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Clinical Evaluation of Coagulation Disorders Prof. A. Inbal Director Thrombosis and Hemostasis Unit, Beilinson Hospital, Rabin Medical Center President.

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Presentation on theme: "Clinical Evaluation of Coagulation Disorders Prof. A. Inbal Director Thrombosis and Hemostasis Unit, Beilinson Hospital, Rabin Medical Center President."— Presentation transcript:

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2 Clinical Evaluation of Coagulation Disorders Prof. A. Inbal Director Thrombosis and Hemostasis Unit, Beilinson Hospital, Rabin Medical Center President of Israeli Society of Thrombosis and Hemostasis

3 NORMAL HEMOSTASIS  Normal PLATELETS -Primary Hemostasis  Normal COAGULATION FACTORS - Secondary Hemostasis  VASCULAR INTEGRITY

4 Primary Hemostasis: Platelet adhesion GPIb EC Sub Endo glycoprotein Ib (GPIb) – platelet receptor for VWF

5 Primary Hemostasis: Platelet aggregation EC GPIIbIIIa Fibrinogen GPIIbIIIa – platelet receptor for fibrinogen

6 Intrinsic Pathway Extrinsic Pathway Secondary hemostasis PTTPTTT FXII,FXI,FIX,FX FVIII,FV,FII,FI Fng, FDP FVII,FX,FV,FII FI

7 A Cell-Based Model of Coagulation Phase 1: Initiation of coagulation Takes place on TF- bearing cells (fibroblasts,) Result: Small amount of Thrombin Thrombin activates platelets, FV, FVIII TFPI

8 Phase 2: Propagation of coagulation Takes place on activated platelets Procoagulant complex assembly: ”tenase” (FVIIIa/FIXa) and ”prothrombinase” (FVa/FXa) → Thrombin generation A Cell-Based Model of Coagulation

9 Phase 3: Amplification of coagulation Takes place on activated platelets: IIa activates FXI FXIa activates additional FIX (FIXa) The burst of Thrombin (IIa) is generated to produce fibrin clot IXa Xa II IIa Fibrinogen Fibrin (clot) XIII XIIIa

10 Diagnosis of Bleeding Disorders

11 Bleeding history: what to look for ? Frequency of bleeding Severity of bleeding Sites of bleeding Age of appearance Positive family history Surgical and post-operative bleeding (early vs. late bleeding) Spontaneous or after trauma (post partum)

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13 Next….

14 Type (and sites) of bleeding

15 Primary Hemostasis Disorder: Superficial mucocutaneous bleeding Petechial lesions – pinpoint < 2 mm Pupuric lesions – 2mm – 1cm Echymoses - > 1cm

16 Purpura

17 Echymoses

18 Hematomas

19 Secondary Hemostasis Disorder: Deep muscular bleeding

20 Joint bleeding

21 Unusual sites

22 Cephal Hematoma

23 Abnormal menstrual bleeding Menorrhagia: Menstrual bleeding > 7 days Heavy bleeding > 3 days 17% of women in north London presenting with menorrhagia had either VWD or FXI deficiency Kadir et al. Lancet 1999

24 Some order….

25 Laboratory evaluation

26 Laboratory evaluation-cont.

27 Tests of Primary Hemostasis: Bleeding time

28 Light source Platelet Rich Plasma Shape change aggregationPhoto detector Agonist: ADP Epinephrine Collagen Ristocetin Tests of Primary Hemostasis: Platelet aggregometry

29 Platelet function studies

30 PTTPT TT Intrinsic Pathway Extrinsic Pathway Tests for secondary hemostasis FXII,FXI,FIX,FX FVIII,FV,FII,FI Fng, FDP FVII,FX,FV,FII FI

31 Assessment of Primary Hemostasis Platelets in circulation  150,000 to 450,000 cells/mm 3  70% in circulation; 30% in spleen  Life span ~ 7 to 10 days  Removed by reticuloendothelial system : liver, spleen

32 MECHANISMS OF THROMBOCYTOPENIA Augmented destruction Impaired production Pooling in the spleen

33 Assessment of Platelet Count Normal platelet count Thrombocytopenia and giant platelet

34 Pseudothrombocytopenia Platelet clumpingPlatelet satellism

35 Platelet countSymptoms ,000 Prolonged bleeding following trauma < 50,000 Easy bruising Purpura following minor trauma < 20,000 Spontaneous bleeding Petechiae May suffer spontaneous internal and intracranial bleeding Thrombocytopenia

