Contents
Introduction Hemostasis Clotting factors Cascade of clotting Disorders of bleeding and clotting Laboratory investigations Anticoagulants Periodontal considerations References
Introduction
Vertebrates
have evolved complex mechanisms to stem hemorrhage after injury. Failure of the hemostatic mechanisms may lead to fatal exsanguination. Any surgical procedure presents a severe challenge to the body s hemostatic mechanism.
HEMOSTASIS
Normal
hemostasis results from well regulated processes that maintain blood in a fluid,clot free state in normal vessels while inducing the rapid formation of hemostatic plug at the site of vascular injury. Dependent on the vascular wall,platelets and the coagulation cascade.
NORMAL HEMOSTASIS
Hemostasis, a complex process, can be divided into Four important steps: 1. Vasoconstriction due to local myogenic spasm, local neural response, and release of endothelin from the endothelium 2.Primary hemostatic plug: due to platelet adhesion, 2.Primary activation, RELEASE REACTION or degranulation (ADP, TXA2) and recruitment of other platelets 3.Secondary hemostasis due to activation of coagulation 3.Secondary cascade by tissue factor and phospholipid via extrinsic pathwaypathway- the end result being fibrin which traps the cells in the blood forming a clot 4. Clot organization/ Clot retractions
Vascular phase
Vasoconstriction
Primary hemostasis
Platelet adhesion Platelet aggregation Platelet plug formation
Coagulation system The coagulation inhibitory system Fibrinolytic system Pathological disturbances may occur in any or more of these systems and lead to bleeding tendency or intravascular coagulation
the blood stream anticoagulants normally predominate, so that the blood does not coagulate while it is circulating in the blood vessels When the blood vessel is ruptured, procoagulants from the area of tissue damage become activated and override the anticoagulants and then clot does develop
GENERAL MECHANISM Clotting takes place in 3 essential steps1. Formation of prothrombin activator 2. Conversion of Prothrombin to thrombin 3. Conversion of Fibrinogen to fibrin
Trauma to the blood Contact of the blood with the damaged endothelial cells or with collagen & other tissue elements outside the blood vessel Each instance leads to the formation of prothrombin activator
3.
Prothrombin Activator generally formed in two ways & interact constantly with each other. Both the pathways occur simultaneously
EXTRINSIC PATHWAY Explosive With severe trauma clotting occurs in 15 sec Begins with trauma to the vascular wall and surrounding tissue INTRINSIC PATHWAY Much slower Clotting occurs in 1- 6min Begins in the blood itself or exposure of the blood to the collagen from the traumatised blood vessel wall
Extrinsic pathway
The
release of Tissue Factor or Tissue Thromboplastin (Composed of Phospholipid from the membrane of the tissue plus lipoprotien complex) Activation of factor X. Effect of activated factor X to form Prothrombin activator
EXTRINSIC PATHWAY
INTRINSIC PATHWAY
Activation of factor XII 1.Trauma Release of platelet Phospholipid 2.Activation of factor XI 3.Activation factor IX - by activated factor XI 4.Activation factor X Role of factor VIII 5. Activation of activated X to form Prothrombin activator Role of factor V
INTRINSIC PATHWAY
COMMON PATHWAY
CLOT RETRACTION
Once the fibrin meshwork has appeared, RBCs & platelets stick to the fibrin strands. The platelets then contract and the clot undergoes clot retraction which: Pulls the torn edges of the vessel closer together, reducing residual bleeding and stabilizing the injury site Reduces the size of the injured area, making it easier for fibroblasts, smooth muscle cells, and endothelial cells to complete repairs
Fibrinolytic system
Contact activation by glass tube Partial thromboplastin Intrinsic pathway time activated by kaolin Prothrombin time Extrinsic pathway activated by brain tissue. Fibrinogen is converted to fibrin by added thrombin Duration of bleeding from skin puncture is timed
Thrombin time
Bleeding time
Normal Range
