This can remove the uncertainty from .... spread within fascial spaces and dissect deeper structures. Bleeding into the ...... (ELFA) method using Biomerux kit.
SPECTRUM OF HEREDITARY BLEEDING DISORDERS IN BASRAH A thesis Submitted to the Iraqi Council for Medical Specializations in Partial fulfillment of the Requirements for the Degree of Fellowship Of the Iraqi Commission for Medical Specialization in Pediatrics
BY Dr.Ahmed Ja`afer Hindy M.B.Ch.B.
Supervised by Dr.Mea`ad Kadhum Hassan C.A.B.P. Professor Department of pediatrics College of Medicine University of Basrah March 2011
بسم الله الرحمن الرحيم ((سنريهم آياتنا في اآلفاق وفي أنفسهم حتى يتبين لهم أنه الحك أولم يكف بربك أنه على كل شئٍ شهيد)) صدق الله العظيم
Certificate I certify that this thesis was prepared under my supervision at the Scientific Council of Pediatrics in partial fulfillment of the requirements for the degree of fellowship of the Iraqi Commission for Medical Specialization of Pediatrics.
Supervisor Dr.Mea`ad Kadhum Hassan C.A.B.P. Professor
Department of Pediatrics College of Medicine University of Basrah
We, the examining committee, after reading this thesis and examining the candidate Dr.Ahmed Ja`afer Hindy , in its content, find that it meets the standards and requirements as a thesis in partial fulfillment for the degree of the Iraqi Council for Medical Specialization in Pediatrics.
Assistant professor Dr.Jinan G. Hasan C.A.B.P (Chief)
Assistant professor Dr.Aida A. Manthar C.A.B.P (Member)
Assistant professor Dr.Sawsan E. Habeeb F.I.C.M.S (Member)
I, the chairman of the Scientific Council of Pediatrics certify that this thesis was prepared by the candidate Dr. Ahmed Ja`afer Hindy and submitted to our Council.
Professor Dr. Mahjoob Al.Naddawi M.R.C.P. (UK), F.R.C.P. (London), F.R.C. (E.)FRCPCH
Chairman of the Scientific Council of Pediatrics
Approved by the Iraqi Council for Medical Specializations
Professor Dr. Zakaria Y. Al-Arajy F.R.C.S President of the Iraqi Board For Medical Specializations
Dedication To whom I’m living for ….. My kind parents My faithful wife My lovely children My brothers and sisters I dedicate this simple work with best regards.
Acknowledgment I would like to express my great thanks to Dr.Mea 'ad Kadhum for her sound supervision, patience and guidance throughout the execution of this study; to her I am so in debt. I would like to thank Dr.Sadeq Khalif Ali, Hematologist, and Khalid Hassan, laboratory assistants, for their great help in the laboratory investigations. I would like to thank Dr.Assad Yehia, Professor of animal breeding for his great help in statistical analysis of data. To them I'm so grateful.
I
List of contents
List of Contents Subject
Page
Acknowledgment
I
List of contents
II
List of abbreviations
V
List of tables
VII
List of figures
VIII
Abstract
IX Chapter One
1.Introduction
1
1.1 Hemophilia A and B
2
1.1.1 Epidemiology
2
1.1.2 Classification
2
1.1.3 Genetics
3
1.1.4 Clinical features
3
1.1.5 Laboratory findings and diagnosis
6
1. 1.6 Tests to detect carriers of hemophilia A or B
7
1.1.7 Prenatal diagnosis
7
1.1.8 Therapy
7
1.1.8.1 General principles
8
1.1.8.2 Factor replacement therapy
8
1.1.8.3 Adjuvant therapy
9
1.1.8.4 Prophylaxis
10 II
List of contents
1.1.9 Chronic complications
11
1.1.9.1 Chronic arthropathy
11
1.1.9.2 Inhibitors
11
1.1.9.3 Transfusion transmitted infectious diseases
13
1.1.10 Liver transplantation & gene therapy
13
1.2 Rare congenital hemorrhagic disorders
14
1.2.1 Fibrinogen deficiency
14
1.2.2 Dysfibrinogenemia
14
1.2.3 Factor XIII deficiency
15
1.2.4 Prothrombin deficiency
15
1.2.5 Factor V deficiency (parahemophilia)