36 Case: 25-year old female with leg purpura

37 IMMUNE THROMBOCYTOPENIA  Primary: Adult & childhood ITP  Secondary: Autoimmune disorders (SLE, Evan’s syndrome)  Antiphospholipid syndrome  Lymphoproliferative disorders  Viral diseases: EBV, HIV, CMV, HCV  Drug-induced (quinidine)  Alloimmune (post transfusion, neonatal): HPA 1 incompatibility

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40 Treatment of Patients with ITP Do not treat platelet count, treat a bleeding patient When bleeding is significant or platelet count is low (<20,000/mm3) give prednisone (1mg/Kg) for 4-6 weeks:  If there is response, taper off slowly  If there is no response- IVIG or anti D ± splenectomy  Rituximab (anti CD 20)

41 Qualitative platelet disorders - thrombocytopathy HereditaryAquired Glanzmann Thrombasthenia Bernard Soulier disease Plt granules deficiency Drugs (aspirin) Inhibitors (Ab)

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43 GLANZMANN THROMBASTHENIA Autosomal recessive Quantitative/qualitative abnormalities of GpIIb/IIIa (receptor of Fng, vWF, fibronectin, vitronectin) Plasma coagulation tests-normal Platelet quantity/morphology - normal, BT- prolonged Platelet aggregation-no response to all agonists except ristocetin Treatment – platelet transfusions (when Ab develop - rVIIa?) Prevention - prenatal diagnosis

44 Acquired Qualitative Disorders of Platelet Function -Thrombocytopathy Normal platelet count, abnormal platelet function Drugs: Aspirin, (Storage Pool Disease) Platelet secretory inhibition is caused by irreversible acetylation of cyclo-oxygenase Aspirin-induced platelet defect lasts for 7-10 days.

45 Intrinsic pathway abnormalities FXII, PK, HMWK

46 בן 71. מעברו: אין סיפור של נטיה לדמם. אין סיפור של דימומים במשפחה. לקראת ניתוח אלקטיבי נבדקו בדיקות קרישה. PT - 95% PTT - 105” (normal < 30”) Fng mg% 320,000 - PLT אבחנה? 2% - F XI Coagulation factors disorders: Case 1

47 FACTOR XI DEFICIENCY  A mild to moderate bleeding tendency  Bleeding is usually related to trauma and is “capricious”  Autosomal recessive inheritance  Heterozygotes rarely manifest bleeding  Frequent in Ashkenazi Jews  Similar deceases in both antigen and activity of FXI  Effective treatment by FFP or by a recently developed Factor XI concentrate

48 Case 2 14 months boy His mother noticed appearance of large hematomas on his buttocks and legs soon after he started walking.. Her father had ‘bleeding troubles” What is the diagnosis ??? PT - 95% PTT - 105” (normal < 30”) Fng mg% 320,000 - PLT

49 Hemophilia Hemophilia A – Factor VIII deficiency Hemophilia B – Factor IX deficiency

50 First description.. “For it was taught: if she circumcised her first child and he died, and a second one also died, she must not circumcise her third child..” Talmud, Yevamoth, 64b Tzipori, Israel fourth century

51 Queen Victoria

52 Map of hemophilia in Europe

53 Alexis -Tzarevits

54 Genetics of hemophilia

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56 Hemophilia A Common hereditary bleeding disorder (1:10,000) X-linked Mainly – joint and muscular bleeding

57 Deep muscular bleeding….

58 Joint bleeding…

59 Joint Deformity

60 Pseudotumor

61 Treatment….

62 FVIII infusion..

63 Inhibitors- Incidence studies Median age: years Median factor exposure days: 9-12, most inhibitors occur within 50 exposure days Inhibitors more frequent in Severe Hemophilia A patients, Afro-Americans, Large gene deletions, no definite HLA class 2 association 41-53% of congenital inhibitors are high- responding, transient inhibitors were reported in recombinant FVIII studies and mild hemophilia (20-60% antibody disappearance)

64 Treatment of patients with inhibitor (30%) - recombinant Factor VIIa (rFVIIa) rFVIIa binds to activated platelets rFVIIa activates FIX on platelet surface FIXa + FVIIIa activate FXa rFVIIa activates FX on platelet surface FXa + FVa generate Thrombin (FIIa) IXa Xa IIa Fibrinogen Fibrin XIII XIIIa rFVIIa II