150,000 to 450,000/mm3 < 7 min (by simplate); 1 6 min (modified Ivy s test) Prothrombin time/international Control 1 s (eg, PT: 11 13 normalized ratio s/INR 1.0 Activated partial thromboplastin time Comparable to control ( eg 15-35 s ) 15Thrombin time Control 3 s (eg, 9 13 s) Fibrin degradation products < 10 g/dL g/dL Fibrinogen assay 200 400 mg/dL mg/dL von Willebrand s antigen 60 150% vWF activity Coagulation factor assays 6060-100% F VIII (eg F VIII assay) activity
PREPRE-OPERATIVE EVALUATION
HISTORY Prolonged bleeding after trauma/dental extraction Medications Bruises without apparent injury Excessive menstrual bleeding Relatives with bleeding problems Bleeding problems associated with major/minor surgery
Acquired
Henoch schonein purpura Easy bruishing purpura Senile purpura Factitial purpura Scurvy Severe infection Drugs
2) Consumption of platelets Immune - ITP - Sec.immune thrombocytopenia - Post transfusion purpura Coagulation - DIC - Gram
ve septicemia
3) Sequestration of platelets - Hypersplenism 4) Loss of platelets - Hemorrhage - Massive transfusion of stored blood - Hemodialysis
COAGULATION DISORDERS
Classification of Coagulation Disorders: Acquired Usually multiple factors are involved Hereditary Usually single factor is involved
Acquired Coagulation Disorders: The followings disorders are associated with acquired coagulation disorders: 1. Vitamin K deficiency a. Obstructive jaundice b. Coeliac disease c. Liver disease i. Defective synthesis of coagulation factors (I, II, V, VII, IV and X) ii. Increased fibrinolytic activity iii. Intravascular coagulation 2. Anticoagulant drugs 3. Disseminated intravascular coagulation 4. Active fibrinolysis 5. Massive transfusion of stored blood 6. Circulating inhibitors of coagulation
Common Hereditary Coagulation Disorders: 1. Hemophilia a. Hemophilia A b. Hemophilia B 2. Von-Willebrand disease 3. Other congenital deficiency disorders a. Fibrinogen deficiency b. Factor V deficiency c. Factor XIII
HEMOPHLIA A
X-linked recessive disorder resulting from deficiency of factor VIII Body fails to synthesize this essential globulin due to the absence of the specific enzyme which is controlled by the mutant gene Affects males. Sons of carriers have 50:50 chance developing hemophilia. Daughters of carriers have 50:50 chance of being carriers All daughters of an affected males are carriers but sons are normal Carriers rarely have bleeding tendency Prevalence of 5 per 100000 of population 10 times more common than hemophilia B
The hemophilia gene is carried on the X chromosome in males who lack a normal allele, the defect is manifested by clinical haemophilia. Women may be carriers
Hemophilia
Clinical manifestations (hemophilia A & B are indistinguishable) Hemarthrosis (most common) Fixed joints Soft tissue hematomas (e.g., muscle) Muscle atrophy Shortened tendons Other sites of bleeding Urinary tract CNS, neck (may be life-threatening) Prolonged bleeding after surgery or dental extractions
ORAL MANIFESTATIONS
Hemorrhage from many sites in oral cavity. Gingival bleeding massive and prolonged. Tooth eruption and exfoliation with severe prolonged hemorrhage Subperiosteal bleeding with reactive new bone formation causing tumor like expansion of bone (MANDIBULAR PSEUDOTUMOR) Uncontrolled or delayed hemorrhage may result from SURGICAL EXCISION,DENTAL EXTRACTION, PERIODONTAL CURETTAGE. Slight trauma may lead to HEMATOMA formation in
Haemophilia
(Christmas Disease)
Christmas disease is a congenital sex-linked hemorrhagic disorder due to absence, reduction or functional abnormality of factor IX Incidence 1 per 50,000 male Clinical features are same as Hemophilia Pathophysiology Factor IX coagulation activities is reduced or absent. A
Level of factor VIIIc activity Normal activity: 50-200% 50(0.5(0.5-2 g/ml) Mild activity : 5-25% 5(0.05(0.05-0.25 g/ml) Moderate activity : 1-5% 1(0.01(0.01-0.05 g/ml) Severe activity : <1% (0.01 g/ml)
Hemorrhage secondary to trauma, surgery and dental extraction. Occasional spontaneous bleeding, hemarthrosis, musculoskeletal bleeding. Severe spontaneous bleeding since childhood. Intracranial bleeding, bleeding into tongue and frenum, Bleeding in facial spaces of the neck.
