Homestasis Surgery
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Transcript of Homestasis Surgery
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Haemostasis&Bleeding disorders
BYBY
Prof.DrProf.Dr. . Mervat Atfy MohamedMervat Atfy Mohamed
Objectives/Outline
Definitions Review pathophysiology of bleeding
Provide a framework for differential diagnosis of purpura
Brief discussion of some of the more common presentations and their management
Purpura
Hemorrhage into skin or mucous membrane
Due to:1. Loss of vascular integrity2. Platelet problems
Number Function
3. Clotting factor deficiency
Purpuric lesions
Petechiae capillary hemorrhages, purple macular lesions 2mm develop in areas of increased venous pressure
Purpura – 2mm-1cm
Ecchymoses – > 1cm, often tender
Non-blanching, may be raised
PlateletPlatelet
platelet platelet countcount
bleeding bleeding timetime
< 8 min< 8 min Platelet Platelet functionfunction
CoagulationCoagulation
ACTACT
PTPT
aPTTaPTT
thrombin thrombin timetime
fibrinogenfibrinogen
90-130 sec90-130 sec
12-15 sec12-15 sec
35-45 sec35-45 sec
< 14 sec< 14 sec
250-500 250-500 mg/dLmg/dL
Monitor Monitor heparinheparin
Extrinsic & Extrinsic & finalfinal
Intrinsic & Intrinsic & finalfinal
Final commonFinal common
↓↓in DICin DIC
FibrinolysisFibrinolysis
FDPFDP
d-dimerd-dimer↑↑during during fibrinolysisfibrinolysis
Hemostasis requires normal:
vessels platelets coagulation pathway components
Coagulation factor disorders
Inherited bleeding disorders
Hemophilia A and B vonWillebrands disease Other factor
deficiencies
Acquired bleeding disorders
Liver disease Vitamin K
deficiency/warfarin overdose
DIC
Hemostasis
Arteriolar vasoconstriction Formation of platelet plug
Activation of coagulation cascade Formation of permanent plug
Secondary Hemostasis
Primary Hemostasis
Four reasons for Cell based model
1. Congenital deficiency of XII, HMW kininogen and pre-kallikrein have prolonged PTT but NO BLEEDING PHENOTYPE.
2. These components are NOT required for hemostasis in vivo
3. TF/VIIa activates not only X but also VIII and IX
4. XI deficiency is not associated with bleeding phenotype
Cell Based coagulation model
TF bearing cells Adventital cells Myo-epithelial cells Endothelial cells
3 phases Initiation Priming Propagation
Initiation
TF bearing cells exposed to plasma
VII binds to TF and is activated VIIa Xa TF/VIIa IXa
TF/VIIa/Xa binds Va converts Prothrombin to Thrombin
Small amount of Thrombin Activate platelets accelerant
Priming
Release of granules containing V Cleaved to Va Formation of VIIIa
Propagation Activated platelets rapidly bind
V/VIII/IX Formation of VIII/IXa complex MAJOR activator of X Major prothrombin activator
Screening tests for bleeding disorders
Prothrombin time Measures function of VII, X,
Prothrombin, fibrinogen Prolonged when V, VII, X fall below
50% And when prothrombin level falls to
<30% Vit K dependent proteins:
Prothrombin, V, VII, X, Proteins C and S Warfarin, Liver Failure
Screening tests for bleeding disorders
aPTT Detects decrease in XII, XI, IX, VIII AS WELL AS Fibrinogen, prothrombin, V and X Heparin
Hemophilia
X linked recessive Deficiency of Factor VIII Degrees of severity:
Mild : 5% - 30% Moderate : 2% - 5% Severe : <2%
Prolonged PTT. Normal PT, vWf, BT
Hemophilia A and BHemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linkedrecessive recessive
Incidence 1/10,000 males 1/50,000 males
Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma
Complications Soft tissue bleeding
Hemophilia
Clinical manifestations (hemophilia A & B indistinguishable)
Hemarthrosis (most common)Fixed joints
Soft tissue hematomas (e.g., muscle)Muscle atrophyShortened tendons
Other sites of bleedingUrinary tractCNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions
Treatment of hemophilia A
Intermediate purity plasma products Virucidally treated May contain von Willebrand factor
High purity (monoclonal) plasma products Virucidally treated No functional von Willebrand factor
Recombinant factor VIII Virus free/No apparent risk No functional von Willebrand factor
Dosing guidelines for hemophilia A
Mild bleeding Target: 30% dosing q8-12h; 1-2 days (15U/kg) Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
Major bleeding Target: 80-100% q8-12h; 7-14 days (50U/kg) CNS trauma, hemorrhage, lumbar puncture Surgery Retroperitoneal hemorrhage GI bleeding
Adjunctive therapy amino caproic acid (Amicar) or DDAVP (for mild disease only)
Complications of therapy
Formation of inhibitors (antibodies) 10-15% of severe hemophilia A patients 1-2% of severe hemophilia B patients
Viral infections Hepatitis B Human parvovirus Hepatitis C Hepatitis A HIV Other
Treatment of hemophilia B Agent
High purity factor IX Recombinant human factor IX
Dose Initial dose: 100U/kg Subsequent: 50 U/kg every 24 hours
Von Willebrand disease
Most common congenital bleeding disorder
Bleeding is usually mild Etiology of bleeding
Platelet aggregation Major carrier for VIII
Types
von Willebrand DiseaseClinical features
von Willebrand factor Carrier of factor VIIIAnchors platelets to
subendothelium Bridge between platelets
Inheritance Autosomal dominant
Incidence 1/10,000
Clinical features Mucocutaneous bleeding
Laboratory evaluation of von Willebrand disease
Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency
Diagnostic tests:
vonWillebrand typeAssay 1 2 3
vWF antigen Normal
vWF activity Multimer analysis Normal Normal
Absent
Treatment of von Willebrand diseaseVaries by Classification Cryoprecipitate
Source of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF
multimers Correction of bleeding time is variable
DDAVP (Deamino-8-arginine vasopressin) Increases plasma VWF levels by stimulating secretion from
endothelium Duration of response is variable Used for type 1 disease Dosage 0.3 µg/kg q 12 hr IV
Factor VIII concentrate (Humate-P) Virally inactivated product Used for type 2 and 3
Type I vW disease
Autosomal dominant Normal vWF Quantitative decrease Normal PT Mildly prolonged aPTT
Rx of vW disease
DDAVP Cryoprecipitate Monitor VIII levels
DDAVP
1-Deamino, 8 D-arginine vasopressin
Rx for mild Hemophilia A , vW disease
Increases plasma fVIII, vWf from endogenous sorces
Amount of increase = factor transfusion
Useful for platelet dysfunction secondary to aspirin, dextran, ticlopidine
0.3- 0.4 mcg/kg Onset 30 min, peak 90-120 min
Cryoprecipitate
useful in treating factor deficiency (hemophilia A), von Willebrand's disease, and hypofibrinogenemia
uremic bleeding Each 5- to 15-mL unit contains more than
80 units of factor VIII and about 200 mg of fibrinogen.
