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Approach of Bleeding Tendency in Adult patients Dr. Alsayed Alspagh Assistant Lecture of Internal Meds.Al-Azhar University Hospitals
BLEEDING DISORDERS
• Hemo = means blood • stasis = arrest or stoppage • Hemostasis = is the process of Stoppage of bleeding from a damaged blood vessel. Hemostasis
Hemostasis is a balancing act! pro-coagulant anti-coagulant plugs up holes in blood vessels keeps clotting under control A disruption of this unique balance may cause bleeding or thrombosis
Hemostasis Anticoagulant Procoagulant Thrombosis Anticoagulant Procoagulant Bleeding Anticoagulant Procoagulant
Pro-Coagulant clot vessel platelets Coagulation cascade
clot Anti-Coagulant FDPs
• Fast and localized reaction when a blood vessel breaks. • Involves a series of reactions. • Involves substances normally found in plasma but not activated. • Occurs in 4 main phases Hemostasis
Phases Of Hemostasis 1. VASCULAR PHASE 2. PLATELET PHASE 3. COAGULATION PHASE 4. FIBRINOLYTIC PHASE
Primary Hemostasis Blood vessel contraction Platelet Plug Formation Secondary Hemostasis Activation of Clotting Cascade Deposition & Stabilization of Fibrin Tertiary Hemostasis Dissolution of Fibrin Clot Dependent on Plasminogen Activation Types Of Hemostasis
NORMAL CLOTTING Response to vessel injury 1. Vasoconstriction to reduce blood flow 2. Platelet plug formation (vWF binds damaged vessel and platelets) 3. Activation of clotting cascade with generation of fibrin clot formation 4. Fibrinolysis (clot breakdown)
Hemostasis BV Injury Platelet Aggregation Platelet Activation Blood Vessel Constriction Coagulation Cascade Stable Hemostatic Plug Fibrin formation Reduced Blood flow Tissue Factor Primary hemostatic plug Neural Lab Tests •CBC-Plt •BT,(CT) •PT •PTT Plt Study Morphology Function Antibody
VASCULAR PHASE WHEN A BLOOD VESSEL IS DAMAGED, VASOCONSTRICTION RESULTS.
PLATELET PHASE PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM A TEMPORARY PLUG.
COAGULATION PHASE THROUGH TWO SEPARATE PATHWAYS THE CONVERSION OF FIBRINOGEN TO FIBRIN IS COMPLETE.
THE CLOTTING MECHANISM INTRINSIC EXTRINSI C PROTHROMBIN THROMBIN FIBRINOGEN FIBRIN (II) (III) (I) V X Tissue Thromboplastin Collagen VII XII XI IX VIII
FIBRINOLYTIC PHASE ANTICLOTTING MECHANISMS ARE ACTIVATED TO ALLOW CLOT DISINTEGRATION AND REPAIR OF THE DAMAGED VESSEL.
HEMOSTASIS DEPENDENT UPON:  Vessel Wall Integrity  Adequate Numbers of Platelets  Proper Functioning Platelets  Adequate Levels of Clotting Factors  Proper Function of Fibrinolytic Pathway
What Causes Bleeding Disorders? VESSEL DEFECTS PLATELET DISORDERS FACTOR DEFICIENCIES OTHER DISORDERS ?
