is not effective in the treatment of factor IX–deficienthemophilia.

Preliminary trials of an adeno-associated virus vector containing thefactor IX gene are underway with some encouraging initial results.

PROPHYLAXISMany patients are now given lifelong prophylaxis to prevent spontane-ous joint bleeding. Te National Hemophilia Foundation recommendsthat prophylaxis be considered optimal therapy for children withsevere hemophilia. Usually, such programs are initiated with the first joint hemorrhage. Young children oen require the insertion of acentral catheter to ensure venous access. Such programs are expensivebut are highly effective in preventing or greatly limiting the degree of joint pathology; however, complications include central line infectionand thrombosis. reatment is usually provided every 2-3 days to main-tain a measurable plasma level of clotting factor (1-2%) when assayed just before the next infusion (trough level). Whether prophylaxisshould be continued into adulthood has not yet been adequatelystudied. If moderate arthropathy develops, prevention of future bleed-

ing will require higher plasma levels of clotting factors. In the olderchild who is not given primary prophylaxis, secondary prophylaxis isfrequently initiated if a target joint develops.

SUPPORTIVE CAREAlthough it is easy to tell parents that their child should avoid trauma,this advice is not practical in active children and adolescents. oddlersare active, are curious about everything, and injure themselves easily.Effective measures include anticipatory guidance, including the use ofcar seats, seatbelts, and bike helmets, and the importance of avoidinghigh-risk behaviors. Older boys should be counseled to avoid violentcontact sports, but this issue is a challenge. Boys with severe hemo-philia oen sustain hemorrhages in the absence of known trauma.Early psychosocial intervention helps the family achieve a balance

disorders, such as Bernard-Soulier syndrome and Glanzmann throm-basthenia; type 3 (severe) von Willebrand disease; and vitamin K defi-ciency. Hemostatic screening tests should differentiate these entitiesfrom hemophilia.

GENETICS AND CLASSIFICATIONHemophilia occurs in approximately 1 : 5,000 males, with 85% havingfactor VIII deficiency and 10-15% having factor IX deficiency. Hemo-philia shows no apparent racial predilection, appearing in all ethnicgroups. Te severity of hemophilia is classified on the basis of thepatient’s baseline level of factor VIII or factor IX, because factor levelsusually correlate with the severity of bleeding symptoms. By definition,1 IU of each factor is defined as that amount in 1 mL of normal plasmareferenced against a standard established by the World Health Orga-nization (WHO); thus, 100 mL of normal plasma has 100 IU/dL (100%activity) of each factor. For ease of discussion, henceforth in thischapter, we use the term % activity to refer to the percentage found innormal plasma (100% activity). Factor concentrates are also referencedagainst an international WHO standard, so treatment doses are usuallyreferred to in IU. Severe hemophilia is characterized as having 5%, may go many years before the conditionis diagnosed, and frequently require significant trauma to cause bleed-

ing. Te hemostatic level for factor VIII is >30-40%, and for factor IX,it is >25-30%. Te lower limit of levels for factors VIII and IX in normalindividuals is approximately 50%.

Te genes for factors VIII and IX are carried near the terminus ofthe long arm of the X chromosome and are therefore X-linked traits.Te majority of patients with hemophilia have reduced clotting factorprotein; 5-10% of those with hemophilia A and 40-50% of those withhemophilia B make a dysfunctional protein. Approximately 45-50% ofpatients with severe hemophilia A have the same mutation, in whichthere is an internal inversion within the factor VIII gene that results inproduction of no protein. Tis mutation can be detected in the bloodof patients or carriers and in the amniotic fluid by molecular techniques.African-Americans oen have a different factor VIII haplotype, andthis difference may be the reason that African-Americans have higherinhibitor formation (see later). Because of the multiple genetic causes

of either factor VIII or factor IX deficiency, most cases of hemophiliaare classified according to the amount of factor VIII or factor IX clottingactivity. In the newborn, factor VIII values may be artificially elevatedbecause of the acute-phase response elicited by the birth process. Tisartificial elevation may cause a mildly affected patient to have normalor near-normal levels of factor VIII. Patients with severe hemophiliado not have detectable levels of factor VIII. In contrast, factor IX levelsare physiologically low in the newborn. If severe hemophilia is presentin the family, an undetectable level of factor IX is diagnostic of severehemophilia B. In some patients with mild factor IX deficiency, the pres-ence of hemophilia can be confirmed only aer several weeks of life.