16
1.2.6 Factor VII deficiency
16
1.2.7 Factor X deficiency
17
1.2.8 Factor XI deficiency (hemophilia C)
17
1.2.9 Factor XII , prekallikrein and high-molecular weight kininogen deficiency (contact factor) 1.3 Von Willebrand disease
18 18
1.3.1 Prevalence
18
1.3.2 Genetics
18
1.3.3 Etiology & pathogenesis
19
1.3.4 Clinical manifestations
19
1.3.5 Laboratory findings
19
1.3.6 Treatment
20
1.4 Hereditary disorders of platelets function
III
21
List of contents
1.4.1 Disorders of platelets adhesion Bernard-Soulier Syndrome (Glycoprotein Ib/IX/V Deficiency) 1.4.2 Disorders of platelets aggregation Glanzmann thrmbasthenia (Glycoprotein IIb-IIIa Deficiency) 1.4.3 Disorders of platelets secretion
21
21 22
1. Disorder of secretion caused by abnormalities of platelets α granules:The Gray Platelet Syndrome (α Granule Deficiency) 2. Disorder of secretion caused by deficiency of platelets dense granules:Dense Granule Deficiency (δ-Storage Pool Disease) 1.5Spectrum of hereditary bleeding tendency in other countries Aim of the study
22
23 24 25
Chapter Two 2. Patients and methods
26
2.1 Patients
26
2.1.1 Data collection
26
2.2 Methods
26
2.2.1 Hematological studies
26
2.2.2 Radiological study
29
2.2.3 Statistical analysis:
30 Chapter Three
3. Results
31 Chapter Four
4.1 Discussion
46
4.2 Conclusions
52 IV
List of contents
4.3 Recommendations
53
4.4 References
54 Appendix(I) الخالصة
V
List of abbreviations
List of abbreviations HA
Hemophilia A
HB
Hemophilia B
F II
Factor two
FV
Factor five
F VII
Factor seven
F VIII
Factor eight
F IX
Factor nine
FX
Factor ten
F XI
Factor eleven
F XII
Factor twelve
F XIII
Factor thirteen
VWD
Von willebrand disease
APTT
Activated partial thromboplastin time
PT
Prothrombin time
DDAVP
Desamino-8-D-arginine vasopressin
PCC
Prothrombin complex concentrate
CPP
Cryoprecipitate
FFP
Fresh frozen plasma
HIV
Human immune virus
HBV
Hepatitis B virus
HCV
Hepatitis C virus
GPI b
Glycoprotein 1 b
GP II b/ III a
Glycoprotein 2 b/3 a
V
List of abbreviations
DIC
Disseminated intravascular coagulopathy
WBC
White blood cells
Hb
Hemoglobin
BU
Betheseda unit
EDTA
Ethylenediaminetetraacetic acid
CHBD
Center of hereditary blood disease
VI
List of tables
List of Tables Title
Page
Table 1-1 Scoring System for Hemophilic Arthropathy b y Magnetic Resonance Imaging
5
Table 1-2 Risk Factors for Inhibitor Formation
12
Table 2-1 Laboratory Evaluation of Abnormalities of Coagulation Protein: aPTT and PT Screening Tests.
28
Table 3-1 Frequency of bleeding disorders registered at CHBD
30
Table 3-2 Age at first Presentation
31
Table 3-3 Age at diagnosis
32
Table 3-4Age at presentation and Age at diagnosis of HA, HB and VWD
33
Table 3-5. Site of bleeding at first Presentation of HA, HB and VWD.
34
Table 3-6. Family history of bleeding disorders
35
Table 3-7 Severity of hemophilia A and B
36
Table 3-8 Age of first presentation and severity of hemophilia A and B
37
VII
List of tables
Table 3-9. Frequency of Inhibitors among patients with hemophilia A and B
38
Table 3-10. Distribution of hemophilic cases with positive inhibitors according to type, severity and family history of inhibitors.
38
Table 3-11. Hepatitis C antibody positivity among patients with different types of bleeding disorders
40
Table 3-12 Distribution of hemophilics with positive HCV antibodies
41
Table 3-13 Hemophilic arthropathy in patients with hemophilia A and B
42
Table 3-14 Joints involved in hemophilic arthropathy
42
Table 3-15 Bleeding complications and hospitalizations during the study period
44
List of Figures Title
page
Figure2-1 various radiological stages of hemophilic arthropathy.