Disorders of Hemostasis • Vascular disorders: o Scurvy, easy bruising, Henoch-Schonlein purpura. • Platelet disorders: o Quantitative – Thrombocytopenia o Qualitative - Platelet function disorders – Glanzmans • Coagulation disorders: o Congenital - Hemophilia (A, B), Von-Willebrands o Acquired - Vitamin-K deficiency, Liver disease • Mixed/Consumption: oDIC
Vascular Purpuras (Vasculopathy): Acquired : 1. Anaphylactoid purpura 2. Infections 3. Scurvy 4. Senile purpura 5. Purpura simplex 6. Mechanical purpura 7. Drugs, e.g. corticosteroids 8. Cushing’s syndrome 9. Factitious purpura Inherited 1. Hereditary hemorrhagic telangiectasia 2. Hereditary connective tissue disorders: • Ehlers-Danlos syndrome • Osteogenesis imperfecta • Marfan’s syndrome • Pseudoxanthoma elasticum
Thrombocytopenia (Thrombocytopenic purpura) 1. Increased destruction of platelets: • Immune; • ITP • Systemic lupus erythematosus • Drugs: heparin, penicillin, quinine • Infections: HIV, malaria, dengue, HCV, H.pylori • Post transfusion purpura • Neonatal alloimmune purpura • Nonimmune; • DIC • TTP/HUS 2. Decreased production of platelets • Hereditary; • Fanconi’s anemia • Wiskott-Aldrich syndrome • Acquired; • Aplastic anemia • BM infiltration (leukemias, myelodysplasia, myelofibrosis, lymphoma, metastatic carcinoma) • Megaloblastic anemia • Drugs (cytotoxic drugs, ethanol), Radiation • Viral infections 3. Dilutional thrombocytopenia • Massive blood transfusion 4. Increased sequestration • Hypersplenism 5. Pseudothrombocytopaenia (spurious thrombocytopenia): represents clumping of platelets in blood samples collected in EDTA, resulting in spuriously low platelet counts. This phenomenon can be avoided by using citrate to anticoagulated blood samples sent for blood counts
Thrombasthenia (disorder of platelet functions): Inherited : 1.Bernard-Soulier syndrome 2.Glanzmann’s thrombasthenia 3.Storage pool deficiency 4.Defective thromboxane synthesis Acquired: 1. Myeloproliferative neoplasms 2. Acute leukemias 3. Myelodysplastic syndrome 4. PNH 5. Paraproteinemias 6. Uremia 7. Cardiopulmonary bypass 8. Drugs (Aspirin, dipyridamole, penicillin,.)
Coagulation disorders (Coagulopathy) Acquired coagulation disorders 1. Disseminated intravascular coagulation 2. Liver disease 3. Vitamin K deficiency 4. Acquired inhibitors of coagulation 5. Heparin, oral anticoagulation, thrombolytic therapy 6. Renal disease 7. Paraproteinaemias 8. Cardiopulmonary bypass 9. Massive transfusion of stored blood Inherited coagulation disorders 1. hemophilia A (Factor VIII deficiency) 2. hemophilia B (Factor IX deficiency) 3. von Willebrand disease.
Evaluation of a bleeding patient • Spontaneous bleeding or related to trauma? o Spontaneous = platelet or vascular defect o Related to trauma = coagulation defect • Site of bleeding ? (superficial or deep) o Superficial bleeding:  Skin bleeding (petechiae, purpura, ecchymosis)  Menorrhagia  Mouth bleeding (gum bleeding)  Epistaxis  Bleeding per rectum  Hematuria o Deep bleeding:  Joint bleeding (Hemarthrosis)  Muscle hematoma (psoas ms hematoma)  Intracavitary he (Intracranial hge) o Superficial bleeding = platelet or vascular defect o Deep bleeding = coagulation defect
• Time after trauma ? o Immediate bleeding = Platelet or vascular defect o Delayed bleeding = Coagulation defect • Onset of bleeding ? o At childbirth, early childhood = congenital ds o At adulthood = acquired ds • Existent comorbidities e.g., liver, renal, malignancy,.. • Drug history e.g., NSAIDs, Antiplatelets, Antibiotics,.. • Nutritional status (Malnutrition): decreased hepatic synthesis • Family history ? o Positive FH = Inherited ds o Negative FH = Acquired • Significant bleeding or not ? o Repeated episodes o Multiple sites of bleeding o Requiring transfusion support o Positive family Hx
Platelet factor Coagulation disorders disorders Site of bleeding Skin Deep in soft tissues • Mucous membranes (joints, muscles) • (epistaxis, gum, vaginal, • GI tract) Petechiae, purpura 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 • Prolonged bleeding time prolonged coagulation time
Ecchymosis, Purpura, Petechiae
Mouth bleeding
Vascular purpura (HSP)
Platelet Coagulation Petechiae, Purpura Hemarthrosis
Senile Purpura
Large Hematoma
CT- Large hematoma of psoas muscle
Laboratory evaluation for patient with bleeding Screening tests: done for all suspected patients ⚫Platelet count ⚫Bleeding time ⚫Prothrombin time (PT) ⚫Partial thromboplastin time (PTT) ⚫Thrombin time (TT) Specific tests : done according to results of screening tests
Platelet Count ⚫A part of complete blood picture (CBC) ⚫ Performed by electronic counters or manually  NORMAL 150,000 - 450,000 CELLS/MM3 < 100,000 Thrombocytopenia 50,000 - 100,000 Mild Thrombocytopenia < 50,000 Severe Thrombocytopenia
Bleeding Time Time needed to stop bleeding after induced needle prick Affected by: •Platelet count •Platelet function •Vessel wall Normal range: : 2-8 min Note: it is not a sensitive test for minor or even moderate abnormality.