Trough lyonization of the X chromosome, some female carriers ofhemophilia A or B have sufficient reduction of factor VIII or factor IXto produce mild bleeding disorders. Levels of these factors should bedetermined in all known or potential carriers to assess the need for

treatment in the event of surgery or clinical bleeding.Because factor VIII is carried in plasma by von Willebrand factor,the ratio of factor VIII to von Willebrand factor is sometimes used todiagnose carriers of hemophilia. When possible, specific genetic muta-tions should be identified in the propositus and used to test otherfamily members who are at risk of either having hemophilia or beingcarriers.

TREATMENTEarly, appropriate therapy is the hallmark of excellent hemophilia care.When mild to moderate bleeding occurs, values of factor VIII or factorIX must be raised to hemostatic levels, in the 35-50% range. For life-threatening or major hemorrhages, the dose should aim to achievelevels of 100% activity.



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increase the plasma concentration by 2%. Tus, infusion of plasma at10-15 mL/kg will result in a plasma level of 20-30%, which is usuallysufficient to control moderate hemorrhage. Frequent infusions ofplasma would be necessary to achieve higher levels of factor XI.Because the half-life of factor XI is usually ≥48 hr, maintaining ade-quate levels of factor XI commonly is not difficult.

Chronic joint bleeding is rarely a problem in factor XI deficiency,and for most patients, the deficiency is a concern only at the time ofmajor surgery unless there is a second underlying hemostatic defect(e.g., von Willebrand disease).

Bibliography is available at Expert Consult.

476.3 Deficiencies of the Contact Factors(Nonbleeding Disorders)J. Paul Scott

Deficiency of the “contact factors” (factor XII, prekallikrein, and high-molecular-weight kininogen) causes prolonged P but no bleedingsymptoms. Because these contact factors function at the step of initia-tion of the intrinsic clotting system by the reagent used to determineP, the P is markedly prolonged when these factors are absent.Tus, there is the paradoxical situation in which P is extremely

prolonged with no evidence of clinical bleeding. It is important thatindividuals with these findings be well informed about the meaning oftheir clotting factor deficiency because they do not need treatment,even for major surgery.

476.4 Factor VII DeficiencyJ. Paul Scott

Factor VII deficiency is a rare autosomal bleeding disorder that isusually detected only in the homozygous state. Severity of bleeding varies from mild to severe with hemarthroses, spontaneous intracra-nial hemorrhage, and mucocutaneous bleeding, especially nosebleedsand menorrhagia. Patients with this deficiency have markedly pro-

longed P but normal P. Factor VII assays show a marked reductionin factor VII. Because the plasma half-life of factor VII is 2-4 hr,therapy with FFP is difficult and is oen complicated by fluid overload.A commercial concentrate of recombinant factor VIIa is effective intreating patients with factor VII deficiency.


476.5 Factor X DeficiencyJ. Paul Scott

Factor X deficiency is a rare (estimated 1/1,000,000) autosomal disor-der with variable severity. Mild deficiency results in mucocutaneous

and posttraumatic bleeding, whereas severe deficiency results in spon-taneous hemarthroses and intracranial hemorrhages. Factor X defi-ciency is the result of either a quantitative deficiency or a dysfunctionalmolecule. A reduced factor X level is associated with prolongation ofboth P and P. In patients with hereditary factor X deficiency, factorX levels can be increased with use of either FFP or prothrombincomplex concentrate. Te half-life of factor X is approximately 30 hr,and its volume of distribution is similar to that of factor IX. Tus,1 unit/kg will increase the plasma level of factor X by 1%.

