Ron Hoffman, MD Thrombosis & Hemostasis Unit Rambam Medical Center Bleeding Tendency Ron Hoffman, MD Thrombosis & Hemostasis Unit Rambam Medical Center 2

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

Primary Hemostasis

Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa KEY POINT: The efficacy/safety ratio for currently available therapies is less than satisfactory due to their ill-defined, multitargeted activity. New antithrombotic strategies are needed that offer an improved efficacy/safety profile compared with existing antithrombotic agents.1,2 Currently available antithrombotic agents include the heparins (UFH and Enoxaparin), vitamin K antagonists (warfarin), and direct thrombin inhibitors (hirudins).3–6 The most widely used agents, heparins and vitamin K antagonists, have a range of actions on various components of the coagulation cascade. This contributes to the unpredictable clinical responses associated with these agents.3–5 Other limitations of currently available antithrombotics include3–7 High incidence of serious adverse effects, particularly bleeding complications Routine monitoring of coagulation markers may be needed and represents a substantial burden in terms of time and costs Narrow therapeutic margin Limited effectiveness in preventing VTE Factor Xa inhibitors are a novel class of antithrombotic agents designed to selectively target only 1 core step in the coagulation cascade, leading to potent and targeted effectiveness.8 Vitamin K dependant factors X Xa V Va II IIa IIa (Thrombin) Fibrinogen Fibrin For training purposes only—Not for distribution

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

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

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

(typical of coagulation factor disorders) Ecchymoses (typical of coagulation factor disorders)

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

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

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!

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

Family history prolonged PT and/or PTT 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

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

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

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

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

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

Pre-analytic errors Biological effects Problems with blue-top tube Hct ≥55 or ≤15 Lipemia, hyperbilirubinemia, hemolysis Laboratory errors Delay in testing Prolonged incubation at 37°C Freeze/thaw deterioration 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

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

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

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

Initial Evaluation of a Bleeding Patient - 4 Abnormal PT Abnormal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: Specific : Factors V, X, Prothrombin, Fibrinogen (rare) Non-specific: anti-phospholipid (common) 50:50 mix is normal 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)

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

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

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

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

Inherited platelet disorders

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

Features of Acute and Chronic ITP Features Acute ITP Chronic ITP Peak age Children (2-6 yrs) Adults (20-40 yrs) Female:male 1:1 3:1 Antecedent infection Common Rare Onset of symptoms Abrupt Abrupt-indolent Platelet count at presentation <20,000 <50,000 Duration 2-6 weeks Long-term Spontaneous remission Common Uncommon

Initial treatment of ITP Platelet count Symptoms Treatment (per µl) >50,000 None 20-50,000 Not bleeding None Bleeding Glucocorticoids IVIG <20,000 Not bleeding Glucocorticoids

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

Hemophilia A and B Hemophilia A Hemophilia B Coagulation factor deficiency Factor VIII Factor IX Inheritance X-linked X-linked recessive recessive Incidence 1/10,000 males 1/50,000 males Severity Related 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

Hemarthrosis (acute)

Treatment of Hemophilia A Intermediate purity plasma products Virucidally treated May contain von Willebrand factor High purity (monoclonal) plasma products No functional von Willebrand factor Recombinant factor VIII Virus free/No apparent risk

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

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

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

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

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

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

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

Objectives Clinical aspects of bleeding Medical history Personal Family Physical exam Approach to laboratory abnormalities Bleeding disorders Therapy 2

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

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.