bleeding disorders and its treatment .pptx

bleeding disorders

1. BLEEDING DISORDERS PRESENTED BY – MS. KHUSHNASIB ASSOCIATE PROFESSOR

2. Introduction History Hemostasis Platelet activation Coagulation cascade Phases of coagulation Role of each coagulation factor Anti thrombolytic mechanism Approach to child with bleeding disorder Laboratory investigations Classification of bleeding disorders contents PART I

3. Bleeding disorders are usually taken to mean coagulopathies with reduced clotting of the blood. Bleeding disorders characterised by abnormal platelet function or blood vessel walls that result in increased bleeding . Bleeding disorders may result from faults at many different levels in the coagulation cascade. introduction

4. 1828 - Term “ haemorrhaphilia ” first used . Later shortened to “haemophilia .” Hemophilia is sometimes referred to as “the royal disease,” because it affected the royal families of England, Germany, Russia and Spain in the 19 th  and 20 th  centuries. Queen Victoria of England, who ruled from 1837-1901, is believed to have been the carrier of H emophilia B, or factor IX deficiency. HISTORY

5. HEMOSTASIS: The ability of the body to control the flow of blood following vascular injury is paramount to continued survival. The process of blood clotting and then the subsequent dissolution of the clot, following repair of the injured tissue. It is composed of 4 major events that occur in a set order following the loss of vascular integrity: HEMOSTASIS Coagulation and Bleeding Disorders: Review and Update Douglas A. Triplett: Clinical Chemistry 46, No. 8(B), 2000

6. Vascular constriction -limits the flow of blood to the area of injury. Platelet aggregation –Blood platelets clump when binding to collagen that becomes exposed following rupture of the endothelial lining of vessels. -Blood platelets become activated and aggregate at the site of injury . -Upon activation, platelets release ADP and TXA2 (which activate additional platelets). Clot formation -To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug. Fibrinolysis -The clot must be dissolved in order for normal blood flow to resume following tissue repair. The dissolution of the clot occurs through the action of plasmin

7. Normally platelets do not adhere to intact vascular endothelium. Subsequent to the vascular injury, platelets adhere to collagen and vWF in the subendothelial tissue and undergo a morphological change by assuming irregular surface, forming numerous pseudopods thus drastically increasing their surface area . Activation of platelets

8. The formation of the platelet plug involves a series of steps: Platelet adhesion After vascular injury V Wf acts as a bridge between endothelial collagen and platelet surface receptors GpIb and promotes platelet adhesion. The platelet glycoprotein complex I (GP- Ib ) is the principal receptor for vWF .

9. Platelet secretion After adhesion, degranulation from both types of granules takes place with the release of various factors. Release of calcium occurs here. Calcium binds to the phospholipids that appear secondary to the platelet activation and provides a surface for assembly of various coagulation factors.

10. Platelet aggregation: Thromboxane A2 produced by activated platelets provide stimulus for further platelet aggregation. TxA2 along with ADP enlarge this platelet aggregate leading to the formation of the platelet plug, which seals off vascular injury temporarily. ADP binding also causes a conformational change in GpIIb / IIIa receptors presents on the platelet surface causing deposition of fibrinogen. Thrombin generation also catalyses the conversion of this fibrinogen to fibrin which adds to the stability of the platelet plug and is now known as secondary haemostasis.

11. Over view of homeostasis and the blood clotting process

12. It is based on cell based theory of coagulation Intiation phase : The initiation phase is localized to the cells that express TF. The FVIIa /TF complex activates small amounts of FIX and FX . FXa associates with its cofactor, FVa , and forms a prothrombinase complex on the surface of the TF-bearing cell. Phases of coagulation

13. Amplification phase: A small amount of thrombin generated on the TFbearing cell has several important functions. A major function is the activation of platelets, exposing receptors and binding sites for activated clotting factors . As a result of this activation, the platelets release partially activated forms of FV onto their surfaces. Thrombin activates platelets, cofactor FVA and FVIII on the platelet surface and FXI on platelet surface.

14. Propagation Phase: As large numbers of platelets are recruited to the site of injury, the propagation phase of clot formation occurs on the surface of activated platelets. First , FIXa activated during the initiation phase can now bind to FVIIIa on the platelet surface .