Although it is rarely a problem in pediatric patients, systemic amy-loidosis may be associated with factor X deficiency, owing to theadsorption of factor X on the amyloid protein. In the setting of amy-loidosis, transfusion therapy oen is not successful because of the rapidclearance of factor X.

off-label (i.e., in a use not approved by the FDA), as an alternate therapyfor patients with high inhibitor titers in whom immune tolerance pro-grams have failed. Some centers first begin with prednisone with orwithout cyclophosphamide; others add cyclosporine if there is a poorresponse. If desensitization fails, bleeding episodes are treated witheither recombinant factor VIIa or activated prothrombin complex con-centrates (factor VIII inhibitor bypassing activity). Te use of theseproducts bypasses the inhibitor in many instances but may increase therisk of thrombosis. Some patients with low titers of inhibitor can betreated with high-dose factor VIII during a bleeding episode. Patientswith inhibitors require referral to a center that cares for many suchpatients and has a comprehensive hemophilia program.

In the past, plasma-derived treatment products transmitted hepatitisB and C as well as HIV to large numbers of patients with hemophilia.In the era of recombinant products, the risk of acquiring such infec-tions should be minimal, but patients should receive appropriateimmunizations against hepatitis B. Tose who are exposed to bloodproducts should be monitored for transfusion-related infections.Reports have also identified the transmission of variant Creutzfeldt-Jakob disease to patients receiving therapeutic plasma and may warrantstudy of patients with hemophilia for prion transmission from plasma-derived factor concentrates.

COMPREHENSIVE CAREPatients with hemophilia are best managed through comprehensive

hemophilia care centers. Such centers are dedicated to patient andfamily education as well as to the prevention and/or treatment of thecomplications of hemophilia, including chronic joint disease andinhibitor development as well as infection, such as hepatitis B and Cor HIV. Such centers involve a team of physicians, nurses, orthopedists,physical therapists, and psychosocial workers, among others. Educa-tion remains crucial in hemophilia care, because patients who arereceiving prophylaxis may be less “experienced” in recognizing bleed-ing episodes than affected children from previous eras.


476.2 Factor XI Deficiency (Hemophilia C)

J. Paul Scott

Factor XI deficiency is an autosomal deficiency associated with mildto moderate bleeding symptoms. It is frequently encountered in Ash-kenazi Jews but has been found in many other ethnic groups. In Israel,1-3/1,000 individuals are homozygous for this deficiency.

Te bleeding tendency is not as severe as in factor VIII or factor IXdeficiency. Te bleeding associated with factor XI deficiency is notcorrelated with the amount of factor XI. Some patients with severedeficiency may have minimal or no symptoms at the time of majorsurgery. Because factor XI augments thrombin generation and leadsto activation of the fibrinolytic inhibitor thrombin-activatable fibrino-lysis inhibitor, surgical bleeding is more prominent in sites of highfibrinolytic activity like the oral cavity. Unless the patient previouslyhad surgery without bleeding, replacement therapy should be con-

sidered and given preoperatively, depending on the nature of the sur-gical procedure. No approved concentrate of factor XI is available inthe United States; therefore, the physician must use fresh-frozenplasma (FFP).