Replacement therapy
Infusion
of plasma products enriched with factor VIII cryoprecipitate,partially purified factor VIII concentrate- Lyophilized concentratepowder Each unit of Factor VIII infused increases plasma level of recipient by 2% per Kg of body weight.
whole blood Fresh frozen plasma Cryoprecipitate prepared from human plasma Freeze-dried animal AHG Freeze Freeze-dried human AHG Freeze-
Precautions
Nerve Blocks - avoid if not on replacement therapy For infiltration no need for cover of antibiotics Tranexamic acid Prophylaxis - 10 ml of 4.8% aqueous solution, QID for 1 week should be prescribed for patients undergoing regional blocks
Preventive dental care: Use of fluorides Fissure sealants Dietary advice Regular dental checkups
Surgical procedure
Simple tooth extraction:
Regime I Regime II
1.
Factor VIII of 1. Epsilon Amino between 50-75% is 50caproic acid 5-6 5required. grams every 6th hrly. 2. Preoperative factor 2. Tranexamic acid 1gr VIII, i.v QID for 10 days. 3. Tranexamic acid 1g 3. If bleeding occurs (30mg/kg) QID during this time, a start 24 hrs preoperative dose of factor VIII
Desmopressin Therapy
0.3 0.5g/kg i.v just before the surgery, repeat 12 hrly if necessary for upto 4 days. Temporary correction of hemostatic defect. In patients with F VIII inhibitors, it releases - Factor VIIIc - von Willebrands factor - Tissue plasminogen activator from endothelial storage.
F VIII replacement Buccal approach to lower 3rd molars Minimal amount of bone should be removed Section teeth for removal whenever possible Extraction socket should be packed with: - Oxidized regenerated cellulose - Absorbable gelatin sponge - Bone wax - Tranexamic acid Acrylic protective splints on palates.
` `
Most common inherited bleeding disorder Due to inherited deficiency of vWF Affects both males & females Inherited as AUTOSOMAL DOMINANT but severe form as sexsexlinked recessive trait like true hemophilia vWF synthesized in endothelium and megakaryocytes Acts as carrier for factor VIII, protecting it from proteolytic degradation, thus deficiency lead to low factor VIII concentration Mediates platelet adhesion to damaged endothelium Mediates platelet aggregation, thus deficiency lead to defective platelet adhesion, which causes secondary deficiency in factor VIII
Type II
Exogenous vWF in cryoprecipitate to obtain 80-100% 80levels of factor VIII 1-2 hrs before surgery.
Maintains F VIII levels at 30-50% by 30infusing exogenous factor VIII every 12 hrs for 5-10 days. 5-
Factor XIII
Mild bleeding
Liver Diseases
The no. of factors may contribute to the haemostatic defect in liver disease. 1. Defective synthesis of clotting factors 2. Increased fibrinolytic activities 3. Intravascular coagulation. 4. Hepatitis. 5. Malabsorption of Vitamin-K due to parenchymatous diseases.
Drugs
Factors influencing susceptibility of the patient to anticoagulant drug. Potentiating
1. 2. 3. 4.
