Approach to Bleeding Diathesis
Dr.Nalini K Pati MD, DNB, DCH (Syd), FRCPA Paediatric Haematologist Royal Children’s Hospital Melbourne Australia
Objectives Objectives - I
I. Clinical aspects of bleeding Clinical aspects of bleeding II. Hematologic disorders causing bleeding • Coagulation factor disorders • Platelet disorders III. Approach to acquired bleeding disorders • Hemostasis in liver disease • Surgical patients • Warfarin toxicity IV. Approach to laboratory abnormalities • Diagnosis and management of thrombocytopenia V. Drugs and blood products used for bleeding
Clinical Features of Bleeding Disorders Petechiae Platelet Coagulation (typical of platelet disorders) 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 Do not blanch with pressure Bleeding after cuts & scratches Yes No (cf. angiomas) Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe Not palpable (cf. vasculitis) Ecchymoses
(typical of coagulation factor disorders)
Objectives - II
Hematologic disorders causing bleeding – Coagulation factor disorders – Platelet disorders Coagulation factor disorders Hemophilia A and B
Inherited bleeding Acquired bleeding Hemophilia A Hemophilia B disorders disorders Coagulation factor deficiency Factor VIII Factor IX – Hemophilia A and B – Liver disease – vonWillebrands disease – Vitamin K Inheritance X-linked X-linked recessive recessive – Other factor deficiencies deficiency/warfarin overdose Incidence 1/10,000 males 1/50,000 males –DIC 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) 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
HISTORY
Bleeding history Forms the basis of the diagnosis Establishing symptoms and therapy of hemorrhagic disorders. A Lead to differential diagnosis HISTORY DOCUMENTING HISTORY
Repeated visits to other physicians Epistaxis Previous need for transfusion of - Whole blood Gingival haemorrhage - Packed cells Petechae / bruise - Plasma Tooth extractions - Platelets Documented anemia & prescription Veni Puncture site bleeding
DOCUMENTING HISTORY Contd., Hemoptysis
Bleeding from minor / major cuts Hematemesis Previous surgical procedure
- Excessive bleeding Hematuria - Needed transfusion - Re operation Hematochezia - Wound healing Bleeding at circumcision Melena
MENSTRUAL HISTORY
CNS bleeding Frequency Duration Ophthalmic bleeding Compared to Peers
Hemarthrosis Required transfusions Local causes CHILD BIRTH Neonatal history Pregnancies Spontaneous / Induced abortions Estimated blood loss Medicines Documented anaemia Required Dietary history . Transfusion . D & C . Hysterectomy Family history / pedigree chart . Iron therapy
EXAMINATION
Age
Sex
General Examination
Systemic examination
THROMBOCYTOPENIA THROMBOCYTOPENIA Contd., Other differential diagnosis must be considered - Additional laboratory abnormalities Congenital WBC - abnormal cells, neutropenia . Is the history since birth RBC - Macrocytosis, Fragmentation . IbldiIs bleeding worse th an count - Are there additional clinical feat ures . Is there a family history Lymphadenopathy, splenomegaly Bone pain, Limping . Are there any physical Sick child congenital abnormalities *In the presence of above findings consider marrow examination Treatment of hemophilia A
Intermediate purity plasma products Underlying disorders – Virucidally treated -SLE – May contain von Willebrand factor . Auto antibody screen - ANF High purity (monoclonal) plasma products and ds DNA – Virucidally treated Anti-phospholipid syndrome – No functional von Willebrand factor HIV infection Recombinant factor VIII – Virus free/No apparent risk – No functional von Willebrand factor
