This literature review was prepared in 2019 and has been presented in kids dentists Brisbane.

• X-linked recessive inherited blood disorder
• Mostly affects men
• Type A: reduction of coagulation factor VIII
• Type B: reduction of coagulation factor IX
• Type C: reduction of coagulation factor XI
• Acquired haemophilia: autoantibodies against coagulation factor VIII
• Bleeding management by factor replacement therapy, use of tranexamic acid, desmopressin in type A haemophilia.

• Autosomal dominant inherited bleeding disorder
• Reduced vWF
• Type 1 — factor levels are low (the most common type).
• Type 2 — factor doesn’t work properly.
• Type 3 — factor is missing (the rarest type).
• More common than haemophili and less sever
• Bleeding management by desmopressin, vWF/FVIII plasma concentrate and tranexamic acid.

• Vit K dependent clotting factor deficiency (VKCFD)
• Disseminated intravascular coagulation (DIC)
• Thrombocytopenia
• Glanzmann Thrombasthenia (GT)
• Collagen Vascular disease such as Ehler Danlos Syndrome
• Hereditary haemorrhagic telangiectasia
• Scurvy

• Warfarin therapy inhibits vit K epoxide reductase, which inhibits extrinsic pathway
• Heparin therapy

• Injury exposes subendothelial extracellular matrix (ECM) allowing platelet adhesion by binding glycoprotein receptors on platelets to vWF.
• Shape change: activated platelet changes from smooth disc shaped to tentacle-like projections that facilitates entanglement into platelet aggregation
• Binding platelets to each other and subendothelial matrix mediated by specific adhesion molecules, fibrinogen and vWF
• Granule release: activated platelets release ADP and Thromboxane A2 recruit more platelets into process.
• Drugs that interfere with platelet: aspirin

• Stabilization of platelet plug through formation of fibrin mesh by coagulation cascade
• Endothelial injury exposes tissue factor (factor III or thromboplastin), pro-coagulant glycoprotein synthesizes by endothelial cells.
• Tissue factor and factor VII is a major trigger of coagulation cascade and activation of thrombin.
• Thrombus and anticoagulant effect: activated thrombin promotes formation of insoluble fibrin clot by cleaving fibrinogen to fibrin meshwork abd activates additional platelets that reinforce haemostatic plug. This is secondary haemostasis; stable clot cleaving fibrin
• Enzyme cascade amplify small initial signals in the coagulation cascade that can be initiated through:
  • Activation of Hegman factor (factor XII) in intrinsic pathway OR
  • Activation of tissue factor in extrinsic pathway

Bleeding disorders are a group of disorders that share the inability to form a proper blood clot. They are characterized by extended bleeding after injury, surgery or trauma. Sometimes the bleeding is spontaneous, without a known or identifiable cause.

Disorders could be considered to defect of:

• Integrity of blood vessels (increased vessel fragility and Purpura)
  • Congenital vascular wall defects (Ehler-Danlos Syndrome)
  • Acquired vascular purpura due to corticosteroid excess, purpura, immune complex deposition,
  • scurvy
• Platelets
  • Defective platelet adhesion or aggregation, inherited or acquired (Aspirin)
• Coagulation factors

The word haemophilia was first used by Hopff in 1828 (Hopff 1828).

• Haemophilia occurs in 1 in 6,000-10,000 males internationally.
• Currently in Australia there are more than 2,800 people diagnosed with varied degrees of severity.

 

Haemophilia can be described as a group of recessive X-linked bleeding disorders due to deficiency of one or more clotting factors (Patton 2003, Brewer and Correa 2005). It primarily affects males.

Types of haemophilia:

• Type A also called Royal disease (deficiency of factor VIII)
• Type B also called Christmas disease (deficiency of factor IX)
• Type C also called Rosenthal syndrome (deficiency of factor XI)

Type A and B were recognized and described by Aggeler et al and Biggs et al.(Biggs, Douglas et al. 1952).

Also called Royal disease because Queen Victoria of England (1837-1901) was a carrier and from her the disease spread to the royal families of Spain, Germany and Russia (Graw, Brackmann et al. 2005).