15. Termination Phase: Once a fibrin platelet clot is formed over an area of injury, the clotting process must be limited to avoid thrombotic occlusion in surrounding normal areas of the vasculature Three types of natural anticoagulants regulate clotting: antithrombin (ATIII) inhibits the activity of thrombin and other serine proteases, such as FIXa , FXa , FXIa , and FXIIa .

16. Fibrinogen (factor I ):   consists of three polypeptide chains - alpha, beta and gamma. It is converted to fibrin (factor Ia ) by thrombin (factor IIa ). Fibrin forms a mesh around the wound ultimately leading to blood clot. The inherited disorders caused due to mutations in fibrinogen include: Afibrinogenemia (complete lack of fibrinogen), Hypofibrinogenemia (reduced levels of fibrinogen) Hyperfibrinogenemia (dysfunctional fibrinogen). These individuals suffer from thromboembolism. The gene for factor I is located on the fourth chromosome. ROLE OF FACTORS CAUSING BLEEDING DISORDERS

17. Tissue factor (factor III)   : It is also called as platelet tissue factor . It is found on the outside of blood vessels and is not exposed to the bloodstream. It initiates the extrinsic pathway at the site of injury . It functions as a high-affinity receptor for factor VII. It acts as a cofactor in the factor VIIa-catalyzed activation of factor X to FXa . The gene for tissue factor is located on the first chromosome.

18. Factor V   : I s also referred to as proaccelerin or labile factor.   It is enzymatically inactive and acts as a cofactor to the serine protease FXa , which in the presence of calcium ions and an appropriate phospholipid (PL) membrane surface enhances the activation of prothrombin to thrombin . Factor V Leiden mutation causes factor V deficiency or parahemophilia , which is a rare bleeding disorder. It may also lead to myocardial infarction and deep vein thrombosis. The gene for factor V is located on the first chromosome (1q21-q25).

19. Factor VII: V itamin K-dependent serine protease. It initiates coagulation by activating factors IX and X simultaneously with tissue factor in the extrinsic pathway. Its deficiency may lead to epitaxis , menorrhagia, hematomas, hemarthrosis , digestive tract or cerebral haemorhages . The gene for factor VII is located on the thirteenth chromosome (13q34-qter).

20. Factor VIII: Is also known as anti- hemophilic factor (AHF). It is a cofactor in the activation of factor X to FXa , which is catalyzed by factor IXa in the presence of calcium and phospholipids . Mutations in the factor VIII gene results in H emophilia A. It is also called classical hemophilia , an X-linked recessive coagulation disorder. It is the most common type of hemophilia . Pateints suffer from clinical manifestations in their early childhood; spontaneous and traumatic bleeds continue throughout their life. The gene for factor VIII is located on the long arm of X chromosome (Xq28).

21. Factor IX:   I s also known as Christmas factor. It is a proenzyme serine protease, which in the presence of calcium activates factor X. Its deficiency cause H emophilia B or Christmas disease . Although , the clinical symptoms of hemophilia A and B are similar, hemophilia B is less severe than hemophilia A. High antigen or activity levels of factor IX is associated with an increased risk of thromboembolism. The gene for factor IX is located on the X chromosome (Xq27.1-q27.2).

22. Factor X:   Is also known as Stuart- Prower factor . In the presence of calcium and phospholipid, it functions in both intrinsic and extrinsic pathway of blood coagulation. Factor X is activated to FXa by factors IX and VII. It is the first member of the common pathway of blood coagulation. FXa cleaves prothrombin to thrombin. Its deficiency may cause bleeding diathesis and hemorrhages .  Patients commonly suffer from epitaxis , gastrointestinal bleeds and  hemarthrosis .  Women with factor X deficiency may be susceptible to miscarriages.  The gene for factor X is located on the thirteenth chromosome (13q32-qter).

23. Factor XI   : I s also known as plasma thromboplastin antecedent . It is a serine protease zymogen which is activated to factor XIa by factor XIIa . Deficiency in factor XI causes injury-related bleeding . The disorder is sometimes referred to as H emophilia C . Individuals with severe deficiency do not show excessive bleeding conditions and hemorrhage normally occurs after trauma or surgery.  Female patients may experience menorrhagia and prolonged bleeding after childbirth . The gene for factor XI is located on the distal end on the long arm of fourth   chromosome (4q35). 