Causes of prolonged bleeding time (BT): 1-Thrombocytopenia (moderate or severe). 2-Disorders of platelet function: • VWD • Glanzmann’s disease • Bernard Soulier syndrome 3-Vascular abnormalities
Prothrombin Time (PT)  Measures The Effectiveness of the Extrinsic Pathway (FVII, FII, FV, X) [majority are vitamin K dependent factor].  Used for monitoring oral anticoagulant therapy and used as a liver function test  Normal range: 10-14 sec
Prothrombin Time (PT) Tissue thromboplastin Ca++ Fibrin clot Plasma
Causes of prolonged PT 1. Oral anticoagulants (Warfarin) 2. Liver disease 3. Vit K deficiency (FII, VII , IX and X ) 4. Congenital deficiency of factors involved in extrinsic pathway. 5. DIC 6. inhibitors
Partial Thromboplastin Time (PTT)  Measures Effectiveness of the Intrinsic Pathway(FVIII, FIX, FXI, FXII, FII, FV, X). It is the test Used for patients receiving heparin therapy NORMAL VALUE 25-40 SECS
Causes of prolonged PTT
Causes of prolonged PTT  Heparin therapy  Deficiency of factors involved in intrinsic pathway, usually congenital: Hemophilia A Hemophilia B and von Willebrand disease)  DIC  Massive transfusion (labile FV, FVIII)  Inhibitors
THROMBIN TIME (TT)  Time for Thrombin To Convert Fibrinogen Fibrin  A Measure of Fibrinolytic Pathway NORMAL VALUE 9-13 SECS
Causes of prolonged TT  Hypofibrinogenemia  Dysfibrinogenemia  Heparin therapy  DIC
Test Mechanism tested Ref value (Varies) Disorder PT Extrinsic & common pathways <12s beyond neonate, 12-18s in neonate Vit K related bleeding, HDN, malabsorption, Liver disease, oral anticoagulants aPTT Intrinsic & common pathways 20-40s beyond neonate, 70s in neonate Hemophilia, VWD, heparin, DIC, lupus anticoagulant, Factor XI & XII deficiency Thrombin Time Fibrinogen to fibrin 10-15s beyond neonate, 12-17s in neonate Fibrin split products, DIC, heparin, uremia, hypofibrinogenemia Bleeding Time Hemostasis, capillary & platelet function 3-7min Platelet dysfunction, thrombocytopenia, aspirin, von Willebrand disease Platelet count Platelet number 150,000-450,000/ mm3 Causes of Thrombocytopenia Thin Film Platelet number, size, RBC morphology Large platets-peripheral destruction, Fragmented RBCs- microangiopathic process
PT and aPTT • Prolonged APTT Defect in Intrinsic No change in PT • No change in APTT Defect in Extrinsic Prolonged PT • Prolonged APTT Defect in common Prolonged PT
Additional labs  Specific factor assays  Mixing study (patient plasma 1:1 normal plasma)  Fibrinogen measurement  Platelet function testing  VWF antigen and activity testing  Genetic testing
Coagulation factor disorders • Inherited bleeding disorders – Hemophilia A – Hemophilia B – vonWillebrands disease – Other factor deficiencies • Acquired bleeding disorders – Liver disease – Vitamin K deficiency/warfarin overdose – DIC
Factor Deficiencies
Factor VIII Deficiency • Classic hemophilia (hemophilia A) • X-linked disorder (affects 1º males) • Most common - severe bleeding • Spontaneous hematomas • Prolonged PTT – Intrinsic path. • Diagnosis - factor VIII assay • Treatment: •factor VIII concentrate •Desmopressin •Cryoprecipitate (less desirable)
Severity of disease depends upon levels of remaining factor activity, with normal range expressed as 50-200% Severity of factor VIII deficiency Severity Factor VIII activity level Age of presentation Percentage of sufferers Severe disease <1% Infancy 43-70% Moderate disease 1-5% Before 2 years 15-26% Mild disease >5% Older than 2 years 15-31%