Haemophilia A is more common that haemophilia B and C, accounting for 80-85% of total haemophilia cases (Patton 2003). It is one of the most common inherited diseases. Family history is known in about two thirds of cases and it appears sporadically in one third of cases.

Decrease in Factor VIII activity due to mutations can cause clotting disorders such as bleeding into joints, muscles and inner organs. Bleeding into the CNS is a major cause of death in haemophilic patients in developed countries.

There has been more than 940 mutations associated with haemophilia type A. Inversions between genes located within intron 22 and Factor VIII gene and sequences outside the gene count for sever cases. In about 4% of these patients no mutation could be found (Graw, Brackmann et al. 2005).

The residual activity of the Factor VIII protein in carrier females is usually ∼50%. However, in some cases, activity falls below this mark and reaches pathological levels, as is manifested by an extended period of menstruation. Homozygous females, although rare, also suffer from haemophilia A in a similar way to hemizygous male patients.

Haemophilia B is a recessive X-linked bleeding disorder due to deficiency of factor IX. Factor IX is located on the long arm of chromosome X at Xq27. It is smaller and less complex than factor VIII. There has been more than 2100 mutations reported associated with IX gene, mostly point mutations. Unusual factor IX leiden phenotype is caused by substitution in the promoter region of the factor IX gene (Bolton-Maggs and Pasi 2003).

Haemophilia C, Rosenthal syndrome or plasma thromboplastin antecedent (PTA) deficiency is an autosomal recessive bleeding disorder with factor XI deficiency. It affects both men and women and is mostly seen in Ashkenazi Jews.

Not caused by inherited gene mutations. This rare condition is characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood. Acquired haemophilia results from autoantibodies that attack and disable coagulation factor VIII. The production of autoantibodies is sometimes associated with pregnancy, immune system disorders, cancer, or allergic reactions to certain drugs. In about half of cases, the cause of acquired haemophilia is unknown.

Haemophilia can be diagnosed by known family history or after presentation with bleeding.

Children that suffer from sever haemophilia may experience bleeding into joints as early as 4 years of age.(Pollmann, Richter et al. 1999). Moderate haemophilia is usually diagnosed by the age of 5. Mild cases may only be diagnosed after trauma or surgery causing excessive bleeding.

Factor VIII deficiency due to haemophilia should be distinguished from Von Willebrand disease. Family history (autosomal dominant inheritance), bleeding symptoms (menorrhagia, easy bruising and epistaxis), assays of vWF can be used to differentiate between the two disorders.

The severity of haemophilia is classified according to the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (White, Rosendaal et al. 2001):

Bleeding investigation (Gupta, Epstein et al. 2007)

Intravenous replacement of deficient clotting factors can be used on demand (as soon as bleeding occurs) or as prophylaxis. Clotting factors may be plasma-derived or recombinant.

Half-life of infused factor VIII is 10 to 14 hours (Thompson 2003). This is the same half life range of endogenous factor VIII.

Recombinant clotting factors are a more suitable alternative to plasma-derived proteins reducing the risk of blood-borne pathogens transmission.

With advances in diagnosis and treatment, haemophilic patients can have a normal life expectancy (Bolton-Maggs and Pasi 2003).

Gene therapy advantages (Graw, Brackmann et al. 2005):

• patient would not need regular prophylactic IV substitution
• help to identify side effects of gene-therapy protocols
• high chance of success (small increase in factor VIII can reduce bleeding)
• success can be monitored using blood coagulation tests.

Despite some progress in developing an effective gene-therapy protocols there are some limitations and further studies and trials are needed for their routine use.

Von Willebrand factor (VWF) is a large multimeric glycoprotein that performs two critical functions in primary haemostasis: it acts as a bridging molecule at sites of vascular injury for normal platelet adhesion, and under high shear conditions, it promotes platelet aggregation. VWF has a third function that is important in fibrin formation, acting as a carrier for factor VIII in the circulation that maintains the normal level of factor VIII by decreasing the clearance of factor VIII.