Because the proteins mentioned previously are in relatively high concentration, a smaller volume may be given than would be required if plasma were used. Cryoprecipitate is usually administered as a transfusion of 10 single units.
NovoSeven
Recombinant f VIIa Activates X and IX (conversion of
prothrombin to thrombin) $$$$ Not FDA approved Anecdotal miraculous rescues
Heparin
Blocks Xa by binding to AT-III and thrombin.
Load 80 mg/kg Infusion 18 mg/kg Cleared from blood in 6hrs Neutralized by protamine 100u of Heparin = 1mg of
protamine
HIT
Heparin induced thrombocytopenia
Formation of IgG against Heparin- PF4 complexes
Upto 5% of patients Onset 4-5 days, but earlier if prior
exposure Can occur with flushes, heparin
bonded catheters also
LMW Heparins
More selective anti-Xa activity Less bleeding complications Do not affect PT Measure anti Xa activity <1% incidence of HIT
Enoxaparin
LMW heparin Porcine intestinal submucosa Binds to and accelerates AT-III
activity
Fondaparinux (Erixtra)
Synthetic pentasaccharide 5 sugar AT-III binding site similar
to Heparin 1000x more potent Very low- no incidence of HIT Cannot be given in CRI
Vitamin K
Necessary for addition of carboxyglutamate residues to the clotting factors synthesized in the liver.
Sites of Calcium binding Prothrombin, VII, IX, X drugs- cephalosporins, quinolones 5mg iv slowly corrects deficit in 6
hrs 10-25 mcg /day sq or im x 3days
Vitamin K deficiency
Source of vitamin K Green vegetablesSynthesized by
intestinal flora
Required for synthesis Factors II, VII, IX ,XProtein C and S
Causes of deficiency MalnutritionBiliary obstruction
MalabsorptionAntibiotic therapy
Treatment Vitamin KFresh frozen plasma
Vitamin K deficiency due to warfarin overdoseManaging high INR values
Clinical situation Guidelines
INR therapeutic-5 Lower or omit next dose;Resume therapy when INR is therapeutic
INR 5-9; no bleeding Lower or omit next dose;Resume therapy when INR is therapeutic
Omit dose and give vitamin K (1-2.5mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)
INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessaryResume therapy at lower dose when INR therapeutic
Chest 2001:119;22-38s (supplement)
Vitamin K deficiency due to warfarin overdoseManaging high INR values in bleeding patients
Clinical situation Guidelines
INR > 20; serious bleeding Omit warfarinAny life-threatening bleeding Vitamin K 10 mg slow IV infusion
FFP ± factor rhVIIa (depending on urgency)Repeat vitamin K injections every 12 hrs as needed
Warfarin
DIC
Consumption coagulopathy Systemic thromb-hemorrhagic
disorder Etiology:
Gram negative sepsis, crush injuries, amniotic fluid embolism, hemolysis, massive transfusion
Activation of clotting and fibrinolysis
Microvascular thrombosis, sequestration of platelets
Pathogenesis of DIC
Coagulation Fibrinolysis
Fibrinogen
FibrinMonomers
FibrinClot
(intravascular)
Fibrin(ogen)Degradation
Products
Plasmin
Thrombin Plasmin
Release of thromboplastic material intocirculation
Consumption ofcoagulation factors;
presence of FDPs aPTT PT TT
Fibrinogen
Presence of plasmin FDP
Intravascular clot Platelets
Schistocytes
Common clinical conditionsassociated with DIC
Sepsis
Trauma Head injury Fat embolism
Malignancy
Obstetrical complications Amniotic fluid embolism Abruptio placentae
Vascular disorders
Reaction to toxin (e.g. snake venom, drugs)
Immunologic disorders Severe allergic reaction Transplant rejection
DIC
Low fibrinogen High FDP Low platelets Elevated D-dimer
Disseminated Intravascular Coagulation (DIC)Mechanism
Systemic activationof coagulation
Intravasculardeposition of fibrin
Depletion of plateletsand coagulation factors
BleedingThrombosis of smalland midsize vesselswith organ failure
DICTreatment approaches
Treatment of underlying disorder
Anticoagulation with heparin
Platelet transfusion
Fresh frozen plasma
Liver Disease
Decreased synthesis of II, VII, IX, X, XI, and fibrinogenProlongation of PT, aPTT and Thrombin Time
Often complicated byGastritis, esophageal varices, DIC
TreatmentFresh-frozen plasma infusion (immediate but
temporary effect)Vitamin K (usually ineffective)
Stopping the bleeding
Direct pressure. More direct pressure. Pack. Pack.
