Evaluation of the bleeding patient V. Kinsella M.D. January,27 2006

MILD bleeding Platelets secretion disorders vW deficiency Platelets dense granules deficiency 4. Unknown

Hemostasis and thrombosis Dependent on 3 factors: Vascular endothelium Platelets Coagulation system

1.Clinical aspects of bleeding 2

1.Clinical aspects of bleeding Evaluation of patients with bleeding is a multi-step process: Complete history Detailed physical exam Laboratory evaluation

history Is there a personal or family history of bleeding after surgical procedures, dental procedures, childbirth, or trauma? When the bleeding episode started? Has the patient received medications that can cause or make worse a bleeding problem?

history Many drugs can contribute to bleeding; semisynthetic penicillins cephalosporins calcium channel blocker dipyridamole thiazides alcohol quinine, quinidine chlorpromazine, sulfonamides INH, rifampin methyldopa phenytoin, barbiturates, warfarin, heparin, thrombolytic agents NSAIDs, ASA allopurinol TMP/SMX

physical exam 1. Assess volume status (correct shock if present) 2. Look for hepatosplenomegaly 3. Do a rectal exam for evidence of GI bleeding 4. Examine oropharynx for evidence of petechiae

Clinical aspects of bleeding 2

physical exam Look for physical signs and symptoms of diseases related to capillary fragility: Cushing’s syndrome, Marfan syndrome or exogenous steroids "senile purpura” Petechiae secondary to coughing, sneezing, Valsalva maneuver, blood pressure measurement vasculitis ("palpable purpura") Telangiectasias (Osler-Weber-Rendu syndrome) (HHT)

(typical of platelet disorders) petechiae (typical of platelet disorders) Do not blanch with pressure (angiomas) Not palpable (vasculitis)

vasculitis (palpable rash)

2. Hematologic disorders causing bleeding Platelet disorders Coagulation factor disorders 2

Clinical differentiation Platelets x Coagulation Defects

Platelets Defects Generally have immediate onset of bleeding after trauma Bleeding is predominantly in skin, mucous membranes, nose, GI tract, and urinary tract Bleeding may be observed as petechiae (<3 mm) or ecchymoses (>3 mm

Clinical aspects of bleeding 2

Coagulation Defects "Deep" bleeding (in the joint spaces, muscles, and retroperitoneal spaces) is common. Observed on exam as hematomas and hemarthroses.

(typical of coagulation factor disorders) Hematoma (typical of coagulation factor disorders)

Hemarthrosis (acute)

Laboratory Evaluation of Bleeding CBC and smear Platelet count Thrombocytopenia RBC and platelet morphology TTP, DIC, etc. Coagulation PT extrinsic/common pathways PTT Intrinsic/common pathways Coag. factor assays Specific factor deficiencies 50:50 mix Inhibitors (e.g., antibodies) Fibrinogen assay Decreased fibrinogen Thrombin time Qualitative/quantitative fibrinogen defects D-dimer Fibrinolysis (DIC)

Laboratory Evaluation of Bleeding Platelet function von Willebrand factor vWD Bleeding time In vivo test (non-specific) Platelet function analyzer (PFA) Qualitative platelet disorders

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 Common pathway Thrombin time Thrombin Fibrin clot

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

Initial Evaluation of a Bleeding Patient Normal PT Normal PTT Consider evaluating for: Platelet disorder Mild factor deficiency Factor XIII Monoclonal gammopathy Abnormal fibrinolysis a2 anti-plasmin deficiency Vascular disorders Dysfibrinogenemia

Initial Evaluation of a Bleeding Patient Elevated PT Normal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: 1.Specific: Factor VII (rare) 2.Non-specific: Anti-phospholipid 50:50 mix is normal Test for factor deficiency: 1.Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC) 2. Deficiency of factor VII (rare)

Initial Evaluation of a Bleeding Patient 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) 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 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)

Bleeding time 5-10% of patients hospitalized patients have a prolonged bleeding time Most of the prolonged bleeding times are due to aspirin or drug ingestion Prolonged bleeding time does not predict excess surgical blood loss Not recommended for routine testing in preoperative patients

Thrombin Time Measures rate of fibrinogen conversion to fibrin Procedure: Add thrombin with patient plasma Measure time to clot Variables: Source and quantity of thrombin

Causes of prolonged Thrombin Time Heparin Hypofibrinogenemia Dysfibrinogenemia Paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies

PLATELETS

Approach to the thrombocytopenic patient History Is the patient bleeding? 2. Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) 3. Is there a history of medications, alcohol use, or recent transfusion?

Approach to the thrombocytopenic patient History 4. Are there risk factors for viral infection? 5.Is there a family history of thrombocytopenia? 6. Do the sites of bleeding suggest a platelet defect?