29
VIII
Abstract A descriptive study had been carried out on patients with hereditary bleeding disorders who registered in the Center for Hereditary Blood Diseases in Basrah over ten months (from the first of February till the end of October 2010). The study designed to look for the frequency and the pattern of hereditary bleeding tendency in Basrah, to assess the severity and to look for complications of these bleeding disorders. A total of (132) patients, their ages ranged from 1month-64 years were included in the study. The study showed that 69(52%) of registered patients have hemophilia A, followed by von Willebrand in 25 (18.93%) patients, then hemophilia B in 9 (6.8%). The age of presentation of most of bleeding disorders is bteween1-12months, while the age of diagnosis was delayed for most of bleeding disorders; the mean delay in diagnosis was 4.8±14.4 months in hemophilia A, 6.15±0.27 months in hemophilia B, 13.76±2.7 months for von Willebrand disease. Sixty (58.2%) patients with hemophilia A, hemophilia B and von Willebrand disease presented for the first time with skin bleeding followed by bleeding from circumcision site in 24(23.3%) of patients with hemophilia A and B, and mucous membrane bleeding in 15(14.5%) of patients with hemophilia A, hemophilia B and von Willebrand disease . Family history of bleeding disorders was reported in two thirds of hemophilia A and B and (56%) of patients with von Willebrand disease.
Concerning disease severity, 33(42.3%) of patients hemophilia A and B have severe disease followed by 26(33.33%) patients with moderate disease and only 19(24.36%) patients have mild disease. Inhibitors were detected in 21(29%) patients with hemophilia A and B; half of them have high inhibitors titer, P-value >0.05. Eight of patients with hemophilia (A and B) were positive for hepatitis C virus antibodies which represent (8%) of 101 screened patients. Twenty- eight (36%) hemophilic patients have hemophilic arthropathy, with (24%) of them are classified to have stage II & III arthropathy according to the Arnold-Hilgartner scale. The knee joints are among the most affected joints. Hemarthrosis in hemophilia A followed by epistaxis and gum bleeding were the most common causes of hospitalization during the study period. From this study it can be concluded that hemophilia A is the most common familial bleeding disorders, followed by von Willebrand disease then hemophilia B. Chronic complications resulted from hemophilic arthropathy, inhibitors and hepatitis C virus in hemophilia A and B are common and important life threatening factor to be prevented or looked for as early as possible and mange properly.
Chapter One Introduction Aims of the study
Chapter One
Introduction
1. Introduction The existence of lifelong bleeding disorders and their familial occurrence was noted in the medical literature as early as the sixteenth
century. (1)
Historically, hemophilia has been recognized as an entity since Biblical times .The term hemophilia has been ascribed to Schonlein in the 1820, s. The prolonged clotting time of hemophilic blood was first noted in 1893. The decreased factor VIII in association with hemophilia A was first discovered in 1947 while the decrease in factor IX in Christmas disease was discovered in 1952
(2)
Hereditary deficiencies of each of the coagulation factors have been described. Hemophilia A (factor VIII deficiency), hemophilia B (Christmas disease , factor IX
deficiency)
and
von
Willebrand
disease
(VWD)
are
the
most
common.(3)Inherited disorders of blood coagulation are due to the lack of synthesis or to the synthesis of a dysfunctional molecule . Many of the coagulation proteins have been cloned and their amino acid sequences are known. (4)As a consequence, these disorders provide a unique opportunity to study the phenomena of blood coagulation. If von Willebrand disease (VWD) is included, the inherited coagulation abnormalities are common; for example, VWD may affect up to 1% of the population. The other inherited coagulation disorders affect at most 1 in 10,000 to 15,000 persons.(5) Advances in protein chemistry and recombinant DNA technology have now produced a comprehensive account both of normal coagulation and of the molecular genetics of hemophilia. Direct identification of the mutation responsible for the factor deficiency in individual kindred has now superseded the use of restriction fragment length polymorphisms (RFLPs). This can remove the uncertainty from carrier detection in many cases. The methodology for these analyses is now a crucial part of hemophilia care. (1)
1
Chapter One
Introduction
1.1 Hemophilia A and B 1.1.1 Epidemiology Hemophilia A is four to six times more common than hemophilia B, and mutations that cause hemophilia occur throughout the genes for factor VIII and factor IX. The annual incidence of hemophilia A has been estimated at approximately 1: 5000 male births, the incidence of hemophilia B is estimated at approximately 1: 30,000 male births. (6) The inheritance is sex-linked, but 30–40% of patients are without a positive family history, thus in these cases, the presence of the factor VIII gene is likely the result of spontaneous mutation.