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66 Case No 11 ללא דימומים בעבר בת 70, ללא דימומים בעבר, מתאשפזת עם דימום תוך בטני ספונטני. לא לוקחת תרופות. במעבדה: PT – תקין, PTT - 104", פיברינוגן 350, טסיות – 250,000 הטסט האבחנתי הוא: PTT של תערובת פלסמה נורמלית ושל החולה (1:1) PTT של התערובת מאורך לביסוס האבחנה יש לבדוק: LAC, FVIII, FIX. FVIII - % 3, אבחנה? Acquired FVIII deficiency

67 Incidence : 1.34 per 1mln Median age : 70 M / F : 1 / 1 50% - Idiopathic 50% - Secondary to immune disorders, malignancy, drugs (penicilline, sulfa, Interteron, M-dopa, Phenytoin), post partum (8%)

68 Spontaneous (life –threatening) bleeding Bleeding in the elderly : Retroperitoneal Intramuscular Hemarthroses Gastrointestinal Clinical features of acquired FVIII deficiency Laboratory: PTT - no normalization after addition of normal plasma, PT – normal; FVIII < 5%. DD : LAC (dilution of LAC positive plasma restores FVIII) Therapy: Steroids Immunosupression IVIG Rituximab (anti CD20)

69 בת 18, סיפור של דימומים מלידה,epistaxis, המטומות בעור, דימום לאחר עקירת שן, מנורגיה, המטוריה. יש אחות גדולה עם סיפור של דימומים כנ”ל כולל דימום אחרי לידה. הורים קרובי משפחה, לא מדממים. בדיקות מעבדה: PT - 92% PTT - 60” Fng - תקין מספר טסיות - תקין בדיקות נוספות: 5% - FVIII 0 - VWF Ag (VWF protein) 0 - Risfocetin cofactor (VWF activity) אבחנה? VWD Case 3

70 Von Willebrand E.A.: HEREDITAR PSEUDO- HAMOFILI Finska Laeksaellsk Handl 68: , 1926 VON WILLEBRAND DISEASE

71 VWD Family: Propositus: III-16bleeding from the nose, lips (trauma), tooth extraction, hemarthrosis of the ankle, at the age of 13 she bled to death during 4 th menstrual period. III7- nose bleed, died (2yr) from GIT bleed. III8- nose bleed, died (4yr) from tongue bleed. III11- GIT bleed (2yr), III12, III13, III14, III16- nose bleeds; III17- nose bleeds died (5yr) from GIT bleed; III18, III19- no bleed. II5- nose bleed; II6- nose bleed and menorrhagia I II III IV

72 Von Willebrand Disease (VWD) Definition: Hereditary bleeding disorder (autosomal dominant/recessive) Incidence: 1:1000 (1-2% by general screening; 1:10000 by bleeding symptoms), one of the most common hereditary bleeding disorders Clinical Presentation: Mucocutaneous bleeding (platelet defect), post-operative bleeding (coagulopathy - FVIII defect); menorrhagia and bleeding at child birth

73 Von Willebrand Factor VWF plays a dual role in hemostasis: 1 - VWF mediates platelet GPIb-subendothelial interaction, 2 - VWF is a carrier protein for FVIII GPIb

74 SUBENDOTHELIUM ENDOTHELIAL CELLS MEGAKARYOCYTES PLATELETS von Willebrand factor (VWF) Weibell Palade bodies  -granules FVIII VWF ECM

75 SDS-agarose gel monomer NC VWF multimerization CN dimer NC NC multimers NC NC >40,000 kD 600 kD NC NC

76 Cleavage of VWF multimers by ADAMTS 13 NC CN NC NC NC NC NC NC 140 kD 170 kD Normal

77 Laboratory tests Screening tests for evaluation of suspected VWD: bleeding time platelet count PTT Specific tests for diagnosis of VWD: von Willebrand factor antigen (VWF:Ag) ristocetin cofactor activity (VWF:RCo) collagen binding activity (VWF:CBA) FVIII Tests to distinguish among subtypes of VWD: ristocetin-induced platelet aggregation (RIPA) plasma VWF multimers VWF-FVIII binding assay

78 Classification of vWD Type 1 - most common (60-80%), partial quantitative deficiency of vWF, autosomal dominant Type 2 – (7-30%) qualitative deficiency of vWF, autosomal dominant Type 3 – (5-20%), complete deficiency of vWF, autosomal recessive Variants of Type 2: Type 2A - decreased affinity for platelet GPIb, absence of high/intermediate-molecular-weight vWF multimers Type 2B - increased affinity for platelet GPIb, absence of high-molecular-weight vWF multimers Type 2M - decreased platelet-dependent function, normal multimers Type 2N –autosomal recessive, decreased affinity to factor VIII (NORMANDY)