Inhibitory
1. 2. 3. 4.
balance of hemostasis is altered Results in the uncontrolled inappropriate formation and lysis of fibrin within the blood vessels Activation of coagulation occurs systemically
y
Fibrin
is deposited diffusely within capillaries, arterioles and venules Clotting proteins, inhibitors and platelets are consumed faster than they are synthesized
diagnosis is difficult
tests are nonspecific No single test can establish the definitive diagnosis of DIC PT, APTT, TT prolonged Fibrin degradation products are (+) Platelet count ; platelet function tests abnormal Schistocytes, thrombocytopenia on peripheral blood smear
DIC Therapy
Eliminate
Acute
Will
Replacement
Platelets,
therapy
plasma
Decreased Prolonged Norm. Norm. Norm./ increased Norm. Prolonged Prolonged Prolonged Norm. Norm. Prolonged
ANTICOAGULANTS
Three classes
Heparin
and Low Molecular Weight Heparins (e.g. enoxaparin, dalteparin) Coumarin Derivatves e.g. Warfarin, Acenocoumarol Indandione Derivatves e.g. Phenindione
Thrombin
AT
II- DIRECT THROMBIN INHIBITORS II Directly bind to the active site of thrombin inhibiting thrombin's downstream effects thus exerting their antithrombotic activity. These (in comparison with UFH) activity. UFH) have equal efficacy, increased bioavailability from the subcutaneous site of injection and less frequent dosing requirements (long half life),
Lepirudin: Lepirudin:
-Is effective in treatment of heparin induced thrombocytopenia and other thromboembolic effects. effects.
The
dose and frequency is controlled by aPTT measurement which is kept at 50 to 80 sec or 1.51.5-2.5 times the patients pretreatment value. Does not cross Blood brain barrier or placenta (It is anticoagulant of choice in pregnancy). Half life 1 4 hrs.
ORAL ANTICOAGULANTS ( VIT. K antagonists): -Coumarin anticoagulants include warfarin and dicumarol. Mechanism of anticoagulant activity (effective only in vivo): Inhibits vit. K epoxide reductase enzyme prevention of reactivation of vitamin K (regeneration of the reduced form from the epoxide form) interfere with synthesis of vitamin K Dependent clotting factors (II, VII, IX, X) in liver by blocking carboxylation of several glutamate residues in the above mentioned factors inactive clotting factors Rapidly and completely absorbed from intestine and is 99 % plasma protein bound. It crosses placenta, and is secreted in milk
Vitamin K reduced
Though the synthesis of clotting factors diminishes within 2-4 hrs of warfarin 2administration, anticoagulant effect develops gradually over the next 1-3 days as the level of 1clotting factors already present in plasma decline progressively. Thus there is always a delay between administration of drug and anticoagulant effect .
INDICATIONS
and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) Prophylaxis and treatment of Atrial fibrillation Valvular stenosis Heart valve replacement Myocardial infarction
Prophylaxis
Time required for blood to coagulate is called PT Performed by adding a mixture of calcium and thromboplastin to citrated plasma As a control, a normal blood sample is tested continuously PT ratio (PTR) = Patient s PT Control PT
ISI
PTpt prothrombin time of patient PTRef prothrombin time of normal pooled sample ISI International Sensitivity Index The International Normalized ratio is a recommended method for reporting prothrombin time results for control of oral anticoagulation (British Community for Standards in Hematology 1990).
(Coumadin) is monitored by a blood test called an INR (International Normalized Ratio). Warfarin belongs to a category of drugs known as narrow range of effectiveness drugs. This means that there is a very narrow range where the drug is considered therapeutic. For most indications, the INR range is 2.0 to 3.0. For people with mechanical 3.0. heart valve replacements and certain other conditions, the range is 2.5 to 3.5.
When your INR falls within your range (for example, between 2.0 and 3.0), this means that your level is therapeutic . When your INR level goes below the range (for example, 1.5) this means your blood is too thick , and places you at risk for blood clots. In this situation, your healthcare provider will prescribe a higher dose of warfarin for you to take. If your INR goes above your range (for example, 4.5) this means your blood is too thin , and places you at risk for bleeding. In this situation, your healthcare provider will prescribe a lower dose of warfarin for you to take. Because warfarin (Coumadin) affects each person differently, some people will be on small doses of warfarin and some will be on very large doses. Some people will achieve their appropriate INR quickly and others more slowly. The dose of warfarin you need is the one that keeps the INR in the therapeutic range for your condition. Many factors can affect your INR level including a change in diet, a change in medications, the onset of a new illness,or having to stop your warfarin for a procedure.