(4)
The disorder
seems to be rare among Chinese, and the early literature indicated that hemophilia A was uncommon in Africans. (5) Hemophilic females are exceedingly rare because the 50% factor levels typical of carriers protect against bleeding so that most carriers are asymptomatic. (6) 1.1.2Classification The Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis recommended revised criteria for the classification of hemophilia based on biological F VIII and FIX levels as follows: (7) • Severe hemophilia: F VIII/FIX concentration < 0.01 IU/mL ( 0.5 IU/mL). Rarely, females who are carriers of hemophilia mutations may have levels as low as affected males within the family due to non random inactivation of the X chromosome, inheritance of a mutated FVIII gene from both maternal and paternal chromosomes, and Turner syndrome.
(7)
No evidence or
history of abnormal bleeding is found in other members of the families of at least one third of all hemophiliacs, In other instances, neonatal deaths or the passage of the trait through a succession of female carriers may explain the negative family history. Mutations that cause hemophilia A originate in males at least three-folds more often than in females. (5) 1.1.4 Clinical features The clinical manifestations of both hemophilia A and B are similar, depending on the concentration of the deficient clotting factor.
(7)
Factor VIII deficiency is
characterized by a lifelong tendency toward serious and often life-threatening hemorrhage. Whereas surface bleeding and purpura can occur, deep soft tissue bleeding and hemarthrosis are the hallmarks of the disease. (9) Neither factor VIII nor factor IX crosses the placenta; bleeding symptoms may be present from birth or may occur in the fetus. Only approximately 2% of neonates with hemophilia sustain intracranial hemorrhages and 30% of male infants with hemophilia bleed with circumcision (10). Excess bleeding is relatively uncommon at birth. The first bleeding problems usually start when a child starts crawling, and this may be from 9 mo to 1 yr of age. Bleeding, however, can occur after surgery, i.e., circumcision. 3
Chapter One
Introduction
The first signs that parents may notice are large skin bruises.(4) The first manifestations of disease in mild hemophilia may be seen at age 2 to 5 years. Severe hemophilia most often manifests as easy bruising. Mild to moderate disease more often is associated with bleeding after trauma or dental procedures .Spontaneous hemarthroses occur in individuals with severe disease but are rare before age 9 months, when weight bearing and walking begin. (6) Because of a lack of factor VIII or factor IX, a delay occurs in the generation of thrombin, which is crucial to forming a normal, functional fibrin clot and solidifying the platelet plug that has formed in areas of vascular injury. (11) The hallmark of hemophilia is bleeding into joints (hemarthrosis), which is painful and leads to chronic inflammation and joint destruction similar to those seen in rheumatoid arthritis. Abnormal bleeding originates from the subsynovial venous plexus underlying the joint capsule, where a lack of thromboplastic activity has been demonstrated. The high degree of factor Xa inhibitory activity conveyed by the tissue factor pathway inhibitor synthesized by human synovial cells also may predispose hemophilic joints to bleeding, which may explain the impressive hemostatic response after intravenous administration of recombinant factor VIIa for acute hemarthroses in patients with factor VIII inhibitors.