24. Factor XII   : Is a plasma protein, also known as Hageman factor . It is the zymogen form of factor XIIa , which activates factor XI and prekallikrein . Its deficiency does not cause excessive hemorrhage due to lack of involvement of factor XIIa in thrombin formation. However , it may increase the risk of thrombosis, due to inadequate activation of the fibrinolytic pathway. The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter).

25. Factor XIII  or fibrin stabilizing factor: It is the proenzyme form of plasma transglutaminase. It is activated by thrombin into factor XIIIa in presence of calcium. It forms ε-(γ- glutamyl )- lysyl bonds between the fibrin chains and stabilizes the blood clot. Thus , it reduces the sensitivity of the clot to degradation by proteases. Genetic defects in the factor XIII gene leads to lifelong bleeding diathesis. Patients may also suffer from intercranial bleeding and death. The gene for F13A is located on the sixth chromosome (6p24-25). The F13B gene is located on the long arm of first chromosome (1q32-32.1)

26. V on Willebrand factor   ( V WF): I s a multimeric glycoprotein involved in hemostasis . It supports binding of platelets to the site of injury by forming a bridge between collagen matrix and platelet-surface receptor complex. Hereditary or acquired defects of vWF lead to von Willebrand disease. Patients may suffer from bleeding diathesis, menorrhagia and gastrointestinal bleeding. The gene for vWF is located on short arm of the twelfth chromosome

27.  It is therefore important that the endothelial surface provides several proteins and receptors that inhibit thrombin and counteract the progress of coagulation. The potent thrombin inhibitor antithrombin III binds to specific heparan sulfates of proteoglycans in the glycocalyx that covers the endothelial surface . Inadequate antithrombin III activity is accompanied by severe thrombotic complications. Furthermore , a triad of endothelial receptors is involved in the generation the important anti-coagulant activated protein C ( aPC ), which can interrupt the coagulation cascade by cleavage of factors Va and VIIIa Anti thrombotic mechanisms

28. The history should determine : The site or sites of bleeding , the severity and duration of hemorrhage, and the age at onset. Was the bleeding spontaneous, or did it occur after trauma? Was there a previous personal or family history of similar problems? If a child or adolescent has had surgery that affects the mucosal surfaces, such as a tonsillectomy or major dental extractions, the absence of bleeding usually rules out a hereditary bleeding disorder Approach to a child with bleeding disorder

29. PHYSICAL EXAMINATION The P/E should focus on whether bleeding symptoms are associated primarily with the mucous membranes or skin ( mucocutaneous bleeding) or with the muscles and joints(deep bleeding). The examination should determine the presence of petechiae , ecchymoses , hematomas, hemarthroses , or mucous membrane bleeding. Patients with defects in platelet-blood vessel wall interaction (VWD or platelet function defects) usually have mucocutaneous bleeding. Individuals with a clotting factor deficiency of factor VIII or IX (hemophilia A or B) have symptoms of deep bleeding into muscles and joints. Individuals with disorders of the collagen matrix and vessel wall may have loose joints and lax skin associated with easy bruising (Ehlers- Danlos syndrome).

30. Blood count and film show the number and morphology of platelets and any blood disorder such as leukaemia or lymphoma. The normal range for the platelet count is 150- 400 × 10 9 /L Bleeding time measures platelet plug formation in vivo normally between 3 and 10 minutes Prolonged bleeding times are found in patients with platelet function defects Laboratory investigations TEXT BOOK of medical physiology: Guyton and hall :12 th Edition

31. Prolonged bleeding times are found in patients with platelet function defects. Performed using blood collected into citrate, which neutralizes calcium ions and prevents clotting. The prothrombin time (PT) The partial thromboplastin time (PTT) The thrombin time (TT) Correction tests Factor assays Special tests of coagulation

32. Coagulation tests The prothrombin time (PT) Time needed for the plasma to clot in the presence of tissue thromboplastin and calcium Evaluates the ability of blood to clot properly Normal time for clotting is 10-14s Prolong PT results from def of: Factor V Factor VII Factor X Prothrombin Fibrinogen

33. BLEEDING DISORDERS PRESENTED BY – MS. KHUSHNASIB ASSOCIATE PROFESSOR PART II

34. Types of bleeding disorders Coagulation factor deficiencies Hemophillia A Hemophillia B Von willibrands disease Vitamin k deficiency Liver disease Platelet disorders/ coagulation factor deficiencies DIC Conclusion References Contents