Von Willebrand disease is an autosomal dominant coagulation disorder characterized by a quantitative or qualitative abnormality of vWF. It has variable clinical presentations and is usually under diagnosed. in some patients, the disorder results from the double inheritance of a recessive gene and these patients tend to be severely affected. It should be noted that occasional cases occur sporadically. It has been reported that as many as 8000 per million of population may be carriers of Von Willebrand gene but that only 125 per million will have clinical symptoms (Sadler 1998).

According to haemophilia foundation Australia, more than 2,100 people have been diagnosed with VWD in Australia. It has been estimated that 200,000 people are affected but not diagnosed due to very mild clinical symptoms.

 

There has been 3 major types of VWD published by the international society of Thrombosis and Haemostatsis (Sadler 1998):

• type 1 VWD—results from a partial quantitative deficiency of VWF
• type 2 VWD—results from a qualitative abnormality of VWF.
• There are four main subtypes, of which the two most common are:
• type 2a VWD in which there is a loss of large multimers. As a result, VWF activity levels are usually lower than VWF antigen levels;
• type 2b VWD in which there is a qualitative abnormality of VWF that results in increased binding to platelets, often leading to thrombocytopenia;
• type 3 VWD—results from a severe deficiency of VWF, with VWF antigen and activity levels being characteristically <5%.

Acquired VWD is a rare bleeding disorder usually seen in elderly patients with no history of abnormal bleeding in the past. Underlying disease associated with acquired VWD include:

• Haematoproliferative disorders including gammapathies
• Lymphoproliferative disorders
• Myeloproliferative disorders

The pathogenesis is not well understood but includes autoantibodies IgG, IgM, IgA against vWF. Levels of vWF are elevated in thyrotoxicosis and acquired VWD has been seen in patients with hyperthyroidism.

Many factors are taken into consideration for diagnosis of VWD including:

1. Personal history of bleeding
2. Family history of bleeding
3. Laboratory testing

Initially:

• measurement of von Willebrand factor (VWF) antigen levels
• VWF platelet binding activity (VWF:RCo, VWF:GPIbM, and VWF:GPIbR)
• factor VIII (FVIII) activity

Additional testing:

• VWF collagen binding activity
• low-dose ristocetin VWF-platelet binding
• FVIII-VWF binding
• VWF multimer analysis
• propeptide antigen

Desmopressin can be used as an injection (DDAVP) or nasal spray (Minirin) which can stimulate the body to release more of the vWF stored in the lining of the blood vessels.

VKCFD is a rare autosomal recessive bleeding disorder. It is usually seen in infants who present with sever haemorrhage.

VKCD was first reported in 1966 in a 3-month-old girl (McMillan and Roberts 1966) with factor II,VII,IX and X deficiency that lacked c-carboxyglutamic acid residues.

VKCD patients have prolonged prothrombin time and activated partial thromboplastin time.

Diagnosis of Vit K deficiency is made on the basis of persistence of bleeding and reduced levels of Vit K- dependent coagulation and anti-coagulation factors (Weston and Monahan 2008).

Management of VKCD patients can be by administration of oral vit K, plasma infusion or four-factor prothrombin complex concentrates (PCCs), which contain factors II,VII,IX,X (Leissinger, Blatt et al. 2008).

DIC is characterized by widespread activation of coagulation resulting in fibrin formation and thrombotic occlusion of small and medium size vessels. Homeostatic balance of controlled thrombin generation is lost in DIC (Toh and Dennis 2003).

As the small clots consume coagulation proteins and platelets, normal coagulation is disrupted and abnormal bleeding occurs from the skin (e.g. from sites where blood samples were taken), the gastrointestinal tract, the respiratory tract and surgical wounds.

Thrombocytopenia is a condition with reduced blood platelet count. A normal platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. Having more than 450,000 platelets is a condition called thrombocytosis; having less than 150,000 is known as thrombocytopenia.

