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Bleeding Tendency Ron Hoffman, MD Thrombosis & Hemostasis Unit Rambam Medical Center.

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Presentation on theme: "Bleeding Tendency Ron Hoffman, MD Thrombosis & Hemostasis Unit Rambam Medical Center."— Presentation transcript:

1 Bleeding Tendency Ron Hoffman, MD Thrombosis & Hemostasis Unit Rambam Medical Center

2 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

3

4 Primary Hemostasis

5 XIIa Coagulation cascade IIa Intrinsic system (surface contact) XII XI XIa Tissue factor IX IXa VIIa VII VIIIVIIIa Extrinsic system (tissue damage) X VVa II FibrinogenFibrin (Thrombin) IIa Vitamin K dependant factors Xa

6 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

7 Clinical Features of Bleeding Disorders PlateletCoagulation disorders factor disorders Site of bleedingSkinDeep in soft tissues Mucous membranes(joints, muscles) (epistaxis, gum, vaginal, GI tract) PetechiaeYesNo Ecchymoses (“bruises”)Small, superficialLarge, deep Hemarthrosis / muscle bleedingExtremely rareCommon Bleeding after cuts & scratchesYesNo Bleeding after surgery or traumaImmediate,Delayed (1-2 days), usually mildoften severe

8 Petechiae Do not blanch with pressure (cf. angiomas) Not palpable (cf. vasculitis) (typical of platelet disorders)

9 Ecchymoses (typical of coagulation factor disorders)

10 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

11 Systemic screening Epistaxis – age, frequency, spontaneous, how long, way of bleeding arrest, blood products. Oral cavity : tooth, gums, tonsils + adenoids. Skin Trauma: minor, major GI & urinary tract. Brain Gynecological: menses, pregnancy and deliveries abortions. Hemarthroses, muscular. Circumcision, umbilical

12 Important aspects Differentiation between hemostatic bleeding and surgical. Immediate vs. late bleeding (primary vs secondary hemostatic problem). Abnormal blood vessel Normal coagulation factors may be present in pregnancy!

13 Medications – most common COX & ADP inhibitors : Aspirin, Clopidogrel, NSAID Background disease Acute leukemia (APL) MPD Uremia Cirrhosis

14 Family history 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 and impaired wound healing PT/ PTT normal; clot solubility abnormal  Factor XII, prekallikrein, HMWK deficiencies do not cause bleeding

15 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

16 Clinical bleeding Senile purpura, purpura simplex Signs of systemic disease : ED, Cushing, Amyloidosis, Cirrhosis, MPD

17 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

18 CBC and blood smear (thrombocytopenia, thrombocytopathia). Basic coagulation tests: PT, aPTT, Fibrinogen. Advanced coagulation tests: TT, Mixing assays, Factor levels, PFA, Fibrinolysis assays.

19 Laboratory Evaluation of the Coagulation Pathways Partial thromboplastin time (PTT) Prothrombin time (PT) Intrinsic pathwayExtrinsic pathway Common pathwayThrombin time Thrombin Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium Thromboplastin Tissue factor Phospholipid Calcium Fibrin clot

20 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

21 Initial Evaluation of a Bleeding Patient - 1 Normal PT Normal PTT Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysisPlatelet disorder (a2 anti-plasmin def)Vascular disorder Elevated FDPs Urea solubility Normal Abnormal Factor XIII deficiency

22 Initial Evaluation of a Bleeding Patient - 2 Normal PT Abnormal PTT Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare) Repeat with 50:50 mix 50:50 mix is normal 50:50 mix is abnormal Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)

23 Initial Evaluation of a Bleeding Patient - 3 Abnormal PT Normal PTT Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC) Repeat with 50:50 mix 50:50 mix is normal 50:50 mix is abnormal Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)

24 Initial Evaluation of a Bleeding Patient - 4 Abnormal PT Abnormal 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) Repeat with 50:50 mix 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)

25 Thrombin Time Bypasses factors II-XII Measures rate of fibrinogen conversion to fibrin Procedure: Add thrombin with patient plasma Measure time to clot Variables: Source and quantity of thrombin

26 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

27 Thrombocytpenia and thrombocytopathia, Hemophilia A,B, Acquired VWD Acquired coagulations factors deficiency: Cirrosis