35. Coagulation factor deficiencies: Congenital Hemophilia A and B V on Willebrand’s disease Other factor deficiencies (rare) Acquired Liver disease Vitamin K deficiency, warfarin use Disseminated intravascular coagulation Types of bleeding disorders

36. Platelet disorders: Quantitative disorder (thrombocytopenia) Immune-mediated Idiopathic Drug-induced Collagen vascular disease Sarcoidosis Non-immune-mediated Disseminated intravascular coagulation Microangiopathic hemolytic anemia Leukaemia Myelofibrosis

37. Qualitative disorder Glanzmann thrombasthenia Liver disease Alcoholism

38. Vascular disorders Scurvy Purpura Hereditary hemorrhagic telangiectasia Cushing syndrome Ehlers- Danlos syndrome Fibrinolytic defects Streptokinase therapy Disseminated intravascular coagulation

39. Coagulation factor deficiencies

40. Hemophilia A is due to a deficiency of clotting factor VIII or antihemophilic factor or Hemophilia B is due to deficiency of clotting factor IX ( hemophilia B ). Inherited X-link disorder Prevelance 1 in 5000 in male population. Haemophilia Naveen Kumar J, Anil Kumar R, Varadarajan R, Sharma N. Specialty dentistry for the hemophiliac: Is there a protocol in place? Indian J Dent Res 2007;18:48-54

41. Hemophilia a : X-LINKED

42. Clinical features Atypical profuse bleeding at circumcision Bruising at neonatal vaccines Joints and soft tissue bleeds and excessive bleeding when they start to be active Prolonged bleeding after teeth extraction Recurrent painful hemarthrosis Muscle haemoatomas Spontaneous haematouria GIT hemorrhage Spontaneous intracranial hemorrhage (rare)

43. Clinical features The clinical severity depend on the level of factor VIII:C = severity of condition Severe = factor level < 1% Moderate = factor level 1 – 5% Mild = factor level > 5 %

44. Severe disease – factor level < 1% Frequent spontaneous bleeding from early life Haemarthroses are common and may lead to joint deformity Bleeding into muscles is also common Moderate disease – factor level 1 – 5 % Post traumatic Bleeding Occasional apparently spontaneous episodes Mild disease – factor level > 5 % Usually with bleeding only after injury or surgery Diagnosis in this group is often delayed until quite late in life

45. Laboratory finding – investigations Coagulation testing Prolonged activated partial thromboplastin time (APTT) Normal prothrombin time (PT) Normal bleeding time (BT) Factor assay (reduced level of factor VIII)

46. Also known as Christmas disease Caused by a deficiency of factor IX The inheritance and clinical features are identical to hemophilia A Only can be distinguished by specific coagulation factor assays The incidence is only about 1 in 30 000 males Hemophilia B is treated with factor IX concentrates HEMOPHILIA B

47. General Management 1. Factor replacement Bleeding is treated by administration of factor VIII concentrate by intravenous infusion. Minor bleeding : the factor VIII:C level should be raised to 20-30% Severe bleeding : the factor VIII:C should be raised to at least 50% Major surgery : the factor VIII:C should be raised to 100% preoperatively and maintained above 50% until healing has occurred . The following formulas were applied for calculating the factor dose: Dosage (units) = body weight (kg) × desired factor VIII rise (IU/ dL or % of normal) × 0.5 Dosage (units) = body weight (kg) × desired factor IX rise (IU/ dL or % of normal)x 0.5

48. 2. Synthetic vasopressin (Desmopressin) An analogue of vasopressin Intravenous, subcutaneous or intranasal Produces a rise in factor VIII:C in mild hemophilia It avoids the complications associated with blood products It is ineffective in severe haemophilia

49. 3.Tranexamic acid is a synthetic derivative of lysine, available for topical and systemic usage. However, nausea is a common adverse effect. 4.The anti- fibrinolytic agent Epsilon amino caprioic acid (EACA) given orally of IV is a potent inhibitor of initial clot dissolution . A regimen of 50 mg/kg body weight EACA given orally as a 25% oral rinse every six hours for seven to ten days appears adequate as an adjunct. Still tranexamic acid is 10 times more potent than EACA with fewer side-effects.

