Haemophilias: Medically Compromised Children in Dentistry

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Haemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken.

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Medically compromised children:

Medically compromised children Haemophilias

Contents:

Introduction Incidence and Prevalance Classifications Haemophilia A Haemophilia B Haemophilia C Von Willebrands disease Dental care Medical management Protocols References Contents

Introduction1:

The inherited disorders of blood coagulation present providers of health and social care with formidable problems. The disorders are eminently treatable, even in their severest form. Untreated, they result in handicaps in early life, while proper treatment is expensive, inadequate treatment is even more so, both to the individual and to the community (Bhattacharya 1987). Introduction 1

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Nearly one third of cases of haemophilia occur with no preceding family history, possibly from new genetic mutation. When recorded family history is available, efforts should be made to identify female carriers. Identification depends on family history, measurement of clotting profile and DNA analysis.

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World Federation of Haemophilia reported haemophilia A prevalence varied considerably among countries, even among the wealthiest of countries. The prevalence (per 100 000 males) High income countries -> 12.8 ± 6.0 (mean ± SD) Rest of the world-> 6.6 ± 4.8

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Haemophilia A and B are X-linked recessive disorders that occur almost exclusively in males. About 30 percent of the mutations arise de novo. Factor VIII gene is very large, about 186kb, with about 9kb of exons . It contains 26 exons and 25 intervening sequences or introns . * Intron : Sequences that are joined together in the final mature RNA * Exon  is any nucleotide sequence encoded by a  gene  that remains present within the final mature RNA product

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The size and complexity of the gene have made it difficult to pinpoint, on a routine basis, specific mutations that result in haemophilia. However, the factor VIII gene has now been cloned and sequenced and numerous specific mutations have been described . ( Williams 2001; Jayandharan et al. 2003).

Haemophilia A2:

Haemophilia A 2 Classic hemophilia Def’ of Fac VIII 80% of Hemophilia Inherited X-linked recessive trait Males affected; Females Carriers No male to male transmission

Reported haemophilia A prevalence (per 100 000 males) Mean: 98-’06 :

In US, 2006 reported prevalence -> 8.0 /100 000 males In UK, 2006 reported prevalence -> 20.7 / 100 000 Highest affected Iceland-> 38 % (mean) UK-> 19 % Croatia-> 18 % Ireland -> 16 % Reported haemophilia A prevalence (per 100 000 males) Mean: 98-’06

Reported haemophilia A prevalence (per 100 000 males) : India:

2003:0.5 2004: 0.9 2005: 1.6 2007: 1.7 Mean: 1.1 Reported haemophilia A prevalence (per 100 000 males) : India

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Pattern of inheritance

Hemophilic M + Normal F :

Hemophilic M + Normal F Males: Normal; Females: Carriers

Hemophilia B2:

Hemophilia B 2 Also known as Christmas Disease Named after the first pt Stephen Christmas Seen in 15 % Hemophiliacs, Def’ of Fac IX ( Plasma Thromboplastin component) X-Linked Recessive trait *First article on it was published in Brit Med J in Christmas edition

Why autosomal recessive:

Both these disorders are inherited as sex linked recessive. Isolated deficiencies of other clotting factors are less common because they are usually inherited in autosomal recessive manner and this requires both parents to carry the abnormal gene. Why autosomal recessive

Hemophilia C3:

Hemophilia C 3 Rosenthal Disease,Def ’ of Fac IX ( Plasma Thromboplastin antecedent, Autosomal recessive trait Males and Female equally affected, Ashkenazi Jewish Descent Other factor deficiencies Fac II, V, XIII (one per one million) Fac VII ( one per five lakh )

Classification of hemophilia5:

Classification of hemophilia 5

Pro-coagulant classification2:

Severe deficiency : Levels less than 1% Moderate deficiency : Levels between 1%-5% Mild deficiency: Levels </= 5% or less than 55% Pro-coagulant classification 2

Bleeding episodes: Severe:

Two - four times / month Bleeding episodes: Spontaneous cout H/o Trauma/Injury Common sites: Joints , muscles, Skin Hemarthoses are common with symptoms of Pain, Stiffness and limited motion Repeated episodes  Chronic musculoskeletal disease culminate in Debilitating painful arthritis Commonly affected joints: Knees, elboes , ankles, hips & shoulders Pseudotumors occur in sev ’ locations including jaw, where curretage is indicated Bleeding episodes: Severe

Bleeding episodes: Moderate:

4-6 times bleeding / year Target joint develops  Spontaneous bleeding might occur Bleeding episodes: Mild Diagnosed during presurgical evaluation Dentist  May be 1 st to identify & unmask a previously undiagnosed individual. Bleeding episodes: Moderate

Common cause of Bleeding: mouth lacerations:

Sonis and Musselman -132 pts - factor VIII– def’ hemophilia "persistent oral bleeding resulted in the diagnosis of 13.6% of all cases of hemophilia ."' 29% cases(mild hemophilia )  bleeding from the oral cavity. Secondary to oral bleeding, 78%  maxillary frenum 22%  tongue bleeds. Common cause of Bleeding: mouth lacerations

Summing up symptoms:

Spontaneous Haemorrhage Deep Hematomas and hematuria Gingival hemorrhage more prolonged and massive. Mandibular pseudo-tumor with tooth displacement enlargement of bony structure delicate trabeculae and areas of radiolucency . Mouth ulceration Increased occurrence of periodontal disease and caries due poor hygiene Summing up symptoms

General clinical features2,3:

General clinical features 2,3

Oral symptoms:

Oral symptoms

Von Willebrand’s disease ( vWD) 2,4:

Von Willebrand’s disease ( vWD ) 2,4 Most common hereditary coagulation disorder occurring due to qualitative / quantitative defect in von Willebrand’s factor( vWF ) Incidence: 1 IN 1000, Both males n females Comprises of complexes of Fac VIII- vWF , which circulate in blood

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Caused as VIII molecule is abnormal, is usually inherited as autosomal dominant fashion and is therefore the most common, but overall is the least severe of the inherited clotting disorders.

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Most imp function: Carrier for FVIII in plasma

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Type 1 VWD is found in 60%-80% of patients.  People with type 1 VWD have a quantitative deficiency of VWF. Levels of VWF in the blood range from 20%-50% of normal. The symptoms are usually mild. Type 2 VWD is found in 15%-30% of patients.  People with type 2 VWD have a qualitative deficiency in their VWF. Type 2 is broken down into four subtypes: type 2A, type 2B, type 2M and type 2N, depending on the presence and behavior of multimers , molecular chains of VWF. Symptoms are mild to moderate.

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Type 3 VWD is found in 5%-10% of patients.  People with type 3 VWD have a quantitative deficiency of VWF. Symptoms are typically severe, and include spontaneous bleeding episodes, often into their joints and muscles. Acquired VWD.  This type of VWD in adults results after a diagnosis of an autoimmune disease, such as lupus, or from heart disease or some types of cancer. It can also occur after taking certain medications.

Clinical Features:

Clinical Features Due to impaired platelet plug formation, It leads to -Hemorrhages from the skin and mucosa Easy bruising Epistaxis Prolonged bleeding after surgery GIT hemorrhage

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Investigations for bleeding disorders

Detection of Haemophilia A Traits in Carriers: De et al. 1989 :

It is known to impose a severe strain on the affected individual and his family as well as on the blood transfusion services of the country. It is therefore essential to detect the potential carriers of haemophilia A, so that they can be given precise genetic counseling . Blood samples are collected from normal women and obligate carriers of haemophilia A in the reproductive age group. Detection of Haemophilia A Traits in Carriers: De et al. 1989

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The obligate carriers were the mothers of known haemophiliacs who are being treated at the center . Blood (4.5 ml) was divided into aliquots, one of which is taken for prothrombin time (PT), activated thromboplastin time (APTT) and factor VIII coagulant activity (FVIII C) measurements while the other was snap frozen and stored at -700C for later use in factor VIII related antigen (FVIII) R: Ag) determination.

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The APTT was significantly higher in carriers. The levels of FVIII C and R: Ag were significantly lower in carriers than in normal individuals. The ratio of FVIII C to FVIII R: Ag in carriers was 0.55 while that in normal was 1.0. By applying the linear discriminating the result of the study indicates that the ratio of FVIII C to FVIII R: Ag can be of use for the routine detection of obligate carriers of haemophilia A

Identification of Hemophilia:

Certain options are available of identificator of carriers of severe haemophilia. These include, preimplantal diagnosis of an embryo following in vitro fertilization, fetal diagnosis of chorionic villus sampling (CVS) using DNA technology, fetoscopy using clotting factor assay and amniocentesis in order to obtain confirmation of fetal status. Identification of Hemophilia

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One third of haemophilia carriers have factor VIII or factor IX levels below normal and are in danger of abnormal bleeding following injury, surgery or dental extraction but not in pregnancy as factor VIII level rises normally ( Choudhry et al 1996; Kashyap and Choudhury 2000).