Pack. Electrocautery. Ligate vessel
Methylcellulose Gelfoam
Absorbable Liquefies in 2-5
days Serves as a scaffold
for coagulation
Microfibrillar collagen
Decellularized bovine source Stimulates latelet adhesion Stops venous ooze Absorbed in 90 days
Thrombin + Gelfoam + CaCl
Thrombin for cleavage/activation Gelfoam as matrix Very useful in vascular surgery
Fibrin glue
Tiseel FDA approved in 1998 Concentrated fibrinogen and f VIII Thrombin and calcium Aprotinin to prevent clot
dissolution Takes time to prepare Good for diffuse oozing, needle
punctures, parenchymal injuries
Hemostasis:
BV Injury
PlateletPlateletAggregation
PlateletActivation
Blood VesselBlood Vessel Constriction
CoagulationCoagulation Cascade
Stable Hemostatic Plug
Fibrin formation
Reduced
Blood flow
Tissue Factor
Primary hemostatic plug
Neural
Lab Tests•CBC-Plt•BT,(CT)•PT•PTT
Plt StudyMorphologyFunctionAntibody
Hemostasis 1. Vascular phase : vasoconstriction,
immediately 2. Platelet phase : adhesion &
aggregation, several seconds after 3. Coagulation phase : later, contains extrinsic
& intrinsic pathways 4. Metabolic (fibrinolytic) phase: release
antithrombotic agent
primary
secondary
Hemostasis The intrinsic pathway : Initiated through surface contact activation of factor
XII by exposed subendothelial tissues--collagen The extrinsic pathway : Initiated through tissue thromboplastin released by
injured tissue, which activates factor VII
Antihemophilic factor; von Willebrand factor, VWF
Plasma thromboplastin component, PTC; Christmas factor
Antihemophilic factor; von Willebrand factor, VWF
Gla domain: activated by vit. K and NADH
Antithrombotic agent
Postaglandin: secretion by endothelial cell Antithrombin III (AT III): main Antithrombotic
agent Protein C: inactivate factor V and VIII with
protein S Plasmin: activated by urokinase and
streptokinase from plasminogen
primary
secondary
Etiology of bleeding disorder
1. Nonthrombocytopenia 2. Thrombocytopenia purpuras 3. Disorders of coagulation
Etiology of bleeding disorder
Nonthrombocytopenia 1. vascular wall alteration : infection,
chemical, allergy 2. Disorder of platelet function : Genetic defects (bernard-soulier disease:
glycoprotein, GP-Ib dysfunction with VWF) Aspirin, NSAIDs, broad-spectrum
antibiotics(Ampicillin, Penicillin, Gentamycin, Vancomycin)
Autoimmue disease
Adjunctive drug therapy for bleeding
Fresh frozen plasmaCryoprecipitateEpsilon-amino-caproic acid (Amicar)DDAVPRecombinant human factor VIIa (Novoseven)
Clinical Features of Bleeding Disorders
Platelet Coagulation disorders factor disorders
Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large, deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe
Correct surgical bleeding
ACT
elevated normal
Protamine 25-50mg PLT 0.1 u/kg
ACT
elevated
normal
Heparin level
yes
no
protamineCoagulation profile
FDP >32mcg/kg TEG abnormal clot lysis
fibrinolysis
FFP 5-10ml/kg CP 0.2-0.4u/kg EACA
PLT<70000
thrombocytopenia
PLT 0.1u/kg
bleeding time >20min
PLT dysfunction
Fibrinogen < 100mg/dL TEG abnormalhypofibrinogenemia
FFP 5-10ml/kg CP 0.2-0.4u/kg
aPTT >1.3x PT >1.5x
Anesthesiologist’s manual of surgical procedures
Fresh frozen plasma
Content - plasma (decreased factor V and VIII) Indications
Multiple coagulation deficiencies (liver disease, trauma) DIC Warfarin reversal Coagulation deficiency (factor XI or VII)
Dose (225 ml/unit) 10-15 ml/kg
Note Viral screened product ABO compatible
Cryoprecipitate
Prepared from FFP Content
Factor VIII, von Willebrand factor, fibrinogen Indications
Fibrinogen deficiency Uremia von Willebrand disease
Dose (1 unit = 1 bag) 1-2 units/10 kg body weight
Etiology of bleeding disorders
Thrombotic Thrombocytopenia purpuras (TTP):血栓性血小板低下紫斑
1. primary 2. secondary : Chemicals, ex: mitomycin C Physical agent (radiation)
Systemic disease (leukemia)Character:1. 1.Thrombocytopenia 2. Micro-angiopathic hemolytic
anemia(MAHA) 3. Fever 4. Hyporenal function 5. Neural systemic desturbance due to ischemic
2. Considered to be an emergency 3. Tx: plasma exchange (血漿置換術 ) and glucocortisone
application
Etiology of bleeding disorders
Disorders of coagulation 1. Inherited : Hemophilia A Christmas disease von Willebrandis Disease 2. Acquired : Liver disease Vitamin K deficiency Anticoagulation drugs (heparin,
coumarin) Anemia
Etiology of bleeding disorders
Thrombotic Thrombocytopenia purpuras (TTP):血栓性血小板低下紫斑
1. primary 2. secondary : Chemicals, ex: mitomycin C Physical agent (radiation)
Systemic disease (leukemia)Character:1. 1.Thrombocytopenia 2. Micro-angiopathic hemolytic
anemia(MAHA) 3. Fever 4. Hyporenal function 5. Neural systemic desturbance due to ischemic
2. Considered to be an emergency 3. Tx: plasma exchange (血漿置換術 ) and glucocortisone