50. Difficulties in the management of a hemophiliac dental patient include the following: Dental neglect necessitating frequent extractions Trauma and surgery Factor VIII inhibitors (recombinant FVIIa is an alternative Solution) Hazards of anesthesia and injections Risk of hepatitis B and liver disease and HIV infection Aggravation of bleeding by drugs Anxiety and drug dependence Dental management .

51. The bleeding tendency can be aggravated by NSAIDs. Safer alternatives for pain control are acetaminophen, codeine and Cox-2 inhibitors. Local anesthetic regional blocks, lingual infiltrations or injections into the floor of the mouth must not be used in the absence of Factor VIII replacement because of the risk of hemorrhage hazarding the airway and being life-threatening . If FVIII replacement therapy has been given, regional LA can be used provided the FVIII level is maintained above 30%. Infiltrations, intraligamentary , intraosseous or intrapulpal injections are still safer.

52. Restorative treatment can be undertaken routinely providing care is taken to protect the mucosa. There is a risk of bleeding with the use of matrix bands or wooden wedges. This can be controlled by local means or the application of topical agents. Cotton rolls should be wetted before removal. High-speed vacuum aspirators and saliva ejectors can cause hematomas. Trauma from the saliva ejector can be minimized by resting it on a gauze swab in the floor of the mouth. RESTORATIVE PROCEDURES

53. Avoiding instrumentation through the periapex is of prime importance in endodontic therapy. The presence of bleeding in the canal is indicative of pulp tissue remaining in the canal. Sodium hypochlorite should be used for irrigation in all cases, followed by the use of calcium hydroxide paste to control the bleeding. Formaldehyde-derived substances may also be used in cases where there is persistent bleeding or even before the pulpectomy . ENDODONTICS

54. Isolation with rubber dam provides retraction of gingiva and improves visibility. It also minimizes the potential for laceration of the buccal mucosa and lips. Notches may be placed in buccal and lingual surfaces with a fissure bur into which clamp prongs will fit tightly. RUBBER DAM ISOLATION

55. Mild hemophiliacs requiring surgeries can be managed usually without factor replacements. Desmopressin and tranexamic acid are primary alternatives. Desmopressin can be as a slow intravenous infusion over 20 min of 0.3-0.5 µg/kg, 30 to 60 min prior to the surgical procedure. This results in a two- to threefold rise in Factor VIII activity with a mean half-life of 9.4h. SURGICAL ENDODONTICS

56. Intranasal administration as a spray of 1.5 mg per ml with each 0.1 ml pump spray is an alternative, limiting treatment to those hemophiliac patients whose basal factor levels are sufficiently high. Tranexamic acid significantly reduces blood loss and can be given topically or systemically

57. Healthy periodontal tissue is essential to prevent bleeding and tooth loss. If oral hygiene is poor treatment must start as soon as possible after the patient has had a dental examination and treatment plan formulated to prevent additional damage to the periodontal tissues. In cases of severe periodontal disease, it may be necessary to carry out supragingival scaling initially along with oral hygiene education. Subgingival scaling can start as soon as the inflammation has decreased. The treatment may need to be carried out over several visits to prevent excessive blood loss. In addition, chlorhexidine gluconate mouthwash can be used to control periodontal problems. Antibiotics may be required to help reduce the initial inflammation. Periodontal treatment

58. Dental pain can usually be controlled with a minor analgesic such as paracetamol (acetaminophen). Aspirin should not be used due to its inhibitory affect on platelet aggregation. The use of any non-steroidal anti-inflammatory drug (NSAID) must be discussed beforehand with the patient's hematologist because of their effect on platelet aggregation A buccal infiltration can be used without any factor replacement. It will anesthetize all the upper teeth and lower anterior and premolar teeth. ANESTHESIA AND PAIN MANAGEMENT

59. Contact the hemophilia unit and consider using additional factor concentrate. Inspect the site of the bleed. If there is any evidence of a tear in the gingiva or other obvious bleeding point this should be treated using local measures. Instruct the patient to sit up and bite on a damp gauze swab for at least 10 minutes. Use a 10% solution of tranexamic acid or EACA to dampen the swab or as a mouthwash if the bleeding is difficult to stop. Monitor the patient’s blood pressure as it may increase due to worry and pain. POST-EXTRACTION HEMORRHAGE