Factor IX Deficiency • Christmas disease (Hemophilia B): •X-linked recessive disorder •Indistinguishable from classic hemophilia (F VIII) •Requires evaluation of factor VIII and IX activity levels to diagnose •Treatment: •factor IX concentrate •Cryoprecipitate if factor IX unavailable •Desmopressin is not working
Factor Deficiencies Hemophilia A (Classic Hemophilia) 80-85% of all Hemophiliacs Deficiency of Factor VIII Lab Results - Prolonged PTT HEMOPHILIA B (Christmas Disease) 10-15% of all Hemophiliacs Deficiency of Factor IX Lab Test - Prolonged PTT
FACTOR DEFICIENCIES VON WILLEBRAND’S DISEASE Deficiency of VWF & amount of Factor VIII Lab Results - Prolonged BT, PTT
OTHER DISORDERS (ACQUIRED) ORAL ANTICOAGULANTS COUMARIN HEPARIN  LIVER DISEASE  MALABSORPTION  BROAD-SPECTRUM ANTIBIOTICS
INHIBITORS 30% of people with haemophilia develop an antibody to the clotting factor they are receiving for treatment. These antibodies are known as inhibitors. These patients are treated with high does of FVIIa for bleeds or surgery. This overrides defect in FVIII or FIX deficiency. Longterm management involves attempting to eradicate inhibitors by administering high dose FVIII (or FIX) in a process called immune tolerance
Dosing guidelines for hemophilia A • General measures: avoid trauma, traumatic sports and IM injections • Local measures: local pressure, ICE application • Surgical: Joint replacement in case of joint deformity • Factor VIII concentrate: • Major surgery – Target: 80-100% q8h; 7-14 days (or until wound healing) – Dose: Desired level/2 x BW (kg) • Minor surgery – Target: 30-60% q12h; 3-5 days (or until wound healing) – Dose: Desired level/2 x BW (kg) • Prophylaxis: – Dose is the same as in minor surgery but twice weekly • Adjunctive therapy – aminocaproic acid or DDAVP (for mild – mod disease
Treatment of hemophilia B • Dose –Dose: Desired level x BW (kg) –The frequency in major and Minor surgery as in Factor VIII –Prophylaxis = 50 IU/kg once weekly –No role for DDAVP in hemophilia B
This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. Pathophysiology • Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF). • vWF is a multimeric glycoprotein encoded for by gene map locus 12p13. • It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions: • It assists in platelet plug formation by attracting circulating platelets to the site of damage. • It binds to coagulation factor VIII preventing its clearance from the plasma. Von Willebrand's Disease
Von Willebrand factor Von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic including thrombotic thrombocyto penic purpura, Heyde's syndrome, and possibly
Etiology I. Hereditary - three types • vWD Type I, vWD Type II, and vWD Type III • Within the three inherited types of vWD there are various subtypes. II. Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in: • Lymphoproliferative • Myeloproliferative disorders • Solid tumors • Immunological disorders • Cardiovascular disorders e.g., aortic stenosis, • Wilms'tumor, • Hypothyroidism. Von Willebrand's 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
Types of hereditary von Willebrand's disease (vWD) Type 1 60-80% Quantitative defect (19-45% of enzyme level present) • Heterozygous for defective gene • Inherited as AD • Normal lifespan • Occasionally easy bruising and/or menorrhagia • Bleeding after dental work, major surgery Type 2 20-30% Qualitative defect - multimers abnormal or subgroups absent Usually AD inheritance (rarely AR) Bleeding tendency varies Four subtypes: 2A, 2B, 2M, 2N Type 3 Rare - the most severe form; 1- Quantitative - levels very low or undetectable • Homozygous for defective gene • AR inheritance • Severe mucosal bleeding • May have haemarthrosis (as Von Willebrand's Disease