application
Evaluation of bleeding disorders
1. Take history 2. Physical examination 3. Screening clinical laboratory tests 4. Observation of excessive bleeding following
a surgical procedure
Physical examination
Jaundice (黃疸 ) Petechiae (淤點 ): < 0.2 cm Purpura (紫斑 ): 0.2 cm-1 cm Eccymoses (淤斑 ): > 1 cm Spider angioma (蜘蛛斑 ) Oral ulcer Hyperplasia of gingiva Hemarthrosis (關節血腫 )
Platelet count
Test platelet phase: evaluation of platelet function
Normal (140,000 to 400,000/mm3) Thrombocytopenia : < 140,000/mm3 Clinical bleeding problem : <50,000/mm3 Spontaneous bleeding with life theartening :
<20,000/mm3
PT (Prothrombin Time)
Activated by tissue thromboplastin Tests extrinsic ( factor VII ) and common
( I,II,V,X ) pathways Normal ( 11-15sec ) Coumarin therapy- PT at 1.5 to 2.5 time International normalized ratio= INR, (1)
surgery can be done under INR< 3.0 (2) when INR=3.0-3.5, consultation is needed (3) delay surgery when INR>3.5
Activated PTT (aPTT)
Activated by contact activator (kaolin) Tests intrinsic and common pathway Normal ( 25-35 sec ) Heparin therapy- PTT in 50-65 sec range by
promote AT III
TT (Thrombin Time)
Activated by thrombin Tests ability to form initial clot from fibrinogen Normal ( 9 to 13 seconds )
1. No historical bleeding problem
3. Aspirin therapy
4. Coumarin therapy
6. Possible liver disease
7. Chronic leukemia
8. Long term antibiotic therapy
5. Renal dialysis (heparin)
2. History bleeding problem
9. Vascular wall alteration
10. Cancer (fibrinogenolysis)
Following surgical procedure
PT, aPTT, TT, BT
BT, aPTT
PT
aPTT
BT, PT
BT
PT
BT
TT
Dental management of the medically compromised patient
condition
8. thrombocytopenia
2. Coumarin therapy
4. Liver disease
7. Vascular wall defect
9. hemophilia
1. Aspirin therapy
Platelet count
5. leukemia
6. Long term antibiotic
3. Heparin therapy
10. fibrinogenolysis
+
-
+
+
+
-
-
++
-
-
BT
+
-
+
+
+
-
+
++
-
-
PTT
+
++
++
++
-
++
-
-
++
+
PT
+
++
-
++
-
++
-
-
-
+
TT
-
-
-
++
-
++
-
-
-
++
-: normal, +: may be abnormal, ++: abnormal
Patient at low risk
1. patient with no history of bleeding disorders, normal
examinations, no medications associated with bleeding
disorders and normal bleeding parameters
2. patients with nonspecific history of excessive bleeding
with normal bleeding parameters (PT, PTT, BT,
platelet count, are within normal time)
Patient at moderate risk
1. patients in chronic oral anticoagulant therapy
(coumadin) 2. patients on chronic aspirin therapy
Patient at high risk
1. patients with known bleeding disorders Thrombocytopenia Thrombocytopathy Clotting factor defects 2. Patient without known bleeding disorders
found to have abnormal , platelet count, BT, PT, PTT
Dental management of bleeding disorders Replacement therapy : 1. platelet concentrate : thrombocytopenia ( 1
unit= 30,000/ uL enough for 1 day ) 2. Fresh frozen plasma : liver disease,
Hemophilia B, vWD type III 3. Factor VIII,IX concentrate : Hemophilia A ( 1
unit /kg can add 2%, so 50 unit /kg add 100% ) 4. Factor IX concentrate : Hemophilia B 5. 1-desamino-8-darginine vesopressin (DDAVP)
: Hemophilia A, vWD type I, II
Antifibrinolytic therapy: 1. E-aminocaproic acid (EACA, Plaslloid) 2. Tranexamic acid (AMCA, Transamin)
Heparin (anticoagulant)
Complex inhibited ( IXa, Xa, XIa, XIIa ) Used in deep vein thrombosis , renal dialysis Rapid onset, Duration 4-6hrs ( given IV ) Monitoring by aPTT: 50-65 sec Discontinue 6 hrs before surgery then
reinstituting therapy 6-12hrs post –op Protamine sulfate can reverse the effect
Coumarin (Vit k anatagonist)
Inhibit Vit K action (Factor II,VII,IX,X) Used venous thrombosis, cerebrovascular
disease Duration haft-life 40hrs Monitored by PT : INR 1.5-2.5 PT>2.5, reduction coumarin dosage ( 2-3
days ) Vit. K can reverse the effect
Local hemostatic methods
splints, pressure packs, sutures; gelfoam with thrombin, surgicel, oxycel, microfibrillar collagen(avitene), topical AHF
Aspirin (antiplatelet)
Inhibit cycloxygenase, TxA2 formation Analgesic drug impairs platelet function Aterial thrombosis, MI Tests-BT, aPTT If tests are abnormal , MD should be consulted
before dental surgery is done Stop aspirin for 5 days, substitute alternative
drug in consultation with MD
Thrombocytopenia
Disease in number of circulation platelets Idiopathic thrombocytopenia, secondary
thrombocytopenia TX : is none indicated unless platelets<20000/mm3, or excessive
bleeding TX : Steroid, platelet transfusion
Von Willebrandis Disease
Gene mutation on Von Willebrandis factor; most common Inherited disease in America ( 1% )
Type I : 70%-80%, partial loss on quantity Type II : poor on quality Type III : severe loss on quantity, inactive to
DDAVP