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 – ε-aminocaproic acid (Amicar) or DDAVP (for mild disease only)
Complications of therapy Viral infections in hemophiliacs
Formation of inhibitors (antibodies) – 10-15% of severe hemophilia A patients HIV -positive HIV-negative (n=382) (n=345) – 1-2% of severe hemophilia B patients 53% 47% Hepatitis serology % positive % negative Viral infections – Hepatitis B Human parvovirus Negative 1 20 Hepatitis B virus only 1 1 – Hepatitis C Hepatitis A Hepatitis C virus only 24 45 – HIV Other Hepatitis B and C 74 34
Blood 1993:81;412-418 Treatment of hemophilia B von Willebrand Disease: Clinical Features
Agent von Willebrand factor – Synthesis in endothelium and megakaryocytes – High purity factor IX – Forms large multimer – Recombinant human factor IX – Carrier of factor VIII – AhAnchors p late lets to su bdhlibendothelium Dose – Bridge between platelets – Initial dose: 100U/kg Inheritance - autosomal dominant – Subsequent: 50U/kg every 24 hours Incidence - 1/10,000 Clinical features - mucocutaneous bleeding
Laboratory evaluation of Understanding of VWD 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 ⇓ Normal ⇓⇓ vWF activity ⇓⇓⇓⇓ Multimer analysis Normal Normal Absent
Treatment of von Willebrand Disease Vitamin K deficiency
Cryoprecipitate Source of vitamin K Green vegetables – Source of fibrinogen, factor VIII and VWF Synthesized by intestinal flora – Only plasma fraction that consistently contains VWF multimers Required for synthesis Factors II, VII, IX ,X Protein C and S DDAVP (deamino -8-arginine vasopressin) – ↑ plasma VWF levels by stimulating secretion from endothelium Causes of deficiency Malnutrition – Duration of response is variable Biliary obstruction Malabsorption – Not generally used in type 2 disease Antibiotic therapy – Dosage 0.3 µg/kg q 12 hr IV Treatment Vitamin K Factor VIII concentrate (Intermediate purity) Fresh frozen plasma – Virally inactivated product Common clinical conditions associated with Disseminated Intravascular Coagulation (DIC) Disseminated Intravascular Coagulation Mechanism Activation of both coagulation and fibrinolysis Systemic activation Triggered by of coagulation Sepsis Obstetrical complications – Amniotic fluid embolism Trauma – Abbupopaceruptio placent ae – Head injury Intravascular Depletion of platelets Vascular disorders – Fat embolism deposition of fibrin and coagulation factors Reaction to toxin (e.g. Malignancy snake venom, drugs)
Immunologic disorders Thrombosis of small Bleeding – Severe allergic reaction and midsize vessels – Transplant rejection with organ failure
Pathogenesis of DIC
Release of thromboplastic material into Consumption of circulation coagulation factors; Coagulation Fibrinolysis presence of FDPs ↑ aPTT ↑ PT Fibri nogen ↑ TT Thrombin Plasmin ↓ Fibrinogen
Presence of plasmin Fibrin ↑ FDP Monomers Fibrin(ogen) Degradation Intravascular clot Products ↓ Platelets Fibrin Schistocytes Clot (intravascular) Plasmin
Laboratory Evaluation of DIC Laboratory Evaluation of DIC- I
1. ASSESS DEPLETION OF COAGULATION • Assess Depletion Of Coagulation Factors FACTORS • PLATELET COUNT
2. ASSESS FIBRINOLYSIS • PROTHROMBIN TIME • PARTIAL THROMBOPLASTIN TIME 3. BLOOD FILM FOR MICRO-ANGIOPATHY • THROMBIN TIME • FIBRINOGEN Laboratory Evaluation of DIC-II Laboratory Evaluation of DIC-III
Tests Of Fibrinolysis • Prothrombin activation peptide [Fl.2] CLOT LYSIS • Thrombin anti-thrombin complexes EUGLOBIN LYSIS TIME
FIBRIN PLATE LYSIS • AT III levels
PARA-COAGULATION FDP These tests are not available for routine D DIMER clinical management.