Approach to the thrombocytopenic patient Assess the number and function of platelets CBC with peripheral smear Bleeding time Platelet aggregation study PFA

Classification of platelet disorders Quantitative disorders Abnormal distribution Dilution effect Decreased production Increased destruction

Classification of platelet disorders Qualitative disorders Inherited disorders (rare) Acquired disorders Immune Medications Chronic renal failure Cardiopulmonary bypass Liver disease

Inherited platelet disorders Rare congenital abnormalities on synthesis or release of secretory granules

Inherited platelet disorders Gray platelets syndrome: No alpha granules

Inherited platelet disorders May-Hegglin: Thrombocytopenia Large platelets Neutrophils – Dohle bodies

Inherited platelet disorders Glazmann’s thrombasthenia: Congenital deficiency or abnormality of GP IIb-IIIa Bernard-Solier syndrome: Congenital deficiency or abnormality of GP Ib

Acquired platelet disorders Decreased production: Ineffective thrombopoiesis - MDS Increased destruction: Immune Non-immune Poor aggregation

Increased platelets destruction 1. Immune-mediated Idiopathic - ITP Drug-induced Collagen vascular disease Lymphoproliferative disease Sarcoidosis 2.Non-immune mediated DIC Microangiopathic hemolytic anemia

ITP is a diagnosis of exclusion !

Initial Treatment of ITP Platelet count Symptoms Treatment >50,000 None 20-50,000 Not bleeding None Bleeding Glucocorticoids IVIG <20,000 Not bleeding Glucocorticoids Bleeding Glucocorticoids Hospitalization Rituximab

COAGULATION FACTOR DEFECTS

Inherited Coagulation factor bleeding disorders vonWillebrand’s disease Hemophilia (A and B)

vonWillebrand disease Most common hereditary coagulation disorder Autossomal dominant Incidence 1:1000 Erik A. vonWillenbrand M.D. (1870-1949)

vonWillebrand factor Synthesis in endothelium and megakaryocytes Forms large multimers Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets

vonWillebrand disease Abnormal synthesis of von Willebrand factor (vWF) causes decreased platelet adhesion and decreased serum levels of factor VIII

vonWillebrand disease Classification Type 1 Partial quantitative deficiency (“decreased”) Type 2 Qualitative deficiency (“abnormal”) Type 3 Total quantitative deficiency (“absent”)

vonWillebrand disease Laboratory evaluation: vonWillebrand type Assay 1 2 3 vWF antigen ß Normal ßß vWF activity ß ß ßß Multimer analysis Normal Normal Absent

Treatment of von Willebrand Disease 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

Treatment of von Willebrand Disease Cryoprecipitate Source of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF multimers Factor VIII concentrate (Intermediate purity) Virally inactivated product Humate-P or Koate-HS

Hemophilia Clinical manifestations (hemophilia A & B are indistinguishable) Prolonged bleeding after surgery or dental extractions Hemarthrosis (most common) Soft tissue hematomas Other sites of bleeding Urinary tract CNS, neck (may be life-threatening)

Dosing guidelines for hemophilia A Mild bleeding: Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria Target: 30% dosing q8-12h; 1-2 days (15U/kg) Major bleeding CNS trauma, hemorrhage, lumbar puncture Surgery Retroperitoneal hemorrhage GI bleeding Target: 80-100% q8-12h; 7-14 days (50U/kg) Adjunctive therapy -aminocaproic acid (Amicar) or DDAVP (for mild disease only)

Treatment of hemophilia B Agent High purity factor IX Recombinant human factor IX Dose Initial dose: 100U/kg Subsequent: 50U/kg every 24 hours

Acquired bleeding disorders: Vitamin K deficiency Liver disease Warfarin overdose DIC Inhibitors to CF

Vitamin K deficiency

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 Billiary obstruction Malabsorption Antibiotic therapy

Vitamin K deficiency Treatment: Vitamin K replacement Fresh frozen plasma

DIC

Disseminated Intravascular Coagulation Activation of both coagulation and fibrinolysis Triggered by 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

Disseminated Intravascular Coagulation (DIC) Mechanism Systemic activation of coagulation Depletion of platelets and coagulation factors Intravascular deposition of fibrin Activation of fibrinolysis Thrombosis of small and midsize vessels tissue hypoxia and organ failure Bleeding

Release of thromboplastic material into Pathogenesis of DIC Release of thromboplastic material into circulation Consumption of coagulation factors; presence of FDPs  aPTT  PT  TT  Fibrinogen Presence of plasmin  D-dimer Intravascular clot  Platelets Schistocytes Coagulation Fibrinolysis Fibrinogen Thrombin Plasmin Fibrin Monomers Fibrin(ogen) Degradation Products Fibrin Clot (intravascular) Plasmin

Disseminated Intravascular Coagulation Treatment approaches Treatment of underlying disorder Anticoagulation with heparin Platelet transfusion Fresh frozen plasma Coagulation inhibitor concentrate (ATIII)

Hemostasis in liver disease 2

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 Thrombocytopenia due to hypersplenism