Laboratory evaluation of von Willebrand disease
Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency
Diagnostic tests:
vonWillebrand typeAssay 1 2
3
vWF antigen Normal
vWF activity Multimer analysis Normal Normal
Absent
Hemophilia
Sex-linked recessive trait, X chromosome, male > female
Prolong aPTT, normal BT,PT Hemophilia A (factor VIII deficiency) Hemophilia B or Christmas disease (factor IX
deficiency) Severity of disorder : severe<1%, moderate 1-
5%, mild 6-30% TX : Replacement factors, antifibrinilytic
agents, steroids
Hemophilia-dental management
Preventive dentistry 1. tooth brushing, flossing, rubber cup
prophylaxis & topical fluoride, supragingival scaling 2. without prior replacement therapy Pain control 1. block anesthesia: factor level>50% 2. Avoid aspirin, NSAIDs
Hemophilia-dental management
Orthodontic treatment : 1. no contraindication in well-motivated
patients 2. care with placement of bands and wires Operative dentistry 1. rubber dam to protect tissue against
accidental laceration 2. wedges should be place to protect and
retract papilla
Hemophilia-dental management
Pulp therapy 1. Preferable to extraction 2. Avoid overinstrumentation and overfilling Periodontal therapy 1. no contraindication of probing and
supragingival scaling 2. deep scaling, curettage, surgery need
replacement therapy
Hemophilia-dental management
Oral surgery : 1. Dental extraction: 40%-50% level 2. Maxillofacial surgery (including surgery extraction of impaction teeth): 80-100% 3. Antifribrinilytic therapy & local hemastatic measure 4. do not open lingual tissue in lower molar
regions to avoid hemorrhage track down a endanger
airway
Summary
History, PE, Lab data Consultation with physician Antibiotics to prevent post-op infection Avoid aspirin and NSAIDs Local hemostatic measure is very important
Haemostasis
Hemostasis
1° hemostasis Vasoconstriction & retraction of cut
ends of blood vessels Release of FVIII-vWF Platelets adhere to endothelium granules release ADP, Ca &
ThromboplastinA2 aggregation Stabilization of platelet plug
Coagulation Cascade:
Intrinsic PathIntrinsic Path (12,11,9,8)
Extrinsic PathExtrinsic Path(7)
Fibrinogen Fibrin
CommonCommon PathPath (5,2)
(PT)(aPTT)
(TT)
(F & FDP)
(Factor 10)
(Thrombin)
Coagulation cascade
Vitamin K dependant factorsVitamin K dependant factors
XIIaXIIa
IIa
Intrinsic system (surface contact)Intrinsic system (surface contact)
XIIXII
XIXI XIa
Tissue factorTissue factor
IXIX IXa VIIa VIIVII
VIIIVIII VIIIaVIIIa
Extrinsic system (tissue damage)Extrinsic system (tissue damage)
XX
VV VaVa
IIII
FibrinogenFibrinogen FibrinFibrin
(Thrombin)(Thrombin)IIa
Xa
Laboratory Evaluation of the Coagulation Pathways
Partial thromboplastin time(PTT)
Prothrombin time(PT)
Intrinsic pathway Extrinsic pathway
Common pathwayThrombin time
Thrombin
Surface activating agent (Ellagic acid, kaolin)PhospholipidCalcium
Thromboplastin Tissue factor PhospholipidCalcium
Fibrin clot
Pre-analytic errors
Problems with blue-top tube Partial fill tubes Vacuum leak and citrate
evaporation
Problems with phlebotomy Heparin contamination Wrong label Slow fill Underfill Vigorous shaking
Biological effects• Hct ≥55 or ≤15
• Lipemia, hyperbilirubinemia, hemolysis
Laboratory errors• Delay in testing
• Prolonged incubation at 37°C
• Freeze/thaw deterioration
Initial Evaluation of a Bleeding Patient - 1
Normal PTNormal PTT
Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (2 anti-plasmin def) Vascular disorder Elevated FDPs
Ureasolubility
Normal
Abnormal
Factor XIIIdeficiency
Initial Evaluation of a Bleeding Patient - 2Normal PT
Abnormal PTT
Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)
Repeatwith
50:50mix
50:50 mix is normal
50:50 mix is abnormal
Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)
Abnormal PTNormal PTT
Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)
Repeatwith
50:50mix
50:50 mix is normal
50:50 mix is abnormal
Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)
Initial Evaluation of a Bleeding Patient - 4
Abnormal PTAbnormal PTT
Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)
Repeatwith
50:50mix
50:50 mix is normal
50:50 mix is abnormal
Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common)
Coagulation factor deficienciesSummary
Sex-linked recessive Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal
Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT
Factor XIII deficiency is associated with bleeding andimpaired wound healing
PT/ PTT normal; clot solubility abnormal
Factor XII, prekallikrein, HMWK deficienciesdo not cause bleeding
Disorders of Hemostasis
Vascular disorders Scurvy, easy bruising,
Platelet disorders Low Number or abnormal function
Coagulation disorders Factor deficiency.