28 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 MPD

29 Inherited platelet disorders

30 Thrombocytopenia Immune-mediated Idioapthic (ITP) Drug-induced Collagen vascular disease Lymphoproliferative disease Viral (HIV) Non-immune mediated DIC Microangiopathic hemolytic anemia Drugs

31 Features of Acute and Chronic ITP FeaturesAcuteITPChronic ITP Peak ageChildren (2-6 yrs)Adults (20-40 yrs) Female:male1:13:1 Antecedent infectionCommon Rare Onset of symptomsAbruptAbrupt-indolent Platelet count at presentation<20,000<50,000 Duration2-6 weeksLong-term Spontaneous remissionCommonUncommon

32 Initial treatment of ITP Platelet countSymptomsTreatment (per µl) >50,000None 20-50,000Not bleedingNone BleedingGlucocorticoids IVIG <20,000Not bleedingGlucocorticoids BleedingGlucocorticoids IVIG

33 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

34 Hemophilia A and B Hemophilia AHemophilia B Coagulation factor deficiencyFactor VIIIFactor IX InheritanceX-linkedX-linked recessive Incidence1/10,000 males1/50,000 males SeverityRelated to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 5-25% - Mild - bleeding with surgery or trauma Complications Soft tissue bleeding

35 Hemarthrosis (acute)

36 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

37 Acquired hemophilia Associated with: auto immunity, post partum, cancer and drugs Bleeding manifestations : muscular, internal, usually not hemarthroses Diagnosis : prolonged aPTT, mixing FVIII levels, r/o LAC Responding to immuno suppressive (IVIG) Control of bleeding by: high dose FVIII, Porcine FVIII, APCC, rFVIIa

38 Congenital Coagulopathies FXII deficiency FXI deficiency Hemophilia A + B Afibrinogenemia FV + FVIII deficiency FVII deficiency FXIII deficiency Type 3 VWD

39 VWD Clinical Features von Willebrand factor Synthesis in endothelium and megakaryocytes Forms large multimer Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets Inheritance - autosomal dominant Incidence - 1/10,000 Clinical features - mucocutaneous bleeding

40 Laboratory evaluation of VWD Classification Type 1 Most common Partial quantitative deficiency Type 2 Qualitative deficiency Type 3Total quantitative deficiency Diagnostic tests: Assay VWD type vWF antigenlow normal very low vWF activity lowlow very low FVIIIlow normal absent Multimer analysis normal abnormal normal

41 Treatment of VWD Cryoprecipitate Source of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF multimers DDAVP (deamino-8-arginine vasopressin)  plasma VWF levels by stimulating secretion from endothelium Duration of response is variable Not generally used in type 2 disease Dosage 0.3 µg/kg q 12 hr IV Factor VIII concentrate (Intermediate purity) Virally inactivated product

42 Vitamin K deficiency Source of vitamin K Green vegetables Synthesized by intestinal flora Required for synthesisFactors II, VII, IX,X Protein C and S Causes of deficiencyMalnutrition Biliary obstruction Malabsorption Antibiotic therapy (coumadin) TreatmentVitamin K Fresh frozen plasma

43 Liver Disease and Hemostasis 1. Decreased synthesis of II, VII, IX, X, XI, and fibrinogen 2. Dietary Vitamin K deficiency (Inadequate intake or malabsortion) 3. Dysfibrinogenemia 4. Enhanced fibrinolysis (Decreased alpha-2- antiplasmin) 5. DIC 6. Thrombocytoepnia due to hypersplenism

44 Objectives I. Clinical aspects of bleeding II. Medical history Personal Family III. Physical exam IV. Approach to laboratory abnormalities V. Bleeding disorders VI. Therapy

45 Treatment Approaches to the Bleeding Patient Red blood cells Platelet transfusions Fresh frozen plasma Cryoprecipitate Amicar DDAVP Recombinant Human factor VIIa

46 Approach to bleeding disorders Medical history – the most important diagnostic “test” Identify and correct any specific defect of hemostasis Laboratory testing is almost always needed to establish the cause of bleeding Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categories Specialized testing is usually necessary to establish a specific diagnosis.


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