60. In some hemophilia centres , fibrin glue is used as a local hemostatic measure, along with an oral antifibrinolytic agent, to achieve hemostasis and reduce the need for clotting factor replacement therapy. All fibrin glue contains human or animal components, which has made a number of physicians and patients being hesitant to use this treatment particularly for patients who are receiving recombinant factor concentrates or have never received blood products derived from humans. Fibrin glue

61. The intraoral examination revealed the following : Missing teeth, numbers 51 and 52 due to normal shedding Decayed teeth, numbers 55, 74, 46 and 85 Badly decayed and infected teeth, numbers 54, 64 and 84 Potential for crowding in the lower anterior segment The treatment plan included the following : Composite resin restoration for teeth numbers 55, 74, 46 and 85 Pulpotomy (ferric sulfate) and steel crowns for teeth numbers 65 and 75 Extraction for teeth 54, 64 and 84 Chairside ready-made space maintainers in place of teeth 54, 64 and 84 Mesial slicing of the lower canines for temporary relief of crowding in the lower incisor region Sealant applications for teeth 16, 26 and 36 Topical fluoride application Batawi HYE. Minimizing the risk of perioperative bleeding in a child with hemophilia A during dental rehabilitation under general anesthesiia : a case report. Int J Clin Ped Dent 2013; 6(3): 217-222.

62. The child was admitted to the hospital 48 hours prior to the operation for factor VIII replacement therapy using the following formula: FVIII dose (IU/kg) = (desired increase in FVIII IU/dl) ÷ 2 to maintain an FVIII level of 70 IU/dl . This level was recommended by the hematologist based on the type of teeth to be removed (primary or permanent) and the anticipated amount of trauma that might be exerted during the dental procedures as stated by the pediatric dentist. The preoperative blood investigation results were taken. The child was advised and educated to perform gentle brushing with a soft toothbrush and to use a povidone iodine mouthwash after meals. The parents were instructed to stop meals for at least 6 hours prior to the time of surgery. Preoperative complete blood counts showed low hemoglobin (10.6 g/dl); other values were within the normal range according to the patient’s age group

63. Oral intubation in a small child requires good intraoral S pace management for proper accessibility and vision. During the course of the dental treatment, the mouth probe was inserted in a reversed position to allow good retraction of the tube, which was accommodated inside the probe to economize the use of the intraoral space U se of local anesthesia , even for patients undergoing treatment under general anesthesia, to minimize postoperative pain and aid patient homeostasis during surgery. The current case was not an exception to this routine. Nerve block injections were avoided to lower the risk of hematoma and/or internal bleeding Batawi HYE. Minimizing the risk of perioperative bleeding in a child with hemophilia A during dental rehabilitation under general anesthesiia : a case report. Int J Clin Ped Dent 2013; 6(3): 217-222.

64. Positioning the Child Children with hemophilia can suffer from internal bleeding of the joints and muscles should these tissues become strained . Adequate support for the knees and neck is routinely provided for all children undergoing dental care under general anesthesia, with special concern for hemophilic children . Hygoformic saliva ejectors ( Orsing Co.) were used to minimize possible trauma and subsequent bleeding risk . The suction holes of these tips were directed away from mucosal tissue.

65. Extractions Avoiding unnecessary trauma was a primary concern . The following were considered: 1. Elective root division was used, and each root was extracted individually . 2. Plastic instrumentation was used to remove broken down teeth instead of root elevators to minimize the use of excessive force.

66. Postoperative Care The patient was hospitalized for 48 hours, during which he continued factor VIII replacement as proposed by his hematologist and pediatrician. Oral amoxicillin and clavulanic acid postoperative antibiotics (457 mg/5 ml ) were administered every 12 hours for 7 days. For postoperative pain control, the preferred drug was acetaminophen 200 mg, administered every 8 hours for 3 days.

67. Case report A 4-year-old boy came along with the parents the exclusive child specialty dental center with the complaints of pain in the right upper back tooth region

68. Hereditary coagulation abnormality caused by either: Reduced level of vWF Abnormality in vWF VON WILLBRAND’S DISEASE Due to Point mutation or Major deletion

69. Vwf is a protein plays two role in action: It promote adhesion of platelets to the endothelium It is a carrier molecule for factor VIII, protecting it from premature destruction So in Vwd : Defective platelet function Factor VIII:C deficiency

70. CLASSIFICATION OF VWD: 3 TYPES: TYPE I: Characterized by a mild reduction in VWF usually inherited as an autosomal dominant. TYPE II: Loss of high-molecular-weight multimers , and it too is usually inherited as an autosomal dominant TYPEIII: Characterized by severe reduction in VWF and usually inherited as autosomal recessive.