Complications2:

Inhibitors : 28% (severe factor VIII deficiency pts) : 3% -5% of patients with severe factor IX deficiency. Accurate knowledge of the classification and level of the inhibitor is necessary for successful treatment. Patients with inhibitors are divided into two general groups, high responders low responders based on the past peak anamnestic response. Complications 2

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Low-response : Continue with factor concentrate, High-response : Bypassing products ( either PCC or activated PCC and recombinant factor VIIa ). Hemophilic patients with inhibitors pose a challenging treatment problem and should be managed only in conjunction with a hemophilia comprehensive center , since hemostasis may be difficult to achieve.

Other complications:

Arthritis & degenerative joint disease , secondary to recurrent bleeding and bloodborne viral infections Hepatitis (either B or C) and resultant liver disease have been a significant source of morbidity and mortality in this patient population. The human immunodeficiency virus (HIV) Other complications

Dental care of children:

Dental care of children Recording past medical, dental & family history Consultation with pediatrician Dental procedures with high risk for bleeding Pharmacological agents for management of bleeding Application of specific dental treatment: Early caries diagnosis and healing of incipient carious lesion.

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Past medical dental and family history

Consultation with pediatrician:

Consultation with pediatrician Consult request should involve: Number of dental procedures in treatment plan that may cause bleeding Plan for local anesthetic administration No of appointments needed to complete the treatment Caries activity and oral health summary of child

Treatment as outpatient Vs general anesthesia:

Treatment as outpatient Vs general anesthesia Depends on extent of dental treatment needed, patient behavior, and severity of bleeding disorder. When full moth rehabilitation is needed, general anesthesia is preferred. Oral intubation is preferred over nasal intubation.

Dental procedures for high risk of bleeding:

Dental procedures for high risk of bleeding Extractions Pulp therapy Class II restoration Administration of inferior alveolar nerve block Other surgical procedures

Extraction :

Extraction Extraction of even primary teeth is associated with risk of bleeding Risk lasts for seven to 10 days

Pharmacological agents in the management of bleeding.:

Pharmacological agents in the management of bleeding. Epsilon aminocaproic acid ( Amicar , Aprotinin )

Tranexemic acid:

Tranexemic acid

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Desmopressin (DDAVP, stimate ) stimulates the release of factor VIII

Local haemostatic agents:

Local haemostatic agents

ε-Aminocaproic acid:

ε - Aminocaproic acid Dose in children: 100 to 200mg/kg upto 10 g oral before procedure After procedure, 50-100gm/kg upto 5 gm oral every 6 hours for 5-7 days If weight of child> 30kg, adult dose i.e.3gm 4 times a day Adv: availability in tablet and liquid form

Tranexemic acid :

Tranexemic acid Dose: 25 mg/kg immediately before treatment Same continued every 8 hours for 5 to 7 days.

Side effect:

Side effect Headache nausea Dry mouth Avoided in case of renal and urinary tract bleeding Or in case of DIC

DDAVP(1-deamino8 p arginine vasopressin):

DDAVP(1-deamino8 p arginine vasopressin) Is synthetic analogue of pituitary hormone vasopressin. When given IV/SC/IN, increases activity of factor VIII and VWF through its release from stored sites. Concentration used: 1.5mg/mL

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Peak activity : 1 hour IV/SC; 90 min IN Side effects: tachyphylaxis, water retention, hyponatremia, seizures.

Frachon et al in 2005:

Frachon et al in 2005 Protocol involved Administration of recobinant factor VIII or Ixnone hour prior to extraction for patients with severe and moderate hemophilia For mild hemophilia , DDAVP was given 1 hour prior After curetting the socket, fibrin glue was applied to socket wall. Gingiva was sutured with resorbable suture A gelatin pack was given, sutures were covered with fibrin glue.

Tranexemic acid prescribed for 3 days :

Tranexemic acid prescribed for 3 days Tranexemic acid prescribed for 3 days First day: 10 min compression every one hour. 2 nd day: 10 min compression every two hour. 3 rd day: 10 min compression every 3 hour.

Analgesia and stress management :

Analgesia and stress management If patient is apprehensive, sedation can be done. Intra-muscular injections are avoided Aspirin should be avoided Acetaminophen and propoxypene hydrochloride can be prescribed. For severe pain, narcotics are given.