(6)
Children begin to
develop hemarthroses at a mean age of 2 years, it may follow minor trauma or may be spontaneous. The large joints, ankles, knees, and elbows are most frequently affected, and many children have one or two joints that are repeatedly affected. Early signs of joint bleeding include pain and tingling, abnormalities in gait and weight-bearing, and limitation of movement. Visible swelling and warmth are signs of late and severe hemarthrosis. After multiple episodes of bleeding into a single joint, hemosiderin deposition with synovial hyperplasia and bony overgrowth may occur. If recurrent bleeding is not prevented or arrested quickly, damage to cartilage, bone demineralization, cyst formation, erosion and narrowing of the joint surface, and degenerative arthritis may ensue. 4
(12)
Standard scoring
Chapter One
Introduction
systems for hemophilic arthropathy, including the Arnold-Hilgartner scale, which measures single joint pathology, and the Pettersson score, which measures multiple joint pathology radiologically, now are used together with MRI, which provides earlier detection of synovial hypertrophy than possible by physical examination or radiography. (6) Table 1-1 Scoring System for Hemophilic Arthropathy by Magnetic Resonance Imaging Score O I II III IV
(5)
Abnormalities on Imaging None Minimal hemosiderin Large amount of hemosiderin and cartilaginous erosion Cartilage destruction, bone erosion, subchondral cysts Osteoarthritis with or without ankylosis
As a result of the vicious circle of bleeding and synovial hypertrophy, a particular joint tends to become the ‗target joint‘ in an individual, whereas other joints may be relatively spared. (1) Hematemesis, melena, or both are not uncommon. The source of the blood is usually the upper gastrointestinal tract. Intramural bleeding into the intestinal wall may result in intussusception or obstruction. Hematuria, although more common than gastrointestinal bleeding, is less often the result of a demonstrable pathologic condition in the genitourinary tract.(5)Large ecchymoses and subcutaneous and intramuscular hematomas are common in hemophilia A and characteristically spread within fascial spaces and dissect deeper structures. Bleeding into the tongue, throat, or neck may develop spontaneously and is especially dangerous because it may compromise the airway with surprising rapidity. Peripheral nerve lesions of varying severity are common complications of hemorrhage into joints or muscles, as in femoral nerve compression caused by hematomas of the iliacus. Bleeding into or around the iliopsoas muscle produces femoral nerve involvement may be partial or complete, with the development of pain on the anterior surface of 5
Chapter One
Introduction
(5)
Pseudotumors are blood cysts that occur in soft tissues or bone. They
the thigh.
are rare but dangerous complications of hemophilia. Most pseudotumors are not associated with pain unless rapid growth or nerve compression occurs. Pseudotumors develop primarily in the lower half of the body, usually in the thigh, buttock, or pelvis, but they can occur anywhere, including the temporal bone. The small bones of the hands or feet are frequently affected in younger patients. (13) 1.1.5 Laboratory findings and diagnosis Patients with severe hemophilia A and B characteristically have a prolonged activated partial thromboplastin time (aPTT). The prothrombin time (PT), thrombin clotting time, and bleeding time (BT) are normal. In mild hemophilia, the aPTT may be only slightly prolonged or at the upper limit of normal, especially if factor VIII activity is 20 percent or greater of normal. (13)
Specific assays show factor VIII clotting activity below 50 U/dL,with all other
factors normal, and also normal von Willebrand factor (VWF) antigen and ristocetin cofactor. (1) Unless the patient has an inhibitor to factor VIII or IX, the mixing of normal plasma with patient plasma results in correction of PTT. The specific assay for factors VIII and IX will confirm the diagnosis of hemophilia. If correction does not occur on mixing, an inhibitor may be present. In 25–35% of patients with hemophilia who receive infusions of factor VIII or factor IX, a factor-specific antibody may develop. These antibodies are directed against the active clotting site and are termed inhibitors. In such patients, the quantitative Bethesda assay for inhibitors should be performed to measure the antibody titer. (10) Caution should be used in making a diagnosis of moderate or mild hemophilia B in the neonatal period because normal levels of factor IX in full-term infants are not reached until 6–9 mo. Factor VIII levels, on the other hand, are in the normal adult range by 28
6
Chapter One
Introduction
wk of gestation. Thus all forms of hemophila are distinguishable by assay in both premature and full-term infants. (4) 1.1.6 Tests to detect carriers of hemophilia A or B Accurate detection of carriers of hemophilia A or B in a family is required for genetic counseling and prenatal diagnosis. A detailed family history is essential. All of the female children of a father with hemophilia will be obligate carriers. The same is true for the mother of more than one hemophiliac son. These individuals do not need to be tested for carrier status. On the other hand, sisters of a hemophilia patient have a 50/50 chance of carrying the abnormal gene. Carrier status for hemophilia A may be identified by measuring the ratio of factor VIII activity to vWF antigen; a 1:1 stoichiometry normally exists between these. Because of the random (Lyonization) inactivation of the X chromosome, female carriers may express from 1% to 100% factor VIII activity, whereas the vWF antigen level is unaffected. Thus, a factor VIII/vWF ratio of less than 1 can identify > 90% of hemophilia A carriers. Identification of hemophlia B carriers is generally based on the detection of abnormally low factor IX activity or by DNA analysis.
(14)
Levels of these factors should be determined in all known carriers to
assess the need for treatment in the event of surgery or clinical bleeding.
