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Bleeding Disorders : 

Bleeding Disorders Morey A. Blinder, MD Division of Hematology Division of Laboratory Medicine

Objectives : 

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

Objectives - I : 

Objectives - I Clinical aspects of bleeding

Clinical Features of Bleeding Disorders : 

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

Petechiae : 

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

Ecchymoses : 

Ecchymoses (typical of coagulation factor disorders)

Objectives - II : 

Objectives - II Hematologic disorders causing bleeding Coagulation factor disorders Platelet disorders

Coagulation factor disorders : 

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 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

Hemophilia : 

Hemophilia Clinical manifestations (hemophilia A & B are indistinguishable) Hemarthrosis (most common) Fixed joints Soft tissue hematomas (e.g., muscle) Muscle atrophy Shortened tendons Other sites of bleeding Urinary tract CNS, neck (may be life-threatening) Prolonged bleeding after surgery or dental extractions

Hemarthrosis (acute) : 

Hemarthrosis (acute)

Treatment of hemophilia A : 

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 : 

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 -aminocaproic acid (Amicar) or DDAVP (for mild disease only)

Complications of therapy : 

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

Viral infections in hemophiliacs : 

Viral infections in hemophiliacs HIV -positive HIV-negative (n=382) (n=345) 53% 47% Hepatitis serology % positive % negative Negative 1 20 Hepatitis B virus only 1 1 Hepatitis C virus only 24 45 Hepatitis B and C 74 34 Blood 1993:81;412-418

Treatment of hemophilia B : 

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

von Willebrand Disease: Clinical Features : 

von Willebrand Disease: 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 von Willebrand disease : 

Laboratory evaluation of von Willebrand disease Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency Diagnostic tests: 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 : 

Treatment of von Willebrand Disease 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 : 

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 Treatment Vitamin K Fresh frozen plasma

Common clinical conditions associated withDisseminated Intravascular Coagulation : 

Common clinical conditions associated withDisseminated Intravascular Coagulation 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 Activation of both coagulation and fibrinolysis Triggered by

Disseminated Intravascular Coagulation (DIC)Mechanism : 

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

Pathogenesis of DIC : 

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

Disseminated Intravascular CoagulationTreatment approaches : 

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

Classification of platelet disorders : 

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

Thrombocytopenia : 

Thrombocytopenia Immune-mediated Idioapthic Drug-induced Collagen vascular disease Lymphoproliferative disease Sarcoidosis Non-immune mediated DIC Microangiopathic hemolytic anemia

Features of Acute and Chronic ITP : 

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

Incidence of adult ITP increases with age : 

Incidence of adult ITP increases with age Incidence (per 105 / year) Age (yrs) Female Male Total 15-39 2.3 1.3 3.6 40-59 3.2 1.1 4.3 60+ 4.6 4.4 9.0 Total 3.2 2.0 2.6 Frederiksen and Schmidt, Blood 1999:94;909

Initial Treatment of ITP : 

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 Bleeding Glucocorticoids IVIG Hospitalization

Summary of case seriesAdults with ITP : 

Summary of case seriesAdults with ITP Variable No./total (%) Complete response With glucocorticoids 370/1447 (26%) With splenectomy 581/885 (66%) Death from hemorrhage 78/1761 (4%) Healthy at last observation 1027/1606 (64%) George, JN. N Engl J Med: 1994;331; 1207

Long-term morbidity and mortalityin adults with ITP : 

Long-term morbidity and mortalityin adults with ITP 134 patients with severe ITP studied for mean of 10.5 yrs CR and PR patients (85%) No increased mortality compared to control population Non-responders/maintenance therapy Increased morbidity due to ITP-related hospitalizations Increased mortality related equally to bleeding and infection Portielje JE et al. Blood 2001:97;2549

Objectives - III : 

Objectives - III Approach to acquired bleeding disorders Hemostasis in liver disease Surgical patients Warfarin toxicity

Liver Disease and Hemostasis : 

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

Management of Hemostatic Defects in Liver Disease : 

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 weight) Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia Replacement therapy

Vitamin K deficiency due to warfarin overdoseManaging high INR values : 

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 (1-2.5 mg po) Rapid reversal: vitamin K 2-4 mg po (repeat) INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessary Resume 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 : 