79 Pattern of VWF Multimers on PAGE 2a VWD 1 VWD 3 VWD 2b VWD Normal

80 Bleeding Symptoms in Patients with von Willebrand Disease Types 1, 2A, 2B, 2M VWD – mucocutaneous bleeding : epistaxis, gingival, after tooth extraction, menorrhagia, easy bruising and hematomas, postoperative, postpartum bleeding Type 2N – post operative, post labor bleeding Type 3 – hemarthrosis, intraabdominal, GIT (soft tissue bleeding) in addition to mucocutaneous bleeding

81 Treatment of von Willebrand Disease Type 1 - DDAVP and Hexacaprone Type 2a - vWF concentrate (Hemate-P); Hexacaprone, (DDAVP?) Type 2b - Hemate-P; Hexacaprone Type 3 - Hemate-P and Hexacaprone

82 Extrinsic pathway abnormalities

83 Case 4 18-years old soldier Prior to nose surgery – PTT normal, PT abnormal, (normal platelets) No personal bleeding history Negative family bleeding history Diagnosis? Factor VII deficiency

84 Factor VII Deficiency Hereditary autosomal recessive disorder Bleeding-only in homozygotes or compound heterozygotes F VII <1% - hemarthrosis, intracerebral heimorrhage F VII 1-5% - mild bleeding: epistaxis, gingival, menorrhagia Surgical procedures-no bleeding Laboratory evaluation: PTT-normal, PT-prolonged Therapy: for minor bleeding episodes - replacement is unnecessary (only Hexacaprone) Replacement - for severe bleeding (trough F VII: 20-25%) with FFP or F VII concentrate

85 Case No 10 בת 68. מתאשפזת בתמונה של בטן חריפה. מעברה - החלפת מסתם מיטרלי וטיפול בקומדין. בבדיקה פיזיקלית בולטת רגישות דיפוזית מעל לבטן עם דיסקולורציה מסביב לטבור. בדיקות מעבדה : PT לא נקרש, INR > 10, PTT – 50”, Plt - 150,000 אבחנה ? Coumadin overdose

86 1. Withhold warfarin 2. Administer 1 mg oral vitamin K 3. Reintroduce warfarin at a lower dose on the following day 4. Recheck INR in h 1. Withhold warfarin 2. Administer mg of oral vitamin K 3. Recheck INR in 24 h OR 1. Withhold warfarin 2.Administer mg of i.v. vitamin K 3. Recheck INR in 24 h Table 1 Suggested treatment strategies for various International Normalized Ratio ( INR ) values in asymptomatic patients receiving warfarin INR INR > 10 Treatment algorithms of coumadin overdose ( JTH 4:1853,2006)

87 1. Withhold oral anticoagulant treatment 2. Administer i.v. vitamin K (1- 10 mg). with higher doses in patients with more prolonged INR values 3. Consider administration of coagulation factors using complex concentrates or plasma 4. Treat remediable causes of hemorrhage 5. Provide medical support. Including transfusion of red blood cells or platelets. As required 1. Withhold oral anticoagulant treatment 2. Replace coagulation factors using complex concentrates or plasma 3. Administer i.v. vitamin K (5-10 mg) 4. Treat remediable causes of hemorrhage 5. Provide medical support, including transfision of red blood cells or platelets, as required Table 2 Treatment of coumarin-associated coagulopathy Suggested treatment strategies for bleeding patients Major but non-life- treatening bleeding with any increase in INR Life-threatening bleeding with any increase in INR Treatment algorithms of coumadin overdose ( JTH 4:1853,2006)

88 Common pathway abnormalities

89 Prolonged PT and PTT - deficiency of Factors II, V and X Rare autosomal recessive disorders In severe deficiency (<1%) spontaneous and posttraumatic bleeding (hemarthrosis, soft tissue, mucous membranes) PT, PTT prolonged; decrease in a specific factor level Treatment: for severe bleeding – FFP, PCC; for mild bleeding - Hexacaprone

90 Everything is abnormal…

91 Disseminated Intravascular Coagulation (DIC ) Widespread activation of coagulation Suppression of fibrinolytic system Impaired clearance of procoagulant material

92 The Mechanism of DIC Activation of Coagulation Intravascular deposition of fibrin Depletion of platelets Depletion of coagulation factors Bleeding Thrombosis & organ failure Microangiopathic hemolysis Fibrinolysis FDP