Reduced number of circulating platelets can be due to:

• Trapped platelets
  • Usually retained in spleen causing low circulating counts

 

• Decreased production of platelets due to
  • Leukemia
  • Some types of anemia
  • Viral infections, such as hepatitis C or HIV
  • Chemotherapy drugs
  • Heavy alcohol consumption
• Increased breakdown of platelets
  • Thrombocytopenia caused by pregnancy is usually mild and improves soon after childbirth.
  • Immune thrombocytopenia. This type is caused by autoimmune diseases, such as lupus and rheumatoid arthritis. The body’s immune system mistakenly attacks and destroys platelets. If the exact cause of this condition isn’t known, it’s called idiopathic thrombocytopenic purpura. This type more often affects children.
  • Bacteria in the blood. Severe bacterial infections involving the blood (bacteremia) may lead to destruction of platelets.
  • Thrombotic thrombocytopenic purpura. This is a rare condition that occurs when small blood clots suddenly form throughout your body, using up large numbers of platelets.
  • Hemolytic uremic syndrome. This rare disorder causes a sharp drop in platelets, destruction of red blood cells and impairment of kidney function. Sometimes it can occur in association with a bacterial Escherichia coli (E. coli) infection, such as may be acquired from eating raw or undercooked meat.
  • Certain medications can reduce the number of platelets in your blood. Sometimes a drug confuses the immune system and causes it to destroy platelets. Examples include heparin, quinine, sulfa-containing antibiotics and anticonvulsants.

 

Heparin associated thrombocytopenia is a complication associated with heparin therapy. Onset usually occurs 6-12 hours after initiation of treatment.

Heparin associated thrombocytopenia if accompanied by arterial thrombosis can cause stroke, heart attack and death.

Testing for the presence of heparin-dependent platelet aggregating factor may help with diagnosis. To prevent this condition oral anticoagulants can be used concomitantly with heparin and discontinued in several days (KING and KELTON 1984).

GT was first described by Glanzmann in 1981 as a hereditary haemorrhagic thrombasthenia (Glanzmann E 1918). It is an autosomal recessive moderate to severe haemorrhagic disorder with quantitative and/or qualitative abnormalities of αIIbβ3 integrin which affects aggregation of platelets (Nurden 2006).

HHT also known as Osler- Weber- Rendu syndrome is an autosomal dominant disorder characterised by mucocutaneous telangiectasia, anaemia and arteriovenous malformations. Nose bleeds, GI bleeding and iron deficiency anaemia associated with characteristics telangiectasia on the lips, oral mucosa and fingertips are usually always present. Generally there are no symptoms at birth and with increasing age nose bleeds are the earliest sign of the disease. (Begbie, Wallace et al. 2003).

The HHT diagnosis is (Shovlin, Guttmacher et al. 2000):

• “Definite” if three criteria are present.
• “Possible” or “suspected” if two criteria are present.
• “Unlikely” if fewer than two criteria are present.

Criteria

1. Epistaxis: spontaneous, recurrent nose bleeds.
2. Telangiectasis multiple, at characteristic sites:

• Oral cavity.
• Visceral lesions such as:
• Gastrointestinal telangiectasia (with or without bleeding).
• Pulmonary AVM.
• Hepatic AVM.
• Cerebral AVM.
• Spinal AVM.

Family history a first degree relative with HHT according to these criteria

Scurvy results from lack of Vit C or ascorbic acid. Vit C is essential for synthesis of collagen, it is required as a cofactor for prolyl hydroxylase and lysyl hydroxylase which are responsible for hydroxylation of the proline and lysin amino acids in collagen. Hydroxyproline and hydroxylysine are important for stabilizing collagen by cross-linking the propeptides in collagen.

Defective collagen leads to defective connective tissue leading to fragile capillaries which can result in abnormal bleeding, bruising and internal haemorrhage.

Diagnosis is usually based on physical signs, low plasma level of Vit C <0.2 mg/dl, radiographic findings and improvement after treatment with Vit C supplements (Agarwal, Shaharyar et al. 2015).

According to Pure Dentistry Emergency Dentists in Carindale, Brisbane Prevention of dental problems is very important in reducing need for treatment and number of dental emergency visits.