Disseminated Intravascular Coagulation Treatment approaches Classification of platelet disorders
Quantitative disorders Qualitative disorders Treatment of underlying disorder – Abnormal distribution – Inherited disorders Anticoagulation with heparin – Dilution effect (rare) – AiddidAcquired disorders Platelet transfusion – Decreased production » Medications Fresh frozen plasma – Increased destruction » Chronic renal failure » Cardiopulmonary bypass Coagulation inhibitor concentrate (ATIII)
Thrombocytopenia Approach to the thrombocytopenic patient
History Immune-mediated – Is the patient bleeding? Idioapthic – Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) Drug-induced – Is there a history of medications, alcohol use, or recent Collagen vascular disease transfusion? Lymphoproliferative disease – Are there risk factors for HIV infection? Sarcoidosis – Is there a family history of thrombocytopenia? – Do the sites of bleeding suggest a platelet defect? Non-immune mediated DIC Assess the number and function of platelets Microangiopathic hemolytic anemia – CBC with peripheral smear – Bleeding time or platelet aggregation study 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
Features of Acute and Chronic ITP Initial Treatment of ITP
Platelet count Symptoms Treatment Features Acute ITP Chronic ITP (per µl) Peak age Children (2-6 yrs) Adults (20-40 yrs) >50,000 None Female:male 1:1 3:1 Antecedent infection Common Rare 20-50,000 Not bleeding None Onset of symptoms Abrupt Abrupt-indolent Bleeding Glucocorticoids Platelet count at presentation <20,000 <50,000 IVIG Duration 2-6 weeks Long-term Spontaneous remission Common Uncommon <20,000 Not bleeding Glucocorticoids Bleeding Glucocorticoids IVIG Hospitalization
Summary of case series with ITP Long-term morbidity and mortality in adults with ITP
Variable No./total (%) 134 patients with severe ITP studied for mean of 10.5 yrs Complete response With glucocorticoids 370/1447 (26%) – CR and PR patients (85%) Wit h sp lenectomy 581/885 (66%) » No increased mortality compared to control population – Non-responders/maintenance therapy Death from hemorrhage 78/1761 (4%) » Increased morbidity due to ITP-related hospitalizations » Increased mortality related equally to bleeding and infection Healthy at last observation 1027/1606 (64%)
George, JN. N Engl J Med: 1994;331; 1207 Portielje JE et al. Blood 2001:97;2549 Objectives - III Liver Disease and Hemostasis
1. Decreased synthesis of II, VII, IX, X, XI, and Approach to acquired bleeding disorders fibrinogen – Hemostasis in liver disease 2. Dietary Vitamin K deficiency (Inadequate – Surgical patients intake or malabsortion) – Warfarin toxicity 3. Dysfibrinogenemia 4. Enhanced fibrinolysis (Decreased alpha-2- antiplasmin) 5. DIC 6. Thrombocytoepnia due to hypersplenism
Management of Hemostatic Vitamin K deficiency due to warfarin overdose Defects in Liver Disease Managing high INR values
Treatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days - usually Clinical situation Guidelines ineffective INR therapeutic-5 Lower or omit next dose; Resume therapy when INR is therapeutic Fresh-frozen plasma infusion 25-30% o f p lasma vo lume (1200-1500 m l) INR 5-9; no bleeding Lower or omit next dose; immediate but temporary effect Resume therapy when INR is therapeutic Omit dose and give vitamin K (1-2.5 mg po) Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight) Rapid reversal: vitamin K 2-4 mg po (repeat)
INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessary Treatment for DIC (Elevated D-dimer, low factor Resume therapy at lower dose when INR therapeutic VIII, thrombocytopenia Replacement therapy Chest 2001:119;22-38s (supplement)
Vitamin K deficiency due to warfarin overdose Approach to Post-operative bleeding Managing high INR values in bleeding patients
1. Is the bleeding local or due to a hemostatic failure? Clinical situation Guidelines 1. Local: Single site of bleeding usually rapid with minimal coagulation test abnormalities INR > 20; serious bleeding Omit warfarin 2. Hemostatic failure: Multiple site or unusual pattern with Vitamin K 10 mg slow IV infusion abnormal coagulation tests FFP or PCC (depending on urgency) Repea t vit am in K in jec tions every 12 hrs as nee de d 2. Evaluate for causes of peri-operative hemostatic failure 1. Preexisting abnormality 2. Special cases (e.g. Cardiopulmonmary bypass) Any life-threatening bleeding Omit warfarin Vitamin K 10 mg slow IV infusion 3. Diagnosis of hemostatic failure PCC ( or recombinant human factor VIIa) 1. Review pre-operative testing Repeat vitamin K injections every 12 hrs as needed 2. Obtain updated testing