Bleeding during minor surgery can be controlled with local pressure.Patients undergoing dental extractions can be monitored closely andmay benefit from treatment with fibrinolytic inhibitors like aminoca-proic acid, with plasma replacement therapy used only if hemorrhageoccurs. In a patient with homozygous deficiency of factor XI, P isoen longer than it is in patients with either severe factor VIII or factorIX deficiency. Te paradox of fewer clinical symptoms in combinationwith longer P is surprising, but it occurs because factor VIIa canactivate factor IX in vivo. Te deficiency of factor XI can be confirmedby specific factor XI assays. Plasma infusions of 1 IU/kg usually



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Chapter 476 ◆ Hereditary Clotting Factor Deficiencies (Bleeding Disorders) 2388.e

BibliographyBerntorp E, Halimeh S, Gringeri A, et al: Management of bleeding disorders in

children, Haemophilia 18(Suppl 2):15–23, 2012.Berntorp E, Shapiro AD: Modern haemophilia care, Lancet 379:1447–1454,

2012.Branchford BR, Monahan PE, Di Paola J: New developments in the treatment of

pediatric hemophilia and bleeding disorders, Curr Opin Pediatr 25:23–30,2013.

Broderick CR, Herbert RD, Latimer J, et al: Association between physical activityand risk of bleeding in children with hemophilia, JAMA 308:1452–1458, 2012.

Coppola A, agliaferri A, Di Capua M, et al: Prophylaxis in children withhemophilia: evidence-based achievements, old and new challenges, Seminromb Hemost 38(1):79–94, 2012.

DiMichele DM: Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication, Pediatr Blood Cancer 60(Suppl 1):S30–S33, 2013.

Fijnvandraat K, Cnossen MH, Leebeck FWG, et al: Diagnosis and management ofhaemophilia, BMJ 344:36–40, 2012.

Gouw SC, van der Bom JG, Ljung R, et al: Factor VIII products and inhibitordevelopment in severe hemophilia A, N Engl J Med 368:231–238, 2013.

Hay CRM, Brown S, Collins PW, et al: Te diagnosis and management of factorVII and IX inhibitors: a guideline from the United Kingdom haemophilia centredoctors organization, Br J Haematol 133:591–605, 2006.

Kruse-Jarres R: Current controversies in the formation and treatment ofalloantibodies to factor VIII in congenital hemophilia A, Hematology 407–412,2011.

Kulkarni R, Soucie JM, Lusher J, et al: Site of initial bleeding episodes, mode ofdelivery and age of diagnosis in babies with haemophilia diagnosed before theage of 2 years: a report from Te Centers for Disease Control and Prevention’s

(CDC) Universal Data Collection (UDC) project, Haemophilia 15:1281–12902009.

Leissinger C, Gringeri A, Antmen B, et al: Anti-inhibitor coagulant complexprophylaxis in hemophilia with inhibitors, N Engl J Med 365:1684–1692,2011.

Ljung R: Hemophilia and prophylaxis, Pediatr Blood Cancer 60(Suppl 1):S23–S262013.

Ljung RC, Knobe K: How to manage invasive procedures in children withhaemophilia, Br J Haematol 157(5):519–528, 2012.

Manco-Johnson MJ, Abshire C, Shapiro AD, et al: Prophylaxis versus episodictreatment to prevent joint disease in boys with severe hemophilia, N Engl J M357:535–544, 2007.

Manco-Johnson MJ: Collision sports and risk of bleeding in children withhemophilia, JAMA 308:1480–1481, 2012.

Montgomery RR, Cox Gill J, Di Paola J: Hemophilia and von Willebrand diseaseIn Orkin SH, Nathan DG, Ginsberg D, et al, editors: Nathan and Oski’shematology of infancy and childhood , ed 7, Philadelphia, 2009, SaundersElsevier, pp 1487–1524.

Nathwani AC, uddenham EGD, Rangarajan S, et al: Adenovirus-associated viru vector-mediated gene transfer in hemophilia B, N Engl J Med 365:2357–2365,2011.

Ross C, Goldenberg NA, Hund D, et al: Athletic participation in severehemophilia: bleeding and joint outcomes in children on prophylaxis, Pediatri124:1267–1272, 2009.

Witmer CM, Huang YS, Lynch K, et al: Off-label recombinant factor VIIa use anthrombosis in children: a multi-center cohort study, J Pediatr 158:820–825,2011.