Treatment of von Willebrand Disease • Cryoprecipitate – Source of fibrinogen, factor VIII and VWF – Only plasma fraction that consistently contains VWF multimers – 1 unit / 10 kg • 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 • Treatment Vitamin K Fresh frozen plasma
Common clinical conditions associated with Disseminated 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 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 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 Coagulation Treatment approaches • Treatment of underlying disorder • Anticoagulation with heparin • Platelet transfusion • Fresh frozen plasma • Coagulation inhibitor concentrate (ATIII)
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
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
Treatment Approaches to the Bleeding Patient • Red blood cells • Platelet transfusions • Fresh frozen plasma • Cryoprecipitate • Aminocaproic acid • DDAVP • Recombinant Human factor VIIa
RBC transfusion therapy Indications • Improve oxygen carrying capacity of blood –Bleeding –Chronic anemia that is symptomatic –Peri-operative management
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
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 • 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,
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 –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 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
Recombinant human factor VIIa (rhVIIa; • 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”
Approach to bleeding disorders Summary • 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
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00- Approach of bleeding Tendency in Adults.ppt

  • 1.
    Approach of Bleeding Tendencyin Adult patients Dr. Alsayed Alspagh Assistant Lecture of Internal Meds.Al-Azhar University Hospitals
  • 2.
  • 3.
    • Hemo =means blood • stasis = arrest or stoppage • Hemostasis = is the process of Stoppage of bleeding from a damaged blood vessel. Hemostasis
  • 4.
    Hemostasis is abalancing act! pro-coagulant anti-coagulant plugs up holes in blood vessels keeps clotting under control A disruption of this unique balance may cause bleeding or thrombosis
  • 5.
  • 6.
  • 7.
  • 8.
    • Fast andlocalized reaction when a blood vessel breaks. • Involves a series of reactions. • Involves substances normally found in plasma but not activated. • Occurs in 4 main phases Hemostasis
  • 9.
    Phases Of Hemostasis 1.VASCULAR PHASE 2. PLATELET PHASE 3. COAGULATION PHASE 4. FIBRINOLYTIC PHASE
  • 10.
    Primary Hemostasis Blood vesselcontraction Platelet Plug Formation Secondary Hemostasis Activation of Clotting Cascade Deposition & Stabilization of Fibrin Tertiary Hemostasis Dissolution of Fibrin Clot Dependent on Plasminogen Activation Types Of Hemostasis
  • 11.
    NORMAL CLOTTING Response tovessel injury 1. Vasoconstriction to reduce blood flow 2. Platelet plug formation (vWF binds damaged vessel and platelets) 3. Activation of clotting cascade with generation of fibrin clot formation 4. Fibrinolysis (clot breakdown)
  • 13.
    Hemostasis BV Injury Platelet Aggregation Platelet Activation Blood Vessel Constriction Coagulation Cascade StableHemostatic Plug Fibrin formation Reduced Blood flow Tissue Factor Primary hemostatic plug Neural Lab Tests •CBC-Plt •BT,(CT) •PT •PTT Plt Study Morphology Function Antibody
  • 14.
    VASCULAR PHASE WHEN ABLOOD VESSEL IS DAMAGED, VASOCONSTRICTION RESULTS.
  • 15.