When a person first starts taking warfarin (Coumadin) the INR level tends to fluctuate up and down until the correct dose of warfarin is found that keeps your INR level stable. It is therefore very important to get your INR level checked frequently. In general, when you first start warfarin you will need to get your INR level checked 2 to 3 times a week for the first two weeks, then one to two times a week for two weeks, then every other week, then once a month. This may vary, depending on how your INR levels are. If the INR level becomes stable quickly, you will go for INR blood tests less often, if the INR level does not become stable, you will need to go for INR blood tests more often. When your INR level is too high or too low, you often will not feel any symptoms. This is why it is so important to get your INR blood tests done regularly!
PERIODONTAL CONSIDERATION
1) Consult the patient physician to determine the nature of the underlying medical problem and the degree of required anticoagulation. 2) A)INFILTRATION ANAESHESIA,SCALING AND ROOT PLANNING may be done-if INR less than done3. B)BLOCK ANAESTHESIA,MINOR PERIODONTAL SURGERY AND SIMPLE EXTRACTION-if INR less than 2 to 2.5 EXTRACTIONC)COMPLEX SURGERY OR MULTIPLE EXTRACTIONS may require INR less than 1.5 to 2.
3) Often, the anticoagulant is discontinued for 2 to 3 days before periodontal treatment(clearance half life of warfarin is 36-42 hours), and INR is checked on the day of therapy.If INR is within acceptable target range,the procedure is done and anticoagulant resumed immediately after treatment. 4)Careful technique and complete wound closure are paramount. For all procedures, application of pressure can minimize hemorrhage. 5)Use of oxidized cellulose, micrifibrillar collagen, topical thrombin,and tranexamic acid should be considered for persistent bleeding.
SIDE EFFECTS
Hemorrhage Skin necrosis Purple toe syndrome Microembolization Teratogenecity Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.
Periodontal Procedures
Periodontal health is critically important because of two principal reasons: 1) Hyperemic gingiva contributes to spontaneous and induced gingival bleeding 2) Periodontitis is a leading cause of tooth morbidity, necessitating extraction Oral hygiene neglect due to fear of toothbrushinduced bleeding Oral physiotherapy can be accomplished Periodontal probing and supragingival scaling and polishing can be done routinely. Careful subgingival scaling with fine scalers
Severely inflamed and swollen tissues are best treated initially with or by gross debridement with a cavitron or hand instruments to allow gingival shrinkage prior to deep scaling
Periodontal surgical procedures warrant elevating circulating factor levels to 50% and use of posttreatment antifibrinolytics
83
Dabigatran and rivaroxaban, new oral anticoagulants. new approaches in dentistry J Clin Exp Dent. 2010;2(1):e1-5. 2010;2(1):e1
New generation of antithrombotic agents not related to coumarin are dabigatran etexilate (Pradaxa ) and rivaroxaban (Xarelto ). Anticoagulant DABIGATRAN is the first direct thrombin inhibitor, orally available. Specifically and available. reversibly inhibits thrombin, so the duration of action is predictable. The anticoagulant effect correlates well with plasma drug concentrations, which implies an effective anticoagulation with low bleeding risk without major problems of interactions with other drugs.
References
PRINCIPLES OF INTERNAL MEDICINE, HARRISON S, 15TH EDITION. BURKET S ORAL MEDICINE 10TH EDITION CONCISE MEDICAL PHYSIOLOGY, CHOUDHARI, 9th EDITION. CLINICAL PERIODONTOLOGY,CARANZZA,10TH EDITION. ESSENTIAL OF MEDICAL PHARMACOLOGY, K.D.TRIPATHI,6TH EDITION. JOURNAL OF CLINICAL AND EXPERIMENTAL DENTISTRY 2010;2(1)