Local anesthesia:

Local anesthesia Pdl injections are preferred Infiltration anesthesia, can be given, but in areas of high vascularity , factor activity of atleast 40% should be maintained.

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Inferior alveolar nerve block and PSA contraindicated Careful aspiration before injecting. If aspiration is positive, replacement therapy should be given.

Preventive care:

Preventive care Tooth brushing, flossing, topical fluoride exposure, diet counseling Rubber cup prophylaxis, and supragingival scaling can be done without factor replacement

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Minor bleeding controlled with local measures like gauze packs and topical application of bovine thrombin, microfibrillar collagen and fibrin glue.

Periodontal therapy:

Periodontal therapy Patients requirement deep scaling, initially to supragingival and then repeat after 7-14 days. Usually requires replacement therapy.

Restorative dental care:

Restorative dental care

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Wedges and matrices used to papillary gingiva High vacuum suction and saliva ejectors and intraoral radiographs used with caution. Periphery wax covering impression tray, subgingival tooth preparation, use retraction cords.

Pulp therapy:

Pulp therapy Pulp therapy (indirect pulp capping, pulpotomy , pulpectomy ) is preferred over extraction Intra-pulpal injections can also be used. Pulpal bleeding controlled with pressure from cotton pellets

Oral surgery:

Oral surgery Tooth extraction For simple extraction of erupted permanent and multi-rooted primary teeth, 30-40% factor correction administered 1 hour before procedure. Antibrinolytic therapy started immediately after and continued for 5-7 days. Clear liquid diet for 72 hours.

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Soft pureed diet for next 1 week No using straws, metallic utensils, pacifiers or bottles. After extraction, topical application of thrombin or micro- fibrillar collagen

Haemostatic agent held in place with sutures:

Haemostatic agent held in place with sutures

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Stomahesive (J knipper and Co) may be placed over wound for protection Sutures if needed, should be absorbable

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Surgical extractions of impacted, partially erupted, unerupted teeth require more extensive replacement therapy. Electro-surgery is preferred over conventional surgery.

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Extraction of single rooted primary teeth Depends on root development

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Shedding of primary teeth: Usually does not cause bleeding Controlled with gauze pressure and topical application of haemostatic agent.

Medical Management:

Medical Management

Management of Hemophilia6,9:

Replacement of Factor VIII in Haemophilia A Management of haemophilia is almost exclusively based on administration of commercial Factor VIII concentrates prepared from plasma obtained from thousands of donors. Treatment with commercial Factor VIII concentrate presents two major problems viz., (a) it is very expensive as often it has to be imported (b) there is a high risk of contamination with hepatitis B virus, hepatitis C virus as well as HIV, from the large number of donors. Management of Hemophilia 6,9

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Production of good quality cryoprecipitate from plasma was achieved, as assessed by quantitating Factor VIII coagulant activity (F VIII C) and Factor related antigen (F VII R: Ag). The method used resulted in good recovery of FVIII in the cryoprecipitate containing FVIII C: Fibrinogen 0.82±0.015 IU/mg.

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The method therefore appears suitable for indigenous preparation of F VIII in standard blood banks as a replacement therapy, which is not expensive (De et al.1989, 1991). High purity cryoprecipitate may be used in surgery ( Ghosh et al. 1998).

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Protocol for management of Hemophilia A patient

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Management of hemophilia B

Management of VWD8:

Decisions about treatment for patients with vwd begin with accurate diagnosis and complete evaluation. The role of oral physician, in emphasizing upon seeking history of the response to hemostatic challenge such as dental extraction, tonsillectomy, surgical procedure, menstruation and peripartum hemorrhage , is of utmost importance in identifying patients with vWD . Management of VWD 8

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The spectrum of therapeutic interventions includes desmopressin (DDAVP) for non-exogenous replacement therapy, and adjunctive therapy with medications that modulate bleeding symptoms. To treat both the factor VIII deficiency and defect in primary hemostasis , it is generally necessary to give a product with factor VIIIc activity that also contains high molecular weight multimers of vWF .

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There are a few clotting factor concentrates that are rich in VWF, and are recommended for patients with VWD. These therapies are given by intravenous infusion. Aminocaproic acid and tranexamic acid are antifibrinolytics agents that prevent the breakdown of blood clots. These drugs are often recommended before dental procedures, to treat nose and mouth bleeds, and for menorrhagia .   Antifibrinolytics are taken orally, as a tablet or liquid.

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Von willebrands disease

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