    PLATELET PHASE PLATELETS ADHERETO THE DAMAGED SURFACE AND FORM A TEMPORARY PLUG.
  • 16.
    COAGULATION PHASE THROUGH TWOSEPARATE PATHWAYS THE CONVERSION OF FIBRINOGEN TO FIBRIN IS COMPLETE.
  • 17.
    THE CLOTTING MECHANISM INTRINSICEXTRINSI C PROTHROMBIN THROMBIN FIBRINOGEN FIBRIN (II) (III) (I) V X Tissue Thromboplastin Collagen VII XII XI IX VIII
  • 18.
    FIBRINOLYTIC PHASE ANTICLOTTING MECHANISMS AREACTIVATED TO ALLOW CLOT DISINTEGRATION AND REPAIR OF THE DAMAGED VESSEL.
  • 19.
    HEMOSTASIS DEPENDENT UPON:  VesselWall Integrity  Adequate Numbers of Platelets  Proper Functioning Platelets  Adequate Levels of Clotting Factors  Proper Function of Fibrinolytic Pathway
  • 20.
    What Causes BleedingDisorders? VESSEL DEFECTS PLATELET DISORDERS FACTOR DEFICIENCIES OTHER DISORDERS ?
  • 21.
    Disorders of Hemostasis •Vascular disorders: o Scurvy, easy bruising, Henoch-Schonlein purpura. • Platelet disorders: o Quantitative – Thrombocytopenia o Qualitative - Platelet function disorders – Glanzmans • Coagulation disorders: o Congenital - Hemophilia (A, B), Von-Willebrands o Acquired - Vitamin-K deficiency, Liver disease • Mixed/Consumption: oDIC
  • 22.
    Vascular Purpuras (Vasculopathy): Acquired: 1. Anaphylactoid purpura 2. Infections 3. Scurvy 4. Senile purpura 5. Purpura simplex 6. Mechanical purpura 7. Drugs, e.g. corticosteroids 8. Cushing’s syndrome 9. Factitious purpura Inherited 1. Hereditary hemorrhagic telangiectasia 2. Hereditary connective tissue disorders: • Ehlers-Danlos syndrome • Osteogenesis imperfecta • Marfan’s syndrome • Pseudoxanthoma elasticum
  • 23.
    Thrombocytopenia (Thrombocytopenic purpura) 1.Increased destruction of platelets: • Immune; • ITP • Systemic lupus erythematosus • Drugs: heparin, penicillin, quinine • Infections: HIV, malaria, dengue, HCV, H.pylori • Post transfusion purpura • Neonatal alloimmune purpura • Nonimmune; • DIC • TTP/HUS 2. Decreased production of platelets • Hereditary; • Fanconi’s anemia • Wiskott-Aldrich syndrome • Acquired; • Aplastic anemia • BM infiltration (leukemias, myelodysplasia, myelofibrosis, lymphoma, metastatic carcinoma) • Megaloblastic anemia • Drugs (cytotoxic drugs, ethanol), Radiation • Viral infections 3. Dilutional thrombocytopenia • Massive blood transfusion 4. Increased sequestration • Hypersplenism 5. Pseudothrombocytopaenia (spurious thrombocytopenia): represents clumping of platelets in blood samples collected in EDTA, resulting in spuriously low platelet counts. This phenomenon can be avoided by using citrate to anticoagulated blood samples sent for blood counts
  • 24.
    Thrombasthenia (disorder ofplatelet functions): Inherited : 1.Bernard-Soulier syndrome 2.Glanzmann’s thrombasthenia 3.Storage pool deficiency 4.Defective thromboxane synthesis Acquired: 1. Myeloproliferative neoplasms 2. Acute leukemias 3. Myelodysplastic syndrome 4. PNH 5. Paraproteinemias 6. Uremia 7. Cardiopulmonary bypass 8. Drugs (Aspirin, dipyridamole, penicillin,.)
  • 25.