93 IL-6 TNF-  DIC and Inflammation IL-1 Bacteremia –> peptidoglycan –> TLR or CD14 ->NF-κB -> cytokines

94 Clinical Conditions Associated with DIC Sepsis Trauma Cancer Obstetric complications Vascular disorders Immunologic disorders

95 Clinical Picture of DIC Bleeding manifestations Neurologic: intracranial bleeding Skin: ecchymoses venipuncture oozing Renal: hematuria GIT: massive bleeding Signs of microvascular thrombosis Neurologic: delirium, coma Skin: ischemia, gangrene Renal: cortical necrosis Pulmonary: ARDS

96 Skin Necrosis Bleeding

97 Acral ischemia or necrosis

98 Laboratory Diagnosis of DIC Prolongation of PT, PTT, TT Decrease in fibrinogen Elevation of FDP, D-dimer Thrombocytopenia Microangiopathic hemolytic anemia Specific tests: TAT complex; PAP complex; F1+2, soluble fibrin-monomer

99 Principles of DIC Treatment Treatment of triggering disease (volume replenishment, antibiotics, evacuation of the uterus) Replacement therapy (transfusion of red cells, fresh-frozen plasma, platelets, cryoprecipitate) Heparin (when indicated) Antifibrinolytic drugs (never indicated)

100 Replacement Therapy in DIC For thrombocytopenia: 6 – 8 units of platelets For hypofibrinogenemia (<100mg/dl): 8 units of cryoprecipitate For prolonged PT, PTT (factors deficiency): 2 units of fresh-frozen plasma Repeat every 8 hours

101 Everything is OK

102 בת 12, בדואית. מעברה : סיפור של דימום מחבל הטבור לאחר הלידה. 2 אישפוזים עם דימום תוך מוחי. אישפוז נוסף בגלל דימום תוך בטני. מספרת שפצעים מתרפאים באופן איטי מאוד. סיפור משפחתי : שני ההורים קרובי משפחה, לא מדממים. עוד 6 אחים במשפחה. לשלושת האחים דימומים דומים לנ ” ל. במעבדה : PT - 87% PTT - 25” Fng Hb - 9 gr% PLT – normal BT - normal תפקוד טסיות תקין אבחנה?FXIII deficiency Case No 5

103 Thrombin Fibrinogen Fibrin (loose clot) Factor XIII – Plasma transglutaminase Fibrin (stable clot) Factor XIIIa  -glutamyl-ε-lysinecross links between fibrin chains  -glutamyl-ε-lysine cross links between fibrin chains Ca ++

104 Factor XIII Deficiency Autosomal recessive disorder Severe life-long bleeding: bleeding from stump of umbilical cord, intracranial, intraabdominal Homozygous females suffer recurrent abortions Delayed wound repair Heterozygotes – asymptomatic Treatment – Factor XIII concentrate (Fibrogammin); Prophylaxis: 20U/kg/4 weeks

105 NORMAL HEMOSTASIS COAGULATION FACTORS PLATELETS VASCULAR INTEGRITY

106 Case 6 מה חשוב לברר אצל התינוק כדי להגיע לאבחנה?

107 Case No year-old female with recurrent nose bleed : PTT, PT, Fng - normal PLT -320,000 Platelet aggregation, BT – normal Diagnosis – Hereditary Telangiectasia (Osler Weber Rendu)

108 Case 7 נולד במועד לאחר הריון תקין, ללא שימוש במכשירים. מה תבדקו?

109 Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu) Autosomal dominant disorder Incidence: 1 in 2351 to 1 in 16,500 Hallmark of HT – telangiectasia of venules and arterioles Molecular genetics: Defects in the gene endoglin (GP of endothelial cell membrane, binds TGF Clinical: Telangiectasia of the nose, face, skin, lung, brain, GIT leading to bleeding Coagulation tests – normal Treatment: Hexacaprone (Tranexamic acid)

110 Senile purpura Very common among elderly people Results from loss of peri-vascular fat and connective tissue No treatment

111 Case No 7 79 years old female Bypass surgery 6 months ago Since then on low dose aspirin Noticed recent appearance of superficial bleeding on hands upon minor contusions Diagnosis: Vascular Purpura

112 Case No 8 24 old female complains about blue marks that appear on her legs from time to time. Diagnosis: Purpura Simplex

113 Normal phenomena Easy bruising – “purpura simplex” Mainly- young females ( ♀ -55%, ♂ -22%) Sometimes – cyclical pattern Confined to limbs Occasionally painful – “devil’s pinch” No treatment

114 Is this abnormal ?

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