71. Clinical features Typically there is mucus membrane bleeding (epistaxis, menorrhage ...) The severity of symptoms are variable with types Type 1, 2 usually mild symptoms Type 3 severe symptoms

72. Laboratory Investigations: The bleeding time is prolonged APTT is prolonged Factor VIII is low V WF is usually low (type 1,2) Platelets count is normal

73. Hemostasis tests in hereditary coagulation disorders

74. Treatment Depends on the severity of the condition. May be similar to that of mild haemophilia , including the use of Desmopressin where possible. Factor VIII or Von Willebrand factor concentrates should be used to treat bleeding or to cover surgery in patients who require replacement therapy.

75. Factor XI deficiency Rare Seen mainly in Ashkenazi Jews Caused bleeding only after trauma Treated by factor XI Factor XII deficiency Usually cause no bleeding Other coagulation factors

76. Acquired coagulation disorders More common than inherited disorders Usually multiple clotting factors Includes Vitamin K deficiency Liver disease Coagulation disorders caused by antibodies Massive transfusion syndrome Acquired coagulation disorders

77. Vitamin K is a fat soluble vitamin Obtained from green vegetables and bacterial synthesis in the gut Important on coagulation factors II, VII, IX and X and on proteins C and S. Without it, these factors cannot bind calcium . Hemorrhagic disease of the newborn Biliary obstruction Malabsorption of vitamin K Vitamin K antagonist drugs Vitamin K deficiency

78. Biliary obstruction results in malabsorption of vitamin K and therefore decreased synthesis of factors II, VII, IX and X. Also there are decreased in factor V and fibrinogen. Dysfibrinogenemia. Thrombocytopenia. Functional abnormalities of platelets. Hypersplenism associated with portal hypertension. DIC. LIVER DISEASE

79. There is widespread deposition of fibrin within blood vessels with consumption of coagulation factors and platelets occurs as a consequence of many disorders which release procoagulant material into the circulation or diffuse endothelial damage or generalized platelet aggregation Disseminated coagulation disorders (DIC) Bleeding Disorders of Importance in Dental Care and Related Patient Management Anurag Gupta, BDS; Joel B. Epstein, DMD, MSD, FRCD(C); Robert J. Cabay , MD, DDSJCDA • • February 2007, Vol. 73, No. 1 •

80. DIC CAUSES Infections Gram neg septicemia Septic abortion M alignancy Widespread mucin secreting adeno-carcinoma Acute promyelocytic leukemia Hypersensitivity reactions Anaphylaxis Incompatible blood transfusion Obstetric complications Amniotic fluid embolism Eclampsia, retained placenta Widespread tissue damage Following surgery/trauma After severe burns Miscellaneous Liver failure Severe burns Hypothermia Snake venoms Acute hypoxia

81. DIC may triggered by the entry of procoagulant material into circulation: Amniotic fluid embolism APML Premature separation of placenta Initiated by widespread endothelial damage and collagen exposure: Septicemia Severe burns Widespread intravascular platelet aggregation Some bacteria, viruses and immune complexes may have direct effect on platelets. DIC: pathogenesis

82. Clinical features Bleeding , particularly from venipuncture Purpura Generalized bleeding in GIT, oropharynx, lungs, urogenital tract, vaginal bleeding Less frequently, microthrombi may cause skin lesions, renal failure, gangrene of fingers dic

83. Laboratory finding The platelet count is low Fibrinogen low Thrombin time is prolonged High level of fibrin degradation products (FDP) PT and APTT are prolonged in acute syndromes Blood film Fragmentation of red cells dic

84. Treatment Treat underlying cause Supportive therapy with fresh frozen plasma (FFP) and platelets concentrates Cryoprecipitate may also required

85. I f there is active bleeding, consultation with a hematologist may be considered to assist with definitive diagnosis and, for patients who are ultimately diagnosed with a bleeding disorder, individualized long-term hemostatic management . Treatment planning is essential for good outcome and should involve liaison between the dentist and the haemophilia centre . Consideration should be given to careful scheduling of invasive dental procedures to minimise re-exposure to factor concentrate. Written post-procedural instructions should be provided and must include emergency contact numbers. conclusion