    Coagulation disorders (Coagulopathy) Acquiredcoagulation disorders 1. Disseminated intravascular coagulation 2. Liver disease 3. Vitamin K deficiency 4. Acquired inhibitors of coagulation 5. Heparin, oral anticoagulation, thrombolytic therapy 6. Renal disease 7. Paraproteinaemias 8. Cardiopulmonary bypass 9. Massive transfusion of stored blood Inherited coagulation disorders 1. hemophilia A (Factor VIII deficiency) 2. hemophilia B (Factor IX deficiency) 3. von Willebrand disease.
  • 26.
    Evaluation of ableeding patient • Spontaneous bleeding or related to trauma? o Spontaneous = platelet or vascular defect o Related to trauma = coagulation defect • Site of bleeding ? (superficial or deep) o Superficial bleeding:  Skin bleeding (petechiae, purpura, ecchymosis)  Menorrhagia  Mouth bleeding (gum bleeding)  Epistaxis  Bleeding per rectum  Hematuria o Deep bleeding:  Joint bleeding (Hemarthrosis)  Muscle hematoma (psoas ms hematoma)  Intracavitary he (Intracranial hge) o Superficial bleeding = platelet or vascular defect o Deep bleeding = coagulation defect
  • 27.
    • Time aftertrauma ? o Immediate bleeding = Platelet or vascular defect o Delayed bleeding = Coagulation defect • Onset of bleeding ? o At childbirth, early childhood = congenital ds o At adulthood = acquired ds • Existent comorbidities e.g., liver, renal, malignancy,.. • Drug history e.g., NSAIDs, Antiplatelets, Antibiotics,.. • Nutritional status (Malnutrition): decreased hepatic synthesis • Family history ? o Positive FH = Inherited ds o Negative FH = Acquired • Significant bleeding or not ? o Repeated episodes o Multiple sites of bleeding o Requiring transfusion support o Positive family Hx
  • 28.
    Platelet factor Coagulationdisorders disorders Site of bleeding Skin Deep in soft tissues • Mucous membranes (joints, muscles) • (epistaxis, gum, vaginal, • GI tract) Petechiae, purpura 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 • Prolonged bleeding time prolonged coagulation time
  • 29.
  • 30.
  • 31.
  • 32.
  • 33.
  • 34.
  • 35.
    CT- Large hematomaof psoas muscle
  • 36.
    Laboratory evaluation forpatient with bleeding Screening tests: done for all suspected patients ⚫Platelet count ⚫Bleeding time ⚫Prothrombin time (PT) ⚫Partial thromboplastin time (PTT) ⚫Thrombin time (TT) Specific tests : done according to results of screening tests
  • 37.
    Platelet Count ⚫A partof complete blood picture (CBC) ⚫ Performed by electronic counters or manually  NORMAL 150,000 - 450,000 CELLS/MM3 < 100,000 Thrombocytopenia 50,000 - 100,000 Mild Thrombocytopenia < 50,000 Severe Thrombocytopenia
  • 38.
    Bleeding Time Time neededto stop bleeding after induced needle prick Affected by: •Platelet count •Platelet function •Vessel wall Normal range: : 2-8 min Note: it is not a sensitive test for minor or even moderate abnormality.
  • 39.
    Causes of prolongedbleeding time (BT): 1-Thrombocytopenia (moderate or severe). 2-Disorders of platelet function: • VWD • Glanzmann’s disease • Bernard Soulier syndrome 3-Vascular abnormalities
  • 40.
    Prothrombin Time (PT) Measures The Effectiveness of the Extrinsic Pathway (FVII, FII, FV, X) [majority are vitamin K dependent factor].  Used for monitoring oral anticoagulant therapy and used as a liver function test  Normal range: 10-14 sec
  • 41.
  • 42.
    Causes of prolonged PT 1.Oral anticoagulants (Warfarin) 2. Liver disease 3. Vit K deficiency (FII, VII , IX and X ) 4. Congenital deficiency of factors involved in extrinsic pathway. 5. DIC 6. inhibitors
  • 43.
    Partial Thromboplastin Time (PTT) Measures Effectiveness of the Intrinsic Pathway(FVIII, FIX, FXI, FXII, FII, FV, X). It is the test Used for patients receiving heparin therapy NORMAL VALUE 25-40 SECS
  • 44.