Management of Hemostatic Defects in Liver Disease Treatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days - usually ineffective Fresh-frozen plasma infusion: 25-30% of plasma volume (1200-1500 ml) (immediate but temporary effect) Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body

Warfarin Toxicity

Warfarin overdose Managing 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 one or two dose; Omit dose and give vitamin K ( 1-2 mg po) Rapid reversal: vitamin K 2-4 mg po (repeat) INR >9; no bleeding Omit dose; vitamin K 10 mg po; repeat as necessary Resume therapy at lower dose when INR therapeutic Chest 2004:126; 213 S (supplement)

Warfarin overdose Managing high INR values in bleeding patients Clinical situation Guidelines Serious bleeding at Any elevation INR Omit warfarin Vitamin K 10 mg slow IV infusion Omit warfarin Repeat vitamin K injections every 12 hrs FFP, PCC or Factor VIIa (depending on urgency) Any life-threatening Vitamin K 10 mg slow IV infusion PCC ( or recombinant human factor VIIa) Chest 2004:126; 213 S (supplement)

Approach to Post-operative bleeding Is the bleeding local or due to a hemostatic failure? Local: Single site of bleeding usually rapid with minimal coagulation test abnormalities Hemostatic failure: Multiple site or unusual pattern with abnormal coagulation tests

Approach to Post-operative bleeding Evaluate for causes of peri-operative hemostatic failure Preexisting abnormality Special cases (e.g. Cardiopulmonmary bypass) Diagnosis of hemostatic failure Review pre-operative testing Obtain updated testing

Approach to bleeding disorders Summary Identify and correct any specific defect of hemostasis Laboratory testing is 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 Use non-transfusional drugs whenever possible RBC transfusions for surgical procedures or large blood loss

THANK YOU!

Recombinant human factor VIIa (rhVIIa; Novoseven) Mechanism Direct activation of common pathway Use Factor VIII inhibitors Bleeding with other clotting disorders Warfarin overdose with bleeding CNS bleeding with or without warfarin Dose 90 µg/kg IV q 2 hr “Adjust as clinically indicated” Cost (70 kg person) - $1 per µg ~$5,000/dose or $60,000/day

Drugs and blood products used for bleeding 2

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

RBC transfusion therapy Indications Improve oxygen carrying capacity of blood Bleeding Chronic anemia that is symptomatic Peri-operative management

Red blood cell transfusions Special preparation CMV-negative CMV-negative patients Prevent CMV transmission Irradiated RBCs Immune deficient recipient Prevent GVHD or direct donor Leukopoor Previous non-hemolytic Prevents reaction transfusion reaction CMV negative patients Prevents transmission Washed RBC PNH patients Prevents hemolysis IgA deficient recipient Prevents anaphylaxis

Transfusion-transmitted disease Infectious agent Risk HIV 1/500,000 Hepatitis C 1/600,000 Hepatitis B 1/500,000 Hepatitis A <1/1,000,000 HTLV I/II 1/640,000 CMV 50% donors are sero-positive Bacteria 1/250 in platelet transfusions Creutzfeld-Jakob disease Unknown Others Unknown

Platelet transfusions Source Platelet concentrate (Random donor) Pheresis platelets (Single donor) Target level Bone marrow suppressed patient (>10-20,000/µl) Bleeding/surgical patient (>50,000/µl)

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 Indications 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

Hemostatic drugs Aminocaproic acid (Amicar) Mechanism Prevent activation plaminogen -> plasmin Dose 50mg/kg po or IV q 4 hr Uses Primary menorrhagia Oral bleeding Bleeding in patients with thrombocytopenia Blood loss during cardiac surgery Side effects GI toxicity Thrombi formation

Hemostatic drugs Aminocaproic acid (Amicar) Mechanism Prevent activation plaminogen -> plasmin Dose 50mg/kg po or IV q 4 hr Uses Primary menorrhagia Oral bleeding Bleeding in patients with thrombocytopenia Blood loss during cardiac surgery Side effects GI toxicity Thrombi formation

Hemostatic drugs Desmopressin (DDAVP) Mechanism Increased release of VWF from endothelium Dose 0.3µg/kg IV q12 hrs 150mg intranasal q12hrs Uses Most patients with von Willebrand disease Mild hemophilia A Side effects Facial flushing and headache Water retention and hyponatremia

Overview Clinical aspects of bleeding Hematologic disorders causing bleeding Coagulation factor disorders Platelet disorders Approach to laboratory abnormalities Diagnosis and management of thrombocytopenia Approach to acquired bleeding disorders Hemostasis in liver disease Surgical patients Warfarin toxicity Drugs and blood products used for bleeding

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

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

Coagulation factor deficiencies 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

Classification of platelet disorders Associated with bleeding Immune-mediated (Idiopathic) thrombocytopenic purpura Most others

Classification of platelet disorders Associated with thrombosis Thrombotic thrombocytopenic purpura Heparin-induced thrombocytopenia Trousseau’s syndrome 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 1/60,000 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

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

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

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