According to the World Federation of Hemophilia Dental Committee prevention includes (Andrew Brewer and Correa 2006):

• Brushing twice daily with a fluoride toothpaste (1000 ppm under 7yrs, 1400 ppm over 7yrs)
• Use of interdental cleaning aids e.g. floss, interdental brushes
• Limit the consumption of foods and drinks with a high sugar or acid content to mealtimes
• Use artificial sweeteners as an alternative to sugar in food and drink
• Regular dental visits, usually every 6 months, to help identify problems early and reinforce prevention

Caution should be taken to prevent any accidental damage to the oral mucosa, this can be achieved by:

• Careful use of saliva ejectors
• Careful removal of impressions
• Care in the placement of X-ray films, particularly in the sublingual region
• Protection of soft tissues during restorative treatment by using a rubber dam or applying yellow soft paraffin (vaseline®).

A thorough treatment planning is required for patients with bleeding disorders according to the bleeding risk, which is usually assessed by considering (Hewson, Daly et al. 2011):

• The type and severity of the bleeding disorder
• Location and extend of dental surgery
• Experience of the treating dentist

Treatments such as examination, fissure sealants, small occlusal restorations without local anaesthesia and supragingival scaling do not require augmentation of coagulation factor levels.

Therapeutic management options depending on the type of the bleeding disorder are (Anderson, Brewer et al. 2013):

1. Coagulation factor replacement therapy- For patients with moderate and severe haemophilia A and B, coagulation factor replacement therapy administered by IV infusion is the main form of therapy. Dental procedure should be carried out within 30 mins to an hour of infusion. Development of inhibitors or antibodies which immediately negate the effect of the infused factor concentrate is a sever complication of factor replacement therapy. Use of Recombinant factor VIIa, tranexamic acid and activated prothrombin complex concentrate can be used in this situation.

 

2. Release of endogenous factor stores using desmopressin (DDAVP) which stimulates release of endogenous FVIII and vWF from stores in patients with mild haemophilia and vWD (Mannucci 2000) and is an established therapy for the control of bleeding associated with injury and minor general and oral surgical procedures. Patients with haemophilia B do not respond to DDAVP. This can be administered subcutaneously or by IV infusion 1 hour before the procedure.

 

3. Improving clot stability by antifibrinolytic drugs, for example, tranexamic acid Tranexamic acid (Cyklokapron®) competitively inhibits the activation of plasminogen to plasmin thereby inhibiting fibrin clot lysis. It is available in intravenous and oral preparations as well as in the form of a mouthwash.

 

4. Local haemostatic measures such as suturing, oxidised cellulose, Surgicel®, resorbable gelatine sponge, Gelfoam®, cyanoacrylate tissue adhesives and surgical splints can be used.

Infiltration in adults can be performed without the need for factor replacement therapy if the injection is done slowly with a fine gauge needle but advice should be sought from a paediatric haemophilia center. for children on regular prophylaxis a dose of factor replacement therapy may be needed (Andrew Brewer and Correa 2006).

Due to risk of muscle haematoma and potential airway compromise due to haematoma formation in the retromolar or pterygoid space factor replacement therapy with or without tranexamic acid is required in all age groups when inferior alveolar and posterior superior alveolar dental nerve blocks are given(Heiland, Weber et al. 2003, Dougall and Fiske 2008).

Factor replacement therapy is also necessary for lingual infiltration and floor-of-mouth injections in all age groups as there may be a significant risk of haematoma.

There are no restrictions regarding the type of local anaesthetic used, and 2% lidocaine with 1 in 80,000 epinephrine is routinely used in restorative dentistry

  (Brewer, Roebuck et al. 2003)

Routine periodontal examination (probing), supra gingival scaling and polishing is    usually safe and does not cause excessive bleeding (Brewer, Roebuck et al. 2003).

If the gingival health is poor, prevention of further damage to periodontal tissues is necessary by instituting an immediate treatment plan that may require several visits to prevent excessive bleeding(Hewson, Daly et al. 2011).

Chlorhexidine mouthwash may be a useful aid in controlling the gingival inflammation. Blood loss during periodontal therapy can be managed locally with direct pressure or periodontal dressings, with or without topical antifibrinolytic agents. Periodontal surgery in patients with bleeding disorders is a high risk procedure associated with a significant risk of blood loss. It should only be considered where conservative therapy has failed and should be planned in consultation with the patient’s haematologist.