Zimmerman B, Valentino LA: Hemophilia: in review, Pediatr Rev 34:289–294,2011.



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2388.e2 Chapter 476 ◆ Hereditary Clotting Factor Deficiencies (Bleeding Disorders)

BibliographyNathwani AC, Reiss UM, uddenham EGD, et al: Long-term safety and efficacy of

factor IX gene therapy in hemophilia B, N Engl J Med 371:1994–2004, 2014.Seligsohn U: Factor XI in haemostasis and thrombosis: past, present and future,

romb Haemost 98:84–89, 2007.



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BibliographyMariani G, Dolce A, Batorova A, et al: Recombinant, activated factor VII for

surgery in factor VII deficiency: a prospective evaluation-the surgical SER, Br J Haematol 152(3):340–346, 2011.



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Chapter 476 ◆ Hereditary Clotting Factor Deficiencies (Bleeding Disorders) 238

able fibrinogen level is diagnostic. In addition to the quantitative deciency of fibrinogen, a number of dysfunctional fibrinogens have bereported (dysfibrinogenemia). Rarely patients with dysfibrinogeemia present with thrombosis. A human fibrinogen concentratecommercially available for therapy of bleeding episodes in afibrinogeemic patients. Because the plasma half-life of fibrinogen is 2-4 daytreatment with either FFP or cryoprecipitate is also effective. Themostatic level of fibrinogen is >60 mg/dL. Each bag of cryopreciptate contains 100-150 mg of fibrinogen. Some clinical assays for fibrogen are inhibited by high doses of heparin. Tus, a markedly prolongthrombin time associated with a low fibrinogen level should be evalated with determination of reptilase time. Prolonged reptilase timconfirms that functional levels of fibrinogen are low and that heparis not present.

476.10 Factor XIII Deficiency(Fibrin-Stabilizing Factor orTransglutaminase Deficiency)J. Paul Scott

Because factor XIII is responsible for the crosslinking of fibrin stabilize the fibrin clot, symptoms of delayed hemorrhage are secon

ary to instability of the clot. ypically, patients have trauma 1 day anthen have a bruise or hematoma the next day. Clinical symptominclude mild bruising, delayed separation of the umbilical stumbeyond 4 wk in neonates, poor wound healing, and recurrent spotaneous abortions in women. Rare kindreds with XIII deficiency whemarthroses and intracranial hemorrhage have been describeResults of the usual screening tests for hemostasis are normal patients with factor XIII deficiency. Screening tests for factor Xdeficiency are based on the observation that there is increased solubity of the clot because of the failure of crosslinking. Te normal clremains insoluble in the presence of 5M urea, whereas in a patiewith XIII deficiency, the clot dissolves. More specific assays for factXIII are immunologic. Te half-life of factor XIII is 5-7 days and themostatic level is 2-3% activity. Tere is a heat-treated, lyophilizconcentrate of coagulation factor XIII available to treat bleeding ep

sodes or for prophylaxis.


476.11 Antiplasmin or PlasminogenActivator Inhibitor DeficiencyJ. Paul Scott

Deficiency of either antiplasmin or plasminogen activator inhibitboth of which are antifibrinolytic proteins, results in increased plasmgeneration and premature lysis of fibrin clots. Affected patients haa mild bleeding disorder characterized by mucocutaneous bleedibut rarely have joint hemorrhages. Because results of the usual hem

static tests are normal, further work-up of a patient with a positibleeding history should include euglobulin clot lysis time (if availablwhich measures fibrinolytic activity and yields a shortened result the presence of these deficiencies. Specific assays for α2-antiplasmand plasminogen activator inhibitor are available. Bleeding episodare treated with FFP; bleeding in the oral cavity may respond to amnocaproic acid.