(10)
Carriers are now better detected with DNA probes. (3) 1.1.7 Prenatal diagnosis Chorionic biopsies at 8-10 weeks' gestation provide sufficient fetal DNA for analysis. Antenatal diagnosis is also possible following the demonstration of low levels of factor VIII in fetal blood obtained at 16-20 weeks' gestation from the umbilical vein by ultrasound-guided needle aspiration. (3)
7
Chapter One
Introduction
1.1.8 Therapy 1.1.8.1 General principles After a diagnosis of hemophilia has been established, families should be offered immediate and ongoing education and support to adjust to the diagnosis and begin to form a healthy and realistic view of the wellness of their child. Routine immunizations, including hepatitis A and B, should be given using small-bore needles. Prophylactic dental care is very important to avoid the need for oral surgery later. Physical exercise and fitness must be emphasized early to develop optimal musculoskeletal strength. In school years, full physical education, swimming, bicycling, and hiking are encouraged. Contact sports are not recommended for children with hemophilia. Home infusions, reduce the trauma of repeated emergency room visits and permit a child to accept hemophilia as a manageable disorder. Parents require comprehensive initial education and continuing support to maintain home infusion therapy successfully. (12) General principles applicable to therapy for hemophilia A include avoidance of aspirin, nonsteroidal antiinflammatory drugs, and other agents that interfere with platelet aggregation. In general, intramuscular injections should be avoided unless the patient receives adequate replacement therapy. In the absence of prophylactic therapy, patients with hemophilia A must be treated as early as possible to avoid bleeding complications. (13) 1.1.8.2 Factor replacement therapy The key to treatment of bleeding in hemophilia is replacement of the missing coagulation protein to achieve hemostasis. The dose and choice of product are influenced by the severity of disease, the site and severity of the bleeding, and the clinical scenario. Patient's weight, inhibitor antibody status, and treatment history 8
Chapter One
Introduction
(especially with respect to exposure to bloodborne pathogens) also are important. (6)
When mild to moderate bleeding occurs, levels of factor VIII or factor IX must
be raised to hemostatic levels in the 35–50% range. For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity. Calculation of the dose of recombinant factor VIII (FVIII) or recombinant factor IX (FIX) is as follows(10): Dose of F VIII= % of F VIII (IU) x body weight (kg) x 0.5 Dose of F IX= % of F IX (IU) x body weight (kg) x 1.4 For factor VIII replacement, each unit of factor VIII per kilogram of body weight is assumed to raise the plasma level by 2% (0.02 U/mL). Because factor VIII has a half-life of 8 to 12 hours, repeat dosing at least two or three times daily is required to maintain the desired factor VIII level. Similar calculations can be made for dosing factor IX concentrates .Factor IX half-life of approximately 24 hours.
(6)
Fresh-frozen plasma and cryoprecipitate both contain factor VIII.
Cryoprecipitate, containing approximately 80 U of factor VIII in 10 ml of solution, can be used to attain normal factor VIII levels. Several commercial lyophilized factor VIII concentrates, using cryoprecipitate of pooled normal human plasmas as starting material (2000–20,000 donors), are available and do not have the disadvantages of plasma and cryoprecipitate (13) 1.1.8.3 Adjuvant therapy DDAVP provides an alternative treatment for increasing the factor VIII levels in patients with a mild form of hemophilia A. A residual factor VIII activity (usually >10%) is required to obtain a moderate rise in the patient‘s factor VIII level following
the
intravenous
administration
of
0.3
μg/kg
DDAVP.