Chest 2001:119;22-38s (supplement) Laboratory Evaluation of Bleeding Objectives - IV Overview CBC and smear Platelet count Thrombocytopenia RBC and platelet morphology TTP, DIC, etc. Approach to laboratory abnormalities Coagulation Prothrombin time Extrinsic/common pathways – Diagnosis and management of thrombocytopenia 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
Blood Film Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage)
XII XIIa Tissue factor
XI XIa
IX IXa VIIa VII
VIII VIIIa
X Xa Vitamin K dependant factors VVVaVa
II IIa (Thrombin)
Fibrinogen Fibrin
Laboratory Evaluation of the Coagulation Pathways Pre-analytic errors
Partial thromboplastin time Prothrombin time Problems with blue-top tube Biological effects (PTT) (PT) – Partial fill tubes –Hct ≥55 or ≤15 Surface activating agent Thromboplastin – Vacuum leak and citrate – Lipemia, hyperbilirubinemia, (Ellagic acid, kaolin) Tissue factor Phospholipid Phospholipid evaporation hemolysis Calcium Calcium
Problems with phlebotomy Laboratory errors – Heparin contamination – Delay in testing Intrinsic pathway Extrinsic pathway – Wrong label – Prolonged incubation at 37°C – Slow fill – Freeze/thaw deterioration – Underfill Thrombin time Common pathway – Vigorous shaking Thrombin
Fibrin clot Initial Evaluation of a Bleeding Patient - 1 Initial Evaluation of a Bleeding Patient - 2 Normal PT Normal PT Normal PTT Abnormal PTT
50:50 mix is Abnormal Repeat abnormal Urea Factor XIII deficiency with Test for inhibitor activity: solubility 50:50 Specific factors: VIII,IX, XI mix Non-specific (anti-phospholipid Ab)
Normal 50:50 mix is normal
Consider evaluating for: Test for factor deficiency: Mild factor deficiency Monoclonal gammopathy Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Abnormal fibrinolysis Platelet disorder Multiple factor deficiencies (rare) (α2 anti-plasmin def) Vascular disorder Elevated FDPs
Initial Evaluation of a Bleeding Patient - 3 Initial Evaluation of a Bleeding Patient - 4 Abnormal PT Abnormal PT Normal PTT Abnormal PTT
50:50 mix is 50:50 mix is Repeat abnormal Repeat abnormal with Test for inhibitor activity: with Test for inhibitor activity: 50:50 Specific: Factor VII (rare) 50:50 Specific : Factors V, X, Prothrombin, mix Non-specific: Anti-phospholipid (rare) mix fibrinogen (rare) Non-specific: anti-phospholipid (common)
50:50 mix is normal 50:50 mix is normal
Test for factor deficiency: Test for factor deficiency: Isolated deficiency of factor VII (rare) Isolated deficiency in common pathway: Factors V, X, Multiple factor deficiencies (common) Prothrombin, Fibrinogen (Liver disease, vitamin K deficiency, warfarin, DIC) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)
Coagulation factor deficiencies Summary Thrombin Time Sex-linked recessive Bypasses factors II-XII Factors VIII and IX deficiencies cause bleeding Prolonged PTT; PT normal Measures rate of fibrinogen conversion to fibrin Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding Procedure: Prolonged PT and/or PTT – Add thrombin with patient plasma Factor XIII deficiency is associated with bleeding and – Measure time to clot impaired wound healing PT/ PTT normal; clot solubility abnormal Variables: Factor XII, prekallikrein, HMWK deficiencies – Source and quantity of thrombin do not cause bleeding Causes of prolonged Thrombin Time Objectives - V
Heparin Drugs and blood products used for bleeding Hypofibrinogenemia Dysfibrinogenemia Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies
Treatment Approaches to RBC transfusion therapy the Bleeding Patient Indications
Red blood cells Improve oxygen carrying capacity of blood Platelet transfusions Fresh frozen plasma – Bleeding Cryoprecipitate – Chronic anemia that is symptomatic Amicar DDAVP – Peri-operative management Recombinant Human factor VIIa
Red blood cell transfusions Red blood cell transfusions Special preparation Adverse reactions
Immunologic reactions CMV-negative CMV-negative patients Prevent CMV transmission Hemolysis RBC incompatibility Irradiated RBCs Immune deficient recipient Prevent GVHD Anaphylaxis Usually unknown; rarely against IgA or direct donor Febrile reaction Antibody to neutrophils Urticaria Antibody to donor plasma proteins Leukopoor Previous non-hemolytic Prevents reaction Non-cardiogenic Donor antibody to leukocytes transfusion reaction pulmonary edema CMV negative patients Prevents transmission
Washed RBC PNH patients Prevents hemolysis IgA deficient recipient Prevents anaphylaxis Red blood cell transfusions Adverse reactions Transfusion-transmitted disease
Infectious agent Risk