476.6 Prothrombin (Factor II) DeficiencyJ. Paul Scott

Prothrombin deficiency is caused either by a markedly reduced pro-thrombin level (hypoprothrombinemia) or by functionally abnormalprothrombin (dysprothrombinemia). Laboratory testing in homozy-gous patients shows prolonged P and P. Factor II, or prothrombin,assays show a markedly reduced prothrombin level. Mucocutaneousbleeding in infancy and posttraumatic bleeding later are common.Patients are treated with either FFP or, rarely, prothrombin complexconcentrates. In prothrombin deficiency, FFP is useful, because thehalf-life of prothrombin is 3.5 days. Administration of 1 IU/kg of pro-thrombin will increase the plasma activity by 1%.


476.7 Factor V DeficiencyJ. Paul Scott

Deficiency of factor V is an autosomal recessive, mild to moderatebleeding disorder that has also been termed parahemophilia. Hem-arthroses occur rarely; mucocutaneous bleeding and hematomas

are the most common symptoms. Severe menorrhagia is a frequentsymptom in women. Laboratory evaluation shows prolonged Pand P. Specific assays for factor V show a reduction in factor Vlevels. FFP is the only currently available therapeutic product thatcontains factor V. Factor V is lost rapidly from stored FFP. Patientswith severe factor V deficiency are treated with infusions of FFP at10 mL/kg every 12 hr. Rarely, a patient with a negative family historyof bleeding has an acquired antibody to factor V. Oen, such a patientdoes not bleed because the factor V in platelets prevents excessivebleeding.


476.8 Combined Deficiencyof Factors V and VIIIJ. Paul Scott

Combined deficiency of factors V and VIII occurs secondary to theabsence of an intracellular transport protein that is responsible fortransporting factors V and VIII from the endoplasmic reticulum to theGolgi compartments. Tis explains the paradoxical deficiency of 2factors, one encoded on chromosome 1 and the other on the X chro-mosome. Bleeding symptoms are oen milder than for hemophilia Aand are treated with FFP to replace both factors V and VIII.

476.9 Fibrinogen (Factor I) Deficiency

J. Paul Scott

Congenital afibrinogenemia is a rare autosomal recessive disorder inwhich there is an absence of fibrinogen. Patients with this disorder donot bleed as frequently as patients with hemophilia and rarely havehemarthroses. Affected patients may present in the neonatal periodwith gastrointestinal hemorrhage or hematomas aer vaginal delivery.In addition to marked prolongation of P and P, thrombin time isprolonged. In the absence of consumptive coagulopathy, an unmeasur-



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BibliographyLancellotti S, De Cristofaro R: Congenital prothrombin deficiency, Semin romb

Hemost 35:367–381, 2009.



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BibliographyAsselta R, Peyvandi F: Factor V deficiency, Semin romb Hemost 35:382–389,

2009.



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BibliographyDreyfus M, Barrois D, Borg JY, et al: Successful long-term replacement therapy

with FXIII concentrate (Fibrogammin(®)P) for severe congenital factor XIIIdeficiency: a prospective multicentre study, J romb Haemost 9(6):1264–1266,2011.

Greenberg CS, Sane DC, Lai S: Factor XIII and fibrin stabilization. In ColmanRW, Marder VJ, Clowes AW, et al, editors: Hemostasis and thrombosis: basic

principles and clinical practice, ed 5, Philadelphia, 2006, Lippincott Williams &Wilkins, pp 317–334.



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BibliographyAgren A, Wiman B, Schulman S: Laboratory evidence of hyperfibrinolysis in

association with low plasminogen activator inhibitor type 1 activity, BloodCoagul Fibrinolysis 18:657–660, 2007.

Bauer KA: Rare coagulation factor abnormalities. In Orkin SH, Nathan DG,Ginsberg D, et al, editors: Nathan and Oski’s hematology of infancy andchildhood , ed 7, Philadelphia, 2009, Saunders Elsevier, pp 1525–1532.

Carpenter SL, Mathew P: Alpha2-antiplasmin and its deficiency: fibrinolysis out ofbalance, Haemophilia 14:1250–1254, 2008.

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