Mixed/Consumption: DIC
Purpura - Manifestations
Platelet petechiae, mucosal bleeding CNS bleeding in severe cases
Coagulation disorders ecchymoses or hemarthroses
Vascular contusion, ecchymosis, hemorrhage palpable purpura
Clinical manifestations of disordered hemostasis
Clinical Characteristic
Platelet defect Clotting factor deficiency
Site of bleeding Skin, mucous membranes
Deep in soft tissues
Bleeding after minor cuts
Yes Unusual
Petechiae Yes No
Ecchymoses Small, superficial Large, palpable
Hemarthroses, muscle hematomas
Rare Common
Bleeding after surgery
Immediate, mild Delayed, severe
Platelet Coagulation
Petechiae, Purpura Hematoma, Hemarthrosis
Thrombocytopenias
Decreased production Platelet pooling and splenic
sequestration Increased destruction
Plt <100 000 Spontaneous bleeding uncommmon with
plt > 20 000 Bleeding time prolonged, PT/PTT normal
Sites of bleeding in thrombocytopenia
Skin and mucous membranes Petechiae Ecchymosis Hemorrhagic vesicles Gingival bleeding and epistaxis
Menorrhagia Gastrointestinal bleeding Intracranial bleeding
Classification of platelet disorders
Quantitative disorders
Abnormal distribution Dilution effect Decreased production
Increased destruction
Qualitative disorders
Inherited disorders (rare) Acquired disorders
Medications Chronic renal failure Cardiopulmonary
bypass
Associated with bleeding
Immune-mediated thrombocytopenia (ITP)
Most drug-induced thrombocytopenias
Most others
Associated with thrombosis
Thrombotic thrombocytopenic purpura
DIC Trousseau’s syndrome Heparin-associated
thrombocytopenia
Acquired thrombocytopenia with shortened platelet survival
Approach to the thrombocytopenic patient History
Is the patient bleeding? Are there symptoms of a secondary illness? (neoplasm, infection,
autoimmune disease) Is there a history of medications, alcohol use, or recent transfusion? Are there risk factors for HIV infection? Is there a family history of thrombocytopenia? Do the sites of bleeding suggest a platelet defect?
Assess the number and function of platelets CBC with peripheral smear Platelet function study
Platelet function screenResults
Epi ADP Interpretation
Normal Normal Normal platelet function
Abnormal Normal “Aspirin effect”
Abnormal Abnormal Abnormal platelet function
Valvular heart disease
Renal failure
Von Willebrand disease
Platelet transfusions
Source Platelet concentrate (Random donor)
Each donor unit should increase platelet count ~10,000 /µl
Pheresis platelets (Single donor)
Storage Up to 5 days at room temperature
“Platelet trigger” Bone marrow suppressed patient (>10-20,000/µl) Bleeding/surgical patient (>50,000/µl)
Platelet transfusions - complications
Transfusion reactions Higher incidence than in RBC transfusions Related to length of storage/leukocytes/RBC mismatch Bacterial contamination
Platelet transfusion refractoriness Alloimmune destruction of platelets (HLA antigens) Non-immune refractoriness
Microangiopathic hemolytic anemia Coagulopathy Splenic sequestration Fever and infection Medications (Amphotericin, vancomycin, ATG,
Interferons)
Laboratory Evaluation of BleedingOverview
CBC and smear Platelet count ThrombocytopeniaRBC and platelet morphology TTP, DIC, etc.
Coagulation Prothrombin time Extrinsic/common pathwaysPartial thromboplastin time Intrinsic/common pathwaysCoagulation factor assays Specific factor deficiencies50:50 mix Inhibitors (e.g., antibodies)Fibrinogen assay Decreased fibrinogenThrombin time Qualitative/quantitative
fibrinogen defectsFDPs or D-dimer Fibrinolysis (DIC)
Platelet function von Willebrand factor vWDBleeding time In vivo test (non-specific)Platelet function analyzer (PFA) Qualitative platelet disorders
and vWDPlatelet function tests Qualitative platelet disorders
Decreased Production
Malignancies (leukemia, lymphoma, neuroblastoma)
Bone marrow suppression Drug-related (aplastic anemia) Infection
Congenital Fanconi anemia TAR syndrome Wiscott-Aldrich Glycogen storage diseases
Platelet Dysfunction
Congenital Glanzmanns thrombasthenia (GP11b/IIIa
deficiency) Bernard Soulier (vWF receptor
deficiency) Acquired
Drugs (ASA/NSAIDs, lasix, nitrofurantoin) Renal disease Liver disease
Increased Platelet Destruction
Immunologic ITP SLE Isoimmunization (post-transfusion, neonatal) Drug related (heparin, quinine, dig, sulphonamides,
phenytoin) Infection
Sepsis Mechanical
DIC HUS-TTP Giant hemangioma (Kasabach-Merritt) Burns Trauma
Thrombocytopenia (cont’d)
Sequestration Hypersplenism Sickle cell anemia
Dilutional Massive transfusion
Loss of Vascular Integrity
Congenital Disorders of
connective tissue Ehlers-Danlos
syndrome Osteogenesis
imperfecta Marfan’s
Disorders of blood vessels
Hemorrhagic telangiectasia
Acquired Trauma/NAI Scurvy Steroid induced Increased intravascular
pressure coughing vomiting straining
Vasculitis Drug-related Infection
Viral Coxsackie A9, B3 Echoviruses 4,9 Atypical measles
Bacterial Meningococcemia Streptococcal
pharyngitis Septic emboli SBE Gonococcus
Rickettsial Rocky Mountain
spotted fever
Immune-mediated HSP SLE Serum sickness Dysgammaglobulinemia
Coagulation Factor Deficiency
Usually cause larger ecchymoses, deep tissue hemorrhage, and mucosal bleeding
Clotting factor deficiencies Congenital
von Willebrand’s disease Hemophilias Protein C and S deficiencies
Acquired Vitamin K deficiency
Liver disease Malabsorption
Diagnosis
Careful history and focused physical exam are keys to diagnosis
Laboratory tests are confirmatory
History
Present history Onset Location Associated symptoms
Fever Abdominal pain Arthralgias/joint swelling meningismus
History
Recent Viral illness Ill contacts Trauma Medications Immunization Travel
Past history Easy bruising or
bleeding Epistaxis, menorrhagia Excessive bleeding
following circumcision or dental extraction
Family History Bleeding disorders
Physical Exam
Sick vs. not sick Fever Lymph nodes Liver, spleen Joints – arthritis, hemarthrosis
Physical exam - Skin
Are lesions petechial, purpuric or ecchymotic?