Non-immunologic reactions HIV ~1/500,000 Hepatitis C 1/600,000 Congestive heart failure Volume overload Hepatitis B 1/500, 000 Hepatitis A <1/1,000,000 Fever and shock Bacterial contamination HTLV I/II 1/640,000 CMV 50% donors are sero-positive Hypocalcemia Massive transfusion Bacteria 1/250 in platelet transfusions Creutzfeld-Jakob disease Unknown Others Unknown
Platelet transfusions Platelet transfusions - complications
Transfusion reactions Source – Platelet concentrate (Random donor) – Higher incidence than in RBC transfusions – Pheresis platelets (Single donor) – Related to length of storage/leukocytes/RBC mismatch – Bacterial contamination Target level Platelet transfusion refractoriness – Bone marrow suppressed patient (>10-20,000/µl) – Alloimmune destruction of platelets (HLA antigens) – Bleeding/surgical patient (>50,000/µl) – Non-immune refractoriness » Microangiopathic hemolytic anemia » Coagulopathy » Splenic sequestration » Fever and infection » Medications (Amphotericin, vancomycin, ATG, Interferons)
Fresh frozen plasma Cryoprecipitate
Content - plasma (decreased factor V and VIII) Prepared from FFP Indications Content – Multiple coagulation deficiencies (liver disease, trauma) – Factor VIII, von Willebrand factor, fibrinogen – DIC Indications – Warfarin reversal – Fibrinogen deficiency – Coagulation deficiency (factor XI or VII) –Uremia Dose (225 ml/unit) – von Willebrand disease – 10-15 ml/kg Dose (1 unit = 1 bag) Note – 1-2 units/10 kg body weight – Viral screened product – ABO compatible Hemostatic drugs Hemostatic drugs Aminocaproic acid (Amicar) Desmopressin (DDAVP)
Mechanism Mechanism – Prevent activation plaminogen -> plasmin – Increased release of VWF from endothelium Dose Dose – 50mg/kg po or IV q 4 hr – 0.3µg/kg IV q12 hrs Uses – 150mg in tranasa l q 12hrs – Primary menorrhagia Uses – Oral bleeding – Most patients with von Willebrand disease – Bleeding in patients with thrombocytopenia – Mild hemophilia A – Blood loss during cardiac surgery Side effects Side effects – Facial flushing and headache – GI toxicity – Water retention and hyponatremia – Thrombi formation
Screening Tests (APTT,PT,Platelet count) Recombinant human factor VIIa (rhVIIa; Novoseven)
Mechanism APTT prolonged, PT APTT and PT prolonged, APTT All screening test Thrombocytopenia with – Direct activation of common pathway And platelet count PT and platelet count results normal other screening test normal prolonged normal results normal Use
• Platelet – Factor VIII inhibitors • VWD •hepp,atitis, cirrhosis •Excessive function defect • Acquired •Severe vitamin K def coumarin – Bleeding with other clotting disorders autoantibody •Excessive • VWD With large platelets Without large – Warfarin overdose with bleeding Against factor VIII anticoagulation (peripheral consumption platelets • Factor XI With heparin of platelets): (lack of deficiency • Excessive coumarin •ITP production) – CNS bleeding with or without warfarin •DIC •HUS •Acute leukemia •Polycythemia* •CCHD •Aplastic anemia • metabolic disorders* •Neonatal isoimmune TP •TAR syndrome –Dose •Kasabach-Merritt Synd •Drug or •TTP Radiation – 90 µg/kg IV q 2 hr •Cardiopulmonary bypass – “Adjust as clinically indicated”
Cost (70 kg person) - $1 per µg – ~$5,000/dose or $60,000/day
Screening Tests (APTT, PT) Screening Tests (APTT, PT,BT, Platelet count NORMAL)
Suspect lack of cross-linking of fibrin clot by factor XII I
APTT prolonged, PT prolonged, PT and APTT PT normal APTT normal prolonged Perform clot lysis test in 5 Mol/L urea
Perform factor VII assay Perform factor V assay Congenital factor VII Probable hemophilia • • Congenital factor V Perform factor VIII and deficiency deficiency factor IX assay
Rapid clot lysis Negative
Factor VIII low Suspect excessive Factor IX low or •Factor XIII deficiency( < 1%) or undetectable undetectable (actual level can be determined Clot lysis due to a deficiency of one of the by specific assay if patients has major physiologic inhibitors of fibrinolysis symptoms) • Hemophilia A ( rarely, severe VWD or • Hemophilia B type 2N VWD) Measure α 2 –antiplasmin and plasminogen activator inhibitor - Approach to bleeding disorders FUTURE Summary
Identify and correct any specific defect of hemostasis A. Endothelium - Major Regulatory Site – Laboratory testing is almost always needed to establish the cause of bleeding B. Cell Mediated – Screening tests (PT,PTT, platelet count) will often allow placement C. Adhesive molecules into one of the broad categories – Specialized testing is usually necessary to establish a specific D. Matrix metalloproteinases diagnosis E. Z-Protein Use non-transfusional drugs whenever possible
RBC transfusions for surgical procedures or large blood loss