Vitamin K deficiency due to warfarin overdoseManaging high INR values in bleeding patients Clinical situation Guidelines INR > 20; serious bleeding Omit warfarin Vitamin K 10 mg slow IV infusion FFP or PCC (depending on urgency) Repeat vitamin K injections every 12 hrs as needed Any life-threatening bleeding Omit warfarin Vitamin K 10 mg slow IV infusion PCC ( or recombinant human factor VIIa) Repeat vitamin K injections every 12 hrs as needed Chest 2001:119;22-38s (supplement)

Approach to Post-operative bleeding : 

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 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

Objectives - IV : 

Objectives - IV Approach to laboratory abnormalities Diagnosis and management of thrombocytopenia

Laboratory Evaluation of BleedingOverview : 

Laboratory Evaluation of BleedingOverview CBC and smear Platelet count Thrombocytopenia RBC and platelet morphology TTP, DIC, etc. Coagulation Prothrombin time Extrinsic/common pathways Partial thromboplastin time Intrinsic/common pathways Coagulation factor assays Specific factor deficiencies 50:50 mix Inhibitors (e.g., antibodies) Fibrinogen assay Decreased fibrinogen Thrombin time Qualitative/quantitative fibrinogen defects FDPs or D-dimer Fibrinolysis (DIC) Platelet function von Willebrand factor vWD Bleeding time In vivo test (non-specific) Platelet function analyzer (PFA) Qualitative platelet disorders and vWD Platelet function tests Qualitative platelet disorders

Coagulation cascade : 

XIIa Coagulation cascade IIa Intrinsic system (surface contact) XII XI XIa Tissue factor IX IXa VIIa VII VIII VIIIa Extrinsic system (tissue damage) X V Va II Fibrinogen Fibrin (Thrombin) IIa Vitamin K dependant factors Xa

Laboratory Evaluation of the Coagulation Pathways : 

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

Pre-analytic errors : 

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 : 

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

Initial Evaluation of a Bleeding Patient - 2 : 

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)

Initial Evaluation of a Bleeding Patient - 3 : 

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)

Initial Evaluation of a Bleeding Patient - 4 : 

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)

Coagulation factor deficienciesSummary : 

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

Thrombin Time : 

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

Causes of prolonged Thrombin Time : 

Causes of prolonged Thrombin Time Heparin Hypofibrinogenemia Dysfibrinogenemia Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies

Classification of thrombocytopenia : 

Classification of thrombocytopenia Associated with bleeding Immune-mediated thrombocytopenia (ITP) Most others Associated with thrombosis Thrombotic thrombocytopenic purpura Heparin-associated thrombocytopenia Trousseau’s syndrome DIC

Approach to the thrombocytopenic patient : 

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 Bleeding time or platelet aggregation study

Bleeding time and bleeding : 

Bleeding time and bleeding 5-10% of 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

Objectives - V : 

Objectives - V Drugs and blood products used for bleeding

Treatment Approaches tothe Bleeding Patient : 

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

RBC transfusion therapyIndications : 

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

Red blood cell transfusionsSpecial preparation : 

Red blood cell transfusionsSpecial 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

Red blood cell transfusionsAdverse reactions : 

Red blood cell transfusionsAdverse reactions Immunologic reactions Hemolysis RBC incompatibility Anaphylaxis Usually unknown; rarely against IgA Febrile reaction Antibody to neutrophils Urticaria Antibody to donor plasma proteins Non-cardiogenic Donor antibody to leukocytes pulmonary edema

Red blood cell transfusionsAdverse reactions : 

Red blood cell transfusionsAdverse reactions Non-immunologic reactions Congestive heart failure Volume overload Fever and shock Bacterial contamination Hypocalcemia Massive transfusion

Transfusion-transmitted disease : 

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 : 

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)

Platelet transfusions - complications : 

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)

Fresh frozen plasma : 

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 : 

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

Hemostatic drugsAminocaproic acid (Amicar) : 

Hemostatic drugsAminocaproic 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 drugsDesmopressin (DDAVP) : 

Hemostatic drugsDesmopressin (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

Recombinant human factor VIIa (rhVIIa; Novoseven) : 

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

Approach to bleeding disordersSummary : 

Approach to bleeding disordersSummary 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 Use non-transfusional drugs whenever possible RBC transfusions for surgical procedures or large blood loss