Fixed and removable orthodontic and prosthetic appliances may be used safely as long as they do not cause injury to the oral mucosa and gingiva. Enhanced preventive advice including oral hygiene instructions should be given to these patients with bleeding disorders.  If there is need for surgical procedures a consultation with the patient’s haematologist should be carried out prior to the surgery.

Routine and advanced restorative treatment can be carried out in patients with inherited bleeding disorders. Care should be taken to protect the oral mucosa. Bleeding resulting from the use to matrix bands or wooden wedges can be controlled using local measures (Andrew Brewer and Correa 2006)

Endodontic therapy is considered low risk in patients with inherited bleeding                disorders. Routine endodontic techniques should be undertaken including the use of rubber dam. It is important not to go over the working length of the canal and to keep instrumentation within the canal space to prevent bleeding in the periapical tissues. Bleeding from pulp tissue can be controlled by thorough removal of any remaining tissue and use of sodium hypochlorite as an irrigant. Calcium hydroxide paste as a medicament may be used to control bleeding. Continuous bleeding at the apical foramen may cause problems if the final root canal filling is placed early but this can be managed by the methods above (Brewer A 2008).

To minimise the risk of bleeding, excessive bruising and haemotoma formation dental extractions should be planned with the patient’s haematologist (Brewer A 2008).

Planning should include (RCH)

• Need for prophylactic factor infusion or desmopressin
• Number of appointments needed for the procedure
• Use of local haemostatic agents such as oxidised celluloise (surgical) or fibrin glue
• Use of anti-fibrinolytic agent such as tranexamic acid (this may be used a day prior to surgery and continued for 7 days.)

Before the surgical procedure oral cavity should be healthy by regular cleaning and use of anti-bacterial mouthwash such as Chlorhexidine mouthwash.

 

The following procedure should be carried out for extractions (W S McLaughlin 2016)

• Dental extractions should be conducted as a traumatically as possible with minimal impact on the gingival tissues.
• Following extraction, the socket should be packed with oxidised cellulose e.g. surgicel and sutured if the margins of the socket do not oppose well.
• Patients should be advised to bite onto a pack post-extraction which has been dampened with tranexamic acid solution. The clinics where haematology patients are seen stock a 10% tranexamic acid solution (5ml) for use on dental packs in the surgery setting only
• Appropriate post-operative monitoring should be arranged in liaison with the patient’s haematology consultant.
• Standard post-operative instructions should be given to patients with particular reference to contact details should they experience postoperative bleeds or complications. The standard instructions should be altered to ensure the information is relevant for patients with inherited bleeding disorders, particularly the removal of ibuprofen as a suitable post-operative pain reliever.

Dental pain management may be altered in patients with bleeding disorders. Aspirin and Aspirin containing medications, should be avoided as it can increase risks of bleeding due to inhibitory effect on platelet functions. The use of NSAIDs should be discussed with the patient’s haematologist prior to use due to their effects on platelets. Paracetamol and codeine based preparations are safe alternatives (Anderson, Brewer et al. 2013)

Dental emergencies can occur at any time; however, no surgical treatment should be carried out on patients with bleeding disorders without first planning with their haematologist. In paediatric patients local anaesthesia is used as for any other patient who presents with acute pulpitis. If patients cannot tolerate this treatment an urgent referral to a specialist paediatric unit is required as use of sedation, happy gas or dental treatment under general anaesthesia may be indicated. A temporary dressing should be used if the tooth is not restorable and the haemophilia centre contacted for planning of the extraction (Anderson, Brewer et al. 2013).

 

Dental trauma is more complex to manage, however local measures can usually be used to control gingival bleeding, and temporary splinting can be used for fractured or loose teeth.

Robbins Basic Pathology (2012)

Agarwal, A., et al. (2015). “Scurvy in pediatric age group – A disease often forgotten?” Journal of clinical orthopaedics and trauma 6(2): 101-107.

Anderson, J. A., et al. (2013). “Guidance on the dental management of patients with haemophilia and congenital bleeding disorders.” Br Dent J 215(10): 497-504.

Andrew Brewer and M. E. Correa (2006). “”Guidelines for dental treatment of patients with inherited bleeding disorders”.” Haemophilia.

Begbie, M. E., et al. (2003). “Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century.” Postgraduate Medical Journal 79(927): 18-24.