Palpable purpura Vasculitis – HSP, RMSF, SLE Embolic lesions, meningococcemia, bacterial
endocarditis Location
Isolated petechiae above nipple line often associated with crying, coughing, vomiting
Purpura in dependent areas with HSP Ecchymoses on upper extremities,, or with
recognizable pattern –
Investigations - initial
CBC, peripheral smear Hgb - Blood loss, hemolysis Plt - thrombocytopenia WBC - Sepsis, leukemia
Prothrombin Time extrinsic and common pathway Factors II, V, VII, X
PTT intrinsic and common pathway all factors except VII and XIII
Specific tests
Factor Level Assays Fibrin, FSP, D-dimer Bleeding time - test of platelet function platelet aggregation - ADP, epinephrine,
collagen, and ristocetin
Cases
Case1 - 2 year old presents with purpuric rash
Acting otherwise well, eating normally
No fever, no weight loss, no systemic Sx
Recovered from a URI Rash is not itchy and is
flat No regular medications No hospitalizations or
chronic illnesses
Idiopathic Thrombocytopenic Purpura
Most common platelet disorder in children (5/100,000 prevalence)
Isolated thrombocytopenia (often < 20 000)
No associated conditions that may cause thrombocytopenia
Peak age 2-4 Male = female
ITP -pathophysiology
Development of IgG Abs to plt membrane glycoproteins as a result of an unbalanced response to an infectious agent or autoimmunity
Sequestration by splenic macrophages 70% cases occur 1-4 weeks following viral
illness VZV, EBV, influenza common causes
ITP - Clinical presentation
Usually acute, sudden onset with history of viral illness in the several weeks preceeding onset
Petechiae, purpura, and easy bruising
Epistaxis, gingival bleeding and menorrhagia are common
ICH very rare
Diagnosis
Hx, PE, CBC and peripheral smear Isolated thrombocytopenia
Bone marrow ex will show megakaryocytes hyperplasia (increased plt production)
Clinical course
Self limiting in 80-90% cases Normalize within months ↑ plt 5-7 days
Serious bleeding in 2-4% Epistaxis, GI, hematuria, menorrhagia ICH - 0.1-0.5%
Plt<10,000, NSAIDs, head trauma, Chronic 10-20%
ED Management – if severe bleeding
No controlled studies to guide management Transfusions of PRBC to HGB > 10 Transfusions of platelets (0.2unit/ kg) Corticosteroids
Prednisone 1-2mg/kg/d x 1-2wk, then taper Methylprednisolone 30mg/kg (max 1g) IV over 30
min QD x3 IgG
IvIG 1g/kg/d over 3 hrs x 2days Anti-Rh D (only if Rh+)
Rhogam 40-80ug/kg single dose over 5 min Splenectomy
Management if not bleeding
80% resolve spontaneously Treatment does shorten duration of
profound thrombocytopenia, but doesn’t alter clinical course
HSP
Vasculitis
Case 2
6 yo boy c/o periumbilical abdominal pain and rash x 2/7
Also c/o knee and ankle pain
Recently recovered from Grp A Strep infection
Henoch Schönlein Purpura
Palpable purpura Arthritis Abdominal pain +/-Glomerulonephritis Most common in spring 75% cases occur between ages 2-11 Often follows URI (grp A strep,
mycoplasma, VZV, EBV, parvovirus B19) Insect stings
HSP - pathophysiology
Exact cause unknown IgA mediated systemic vasculitis of
small vessels of skin, GIT, kidneys, synovium
HSP – Clinical features
Gradual or acute onset Blanching macules or papules on buttocks and
lower extremities that evolve into palpable purpura
Younger children - face, torso and extremities Arthritis of large joints (65-85%) 50% will have GI symptoms
Crampy abdominal pain +/- hematochezia Intussusception, bowel infarct, pancreatitis
25-50% develop glomerulonephritis Self limited, CRF in 1%
HSP - Diagnosis
Clinical diagnosis CBC, Urea, Cr, urine analysis DDx
Meningococcemia Rheumatic fever Rocky Mountain spotted fever Bacterial endocarditis Juvenile rheumatoid arthritis Systemic lupus erythematosis Reactive arthritis
HSP- Treatment
No specific Tx Majority resolve over 2-4 wks Symptomatic treatment of arthritis,
malaise, fever – acetaminophen or NSAIDs*
If severe abdo pain: prednisone 1-2mg/kg/d
Case 3
13 year boy c/o fever,, myalgias
Developed rash that started on hands and feet, now all over
Recent travel to camp in Colorado
Rocky Mountain Spotted Fever
1-2 weeks after bite by tick infected with Rickettsia rickettsii
fever, headache, myalgias, nausea, vomiting
petechial rash that begins on day 2-6 of fever
Starts on palms and soles and spreads centripedally over the torso within hours
Vasculitis 2º to rickettsial invasion of endothelial cells
RMSF - Epidemiology
SE and South Central US
Between April and October
Most common in under 15 yrs
Not contagious
RMSF - Treatment
Tx based on clinical suspicion
Abx, supportive care, +/- steroids <8 chloramphenicol 50mg/kg/day x 7-10 d 8 doxycycline 100mg PO BID x 7-10 d
Delayed treatment may result in DIC, shock, encephalopathy, gastrointestinal bleeding and myocarditis
Meningococcemia
most often seen in children younger than 5 years old
peak attack rate in infants < 6 months
gram-negative diplococcus
spread by respiratory droplets