Local supportive measures in treating hemarthrosis and hematomas include resting the affected extremity and administration of systemic nonspecific drugs such as 9
Chapter One
Introduction
antifibrinolytic agents (e.g., tranexamic acid), which may be helpful in prevention or treatment of mucocutanous hemorrhage and after dental procedures. (4) 1.1.8.4 Prophylaxis Many patients are now given lifelong prophylaxis to prevent spontaneous joint bleeding. Usually, such programs are initiated with the first joint hemorrhage. Young children often require the insertion of a central catheter to ensure venous access. Such programs, although expensive, are highly effective in preventing or greatly limiting the degree of joint pathology (10). Prophylaxis reduces or prevents acute joint bleeds as well as clinical joint damage and is superior to episodic ondemand treatment. The success of prophylaxis is based on administering factor VIII or factor IX concentrates 25 to 40 U/kg three times weekly for hemophilia A and twice weekly for hemophilia B to achieve factor levels of 1% to 2%, essentially converting a patient with severe disease into one with mild or moderate disease, essentially eliminating spontaneous bleeds. ―Primary prophylaxis‖ (i.e., prophylaxis initiated prior to joint damage and/or recurrent hemarthroses in a target joint) is the preferred ―preventive‖ approach. ―Secondary prophylaxis‖ (i.e., prophylaxis initiated after onset of significant joint damage) may be beneficial in patients reluctant to begin primary prophylaxis. However, it should be recognized that although stabilization of articular function and joint scores may occur over time, reversal of joint damage or radiographic deterioration of previously damaged joints may not be possible. (6) Analysis of the economic impact of prophylactic therapy, weighing the benefits against the high costs of factor VIII concentrates, suggests the clinical benefit of prophylaxis is warranted, as evidenced by significant improvement in the clinical condition of patients and improvement in quality of life.(5)
10
Chapter One
Introduction
1.1.9 Chronic complications Long-term complications of hemophilia A and B include chronic arthropathy, the development of an inhibitor to either factor VIII or factor IX, and the risk of transfusion-transmitted infectious diseases. (10) 1.1.9.1 Chronic arthropathy Daily or alternate-day prophylactic therapy with factor concentrates may prevent or significantly delay progression of hemophilic arthropathy. alternative
approach,
nonoperative
synovectomy
(5)
(―synoviorthesis‖
An or
―radionuclide synovectomy‖), involves injection of a radioisotope (usually phosphorus-32) into the joint space. Orthotics may play an important role in management of joint disease, and orthotic intervention can serve as an interim measure before definitive reconstructive surgery. The goal of orthotic intervention is to transform a subluxed, flexed joint into a functional stiff limb rather than a functional articulation. Pain and deformity that limit mobility, quality of life, and performance status are indications for joint reconstruction. Arthrodesis (surgical fixation) is reserved for painful joints with greatly compromised mobility. (6) 1.1.9.2 Inhibitors Patients with severe hemophilia A and less often hemophilia B can develop antibodies (inhibitors) to infused factors.
(8)
Failure of a bleeding episode to
respond to appropriate replacement therapy is the first sign of an inhibitor.
(10)
A patient with mild disease may convert to a severe phenotype and present with spontaneous bleeding, reminiscent of severe hemophilia, when the inhibitor crossreacts with endogenous factor VIII, reducing the patient's factor VIII activity to less than 1%.(15) Inhibitors develop in approximately 25–35% of patients with hemophilia A; the percentage is somewhat lower in patients with hemophilia B.
(10)
However, many patients have only transient inhibitors, and perhaps only 5 to 10% 11
Chapter One
Introduction
of hemophiliacs have persistent inhibitors. Hemophiliacs with inhibitors can be categorized as either strong or weak responders to administered factor VIII.(16) Based upon the results of the inhibitor assay, a value less than 5 BU is considered a low-titer inhibitor. If the inhibitor titer fails to rise despite repeated challenges with factor, the patient is termed a low responder. In contrast, a patient in whom the inhibitor titer is greater than 5 BU is considered a high responder. (6) Table 1-2 Risk Factors for Inhibitor Formation Established Risk Factors
Possible
Type (hemophilia A > hemophilia B)
Age at first exposure
Severity (severe > mild/moderate)
(6)
Type of factor concentrate (plasma-derived vs recombinant factor VIII)
Underlying mutation (e.g., intron 22)
Method of infusion (continuous vs bolus)
Race (African/Latino > Caucasian)
Prophylaxis vs on-demand
Family history
Laboratory tests disclose a prolonged aPTT, which is not corrected by a 1:1 mixing study with normal plasma. Quantification is done with a Bethesda inhibitor assay (1 Bethesda unit is the amount of antibody in the patient's plasma that permits detection of 50% residual factor activity when mixed with normal plasma). (17)
Many patients who have an inhibitor lose this inhibitor with continued regular
infusions. Others have a higher titer of antibody with subsequent infusions and may need to go through desensitization programs, which uses high doses of factor VIII (100 IU/kg) given twice daily. APCC concentrates are administered based on the bleeding tendency of the patient. This regimen is followed until the inhibitor has disappeared, sometimes as long as3years (Bonn protocol).Other immune tolerance protocols use a low-dose regime has been used with success using lowdose factor VIII infusions, starting at 25 IU/kg every other day, a 16- to 24-fold fewer doses than the other high-dose immune tolerance protocols used. most registries have found that the most consistent predictors of success were (a) beginning immune tolerance therapy when the inhibitor titer is as low as possible 12
Chapter One
Introduction
(ideally