Biggs, R., et al. (1952). “Christmas disease.” British medical journal 2(4799): 1378.

Bolton-Maggs, P. H. and K. J. Pasi (2003). “Haemophilias a and b.” The lancet 361(9371): 1801-1809.

Brewer A (2008). “Dental management of patients with inhibitors to factor VIII or factor IX.” World Federation of Hemophilia

Brewer, A. and M. E. Correa (2005). “Guidelines for dental treatment of patients with inherited bleeding disorders.” Haemophilia 11: 504-509.

Brewer, A. K., et al. (2003). “The dental management of adult patients with haemophilia and other congenital bleeding disorders.” Haemophilia 9(6): 673-677.

Dougall, A. and J. Fiske (2008). “Access to special care dentistry, part 5. Safety.” Br Dent J 205(4): 177-190.

Glanzmann E (1918). “Hereditare hamorrhagische thrombasthenie. Ein Beitrag zur Pathologie der Blutplattchen.” J Kinderkranken 88: 113.

Graw, J., et al. (2005). “Haemophilia A: from mutation analysis to new therapies.” Nat Rev Genet 6(6): 488-501.

Gupta, A., et al. (2007). “Bleeding disorders of importance in dental care and related patient management.” J Can Dent Assoc 73(1): 77-83.

Heiland, M., et al. (2003). “Life-threatening bleeding after dental extraction in a hemophilia A patient with inhibitors to factor VIII: a case report.” J Oral Maxillofac Surg 61(11): 1350-1353.

Hewson, I. D., et al. (2011). “Consensus statement by hospital based dentists providing dental treatment for patients with inherited bleeding disorders.” Aust Dent J 56(2): 221-226.

Hopff, F. (1828). “Ueber die Haemophilie oder die erbliche Anlage zu todtlichen Blutungen.” Inaugural-Abhandlung.

KING, D. J. and J. G. KELTON (1984). “Heparin-Associated Thrombocytopenia.” Annals of Internal Medicine 100(4): 535-540.

Leissinger, C. A., et al. (2008). “Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature.” Am J Hematol 83(2): 137-143.

Mannucci, P. M. (2000). “Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years.” Haemophilia 6 Suppl 1: 60-67.

McMillan, C. W. and H. R. Roberts (1966). “Congenital combined deficiency of coagulation factors II, VII, IX and X. Report of a case.” N Engl J Med 274(23): 1313-1315.

Nurden, A. T. (2006). “Glanzmann thrombasthenia.” Orphanet journal of rare diseases 1: 10-10.

Patton, L. (2003). Bleeding and clotting disorders, Hamilton (ON): BC Decker.

Pollmann, H., et al. (1999). “When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study.” Eur J Pediatr 158 Suppl 3: S166-170.

RCH, M. “Haemophilia Clinical Practice Guideline.” Melbourne, Victoria: The Royal Children’s Hospital.

Sadler, J. E. (1998). “BIOCHEMISTRY AND GENETICS OF VON WILLEBRAND FACTOR.” Annual Review of Biochemistry 67(1): 395-424.

Sharma, R. and S. L. Haberichter (2019). “New advances in the diagnosis of von Willebrand disease.” Hematology Am Soc Hematol Educ Program 2019(1): 596-600.

Shovlin, C. L., et al. (2000). “Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu‐Osler‐Weber syndrome).” American journal of medical genetics 91(1): 66-67.

Thompson, A. R. (2003). Structure and function of the factor VIII gene and protein.

Toh, C. H. and M. Dennis (2003). “Disseminated intravascular coagulation: old disease, new hope.” BMJ (Clinical research ed.) 327(7421): 974-977.

W S McLaughlin, R. R., P Collins,E Hingston (2016). “Protocol for dental care of patients with Inherited Bleeding Disorders.” Managed Clinical Network – Special Care Dentistry South East Wales.

Weston, B. and P. Monahan (2008). “Familial deficiency of vitamin K‐dependent clotting factors.” Haemophilia 14(6): 1209-1213.

White, G. C., 2nd, et al. (2001). “Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis.” Thromb Haemost 85(3): 560.