outbreaks are common after index case exposes others
day care centers, schools, and colleges
Meningococcemia
begins abruptly with fever, lethargy, and rash
Initially the rash may be maculopapular or urticarial
Rapidly becomes purpuric as the disease progresses
15-25% of patients -purpura fulminans syndrome characterized by very large purpuric
lesions secondary to cutaneous hemorrhage and necrosis with DIC
Meningococcemia -Treatment
ABCs, supportive care Abx:
Ceftriaxone 200mg/kg/d IV q6H Vancomycin 60 mg/kg/d IV q6HIf severe B-lactam allergy: Chloramphenicol 75-100mg/kg/d IV q6H Vancomycin 60 mg/kg/d IV q6H
Case 4
5yo male with 3/7 hx watery diarrhea after attending a birthday party
Today developed fever and petechial rash
Looks unwell
Hemolytic Uremic Syndrome
Acute renal failure Microangiopathic hemolytic anemia Thrombocytopenia Fever
90% of cases follow a diarrheal illness Most often E. coli 0157:H7 Also Shigella, Salmonella, Yersinia, and
Campylobacter species From undercooked meats, unpasteurized dairy
HUS - pathophysiology
Verotoxins from bacteria endothelial cell injury cascade of events leading to hyaline microthrombi formation and consumptive thrombocytopenia
TTP seems to have similar pathophysiology but has predominately CNS effects cf predominately renal involvement with HUS
HUS-Tx
Diagnosis is clinical with supportive lab investigations CBC and smear - MAHA, thrombocytopenia PT/PTT, fibrinogen – normal Elevated BUN, Cr E. coli 0157:H7 on stool culture
Treatment - consultation with hematology and nephrology early dialysis, plasma exchange, treatment of
hypertension
Mortality 5-15%
Disorders of Coagulation
von Willebrand’s Disease
Most common inherited bleeding disorder 2 functions of vWF:
plt aggregation at site of injury carrier protein for FVIII
3 phenotypes: Type I - ↓ amount vWF (60-80% cases) Type II – vWF abnormal (10-30%) Type III – no vWF (1-5%)
patients typically present with bruising, menorrhagia, epistaxis or excessive bleeding after surgical procedures
von Willebrand’s Disease
Difficult to diagnose Platelets normal Prolonged bleeding time PTT – may be prolonged vWF activity, levels Factor VIII levels
von Willebrand’s Disease - Tx
DDAVP 0.3 ugkg IV over 30 min or SC 150ug nasal inh Releases FVIII and vWF from
endothelial cells (3-5x ↑ level)* Factor VIII/vWF concentrates Cryoprecipitate 1 bag/ 10kg Aminocaproic acid (Amicar®) Tranexamic acid (Cyclokapron®)
Hemophilia A and B
X-linked recessive Deficiency factor VIII (A) and IX (B) Multiple cutaneous bruises, muscular
bleeding and hemarthroses Prolonged PTT but normal PT and
bleeding time Tx - FFP or factor replacement – Life long
Summary
Bleeding caused by vascular, platelet or clotting factor problems
Broad differential diagnosis Relatively benign to potentially fatal
Most causes can be diagnosed by good history, physical exam and simple laboratory tests
Infections
Viral Atypical measles Congenital rubella Cytomegalovirus Enterovirus HIV Hemorrhagic varicella
Bacterial Meningococcemia Gonnococcemia Pneumococcal sepsis Haemophilus
influenzae sepsis Pseudomonas
aeruginosa sepsis
Rickettsial Rocky Mountain
spotted fever Protozoal
Malaria
BV Injury
PlateletPlateletAggregation
PlateletActivation
Blood VesselBlood Vessel Constriction
CoagulationCoagulation Cascade
Stable Hemostatic Plug
Fibrin formation
Reduced
Blood flow
Contact/ Tissue Factor
Primary hemostatic plug
Neural
Questions?
1. What is the mechanism for the thrombocytopenia in ITP?
2. What is the classic triad associated with hemolytic uremic syndrome?
3. How is hemophilia inherited? 4. Describe some indications for factor VIII
administration in a patient with hemophilia A.
5. What are the functions of von Willebrand factor?
6. What combination of laboratory tests are good screening studies for von Willebrand disease?
7. Why is it important to test for blood type in a person with suspected von Willebrand disease?
8. Name the vitamin K dependent factors. 9. Explain why the addition of normal
plasma to a patient's PTT test, will help to identify a circulating anticoagulant such as the lupus anticoagulant.
1. True/False: Newborns with Down syndrome and elevated white counts and immature forms frequently progress to leukemia.
2. True/False: Factor VIII deficiency is on the vitamin K dependent factors leading to Hemorrhagic disease of the newborn.
3. Rh antibodies in mothers can result from: . . . . . a. previous mismatched transfusions . . . . . b. prior miscarriages . . . . . c. fetal maternal transfusion . . . . . d. all of the above.
4. True/False: Red cell problems are usually seen with abnormalities of white cells and platelets.
5. True/False: Neonatal immune thrombocytopenia can result from maternal auto sensitization or fetal maternal transfusion.
6. True/False: Thalassemia and hemoglobinopathies can present in the neonatal period with severe anemia.