  • 45.
    Causes of prolongedPTT  Heparin therapy  Deficiency of factors involved in intrinsic pathway, usually congenital: Hemophilia A Hemophilia B and von Willebrand disease)  DIC  Massive transfusion (labile FV, FVIII)  Inhibitors
  • 46.
    THROMBIN TIME (TT)  Timefor Thrombin To Convert Fibrinogen Fibrin  A Measure of Fibrinolytic Pathway NORMAL VALUE 9-13 SECS
  • 47.
    Causes of prolongedTT  Hypofibrinogenemia  Dysfibrinogenemia  Heparin therapy  DIC
  • 48.
    Test Mechanism testedRef value (Varies) Disorder PT Extrinsic & common pathways <12s beyond neonate, 12-18s in neonate Vit K related bleeding, HDN, malabsorption, Liver disease, oral anticoagulants aPTT Intrinsic & common pathways 20-40s beyond neonate, 70s in neonate Hemophilia, VWD, heparin, DIC, lupus anticoagulant, Factor XI & XII deficiency Thrombin Time Fibrinogen to fibrin 10-15s beyond neonate, 12-17s in neonate Fibrin split products, DIC, heparin, uremia, hypofibrinogenemia Bleeding Time Hemostasis, capillary & platelet function 3-7min Platelet dysfunction, thrombocytopenia, aspirin, von Willebrand disease Platelet count Platelet number 150,000-450,000/ mm3 Causes of Thrombocytopenia Thin Film Platelet number, size, RBC morphology Large platets-peripheral destruction, Fragmented RBCs- microangiopathic process
  • 49.
    PT and aPTT •Prolonged APTT Defect in Intrinsic No change in PT • No change in APTT Defect in Extrinsic Prolonged PT • Prolonged APTT Defect in common Prolonged PT
  • 50.
    Additional labs  Specificfactor assays  Mixing study (patient plasma 1:1 normal plasma)  Fibrinogen measurement  Platelet function testing  VWF antigen and activity testing  Genetic testing
  • 51.
    Coagulation factor disorders •Inherited bleeding disorders – Hemophilia A – Hemophilia B – vonWillebrands disease – Other factor deficiencies • Acquired bleeding disorders – Liver disease – Vitamin K deficiency/warfarin overdose – DIC
  • 52.
  • 53.
    Factor VIII Deficiency •Classic hemophilia (hemophilia A) • X-linked disorder (affects 1º males) • Most common - severe bleeding • Spontaneous hematomas • Prolonged PTT – Intrinsic path. • Diagnosis - factor VIII assay • Treatment: •factor VIII concentrate •Desmopressin •Cryoprecipitate (less desirable)
  • 54.
    Severity of diseasedepends upon levels of remaining factor activity, with normal range expressed as 50-200% Severity of factor VIII deficiency Severity Factor VIII activity level Age of presentation Percentage of sufferers Severe disease <1% Infancy 43-70% Moderate disease 1-5% Before 2 years 15-26% Mild disease >5% Older than 2 years 15-31%
  • 55.
    Factor IX Deficiency •Christmas disease (Hemophilia B): •X-linked recessive disorder •Indistinguishable from classic hemophilia (F VIII) •Requires evaluation of factor VIII and IX activity levels to diagnose •Treatment: •factor IX concentrate •Cryoprecipitate if factor IX unavailable •Desmopressin is not working
  • 56.
    Factor Deficiencies Hemophilia A(Classic Hemophilia) 80-85% of all Hemophiliacs Deficiency of Factor VIII Lab Results - Prolonged PTT HEMOPHILIA B (Christmas Disease) 10-15% of all Hemophiliacs Deficiency of Factor IX Lab Test - Prolonged PTT
  • 57.
    FACTOR DEFICIENCIES VON WILLEBRAND’SDISEASE Deficiency of VWF & amount of Factor VIII Lab Results - Prolonged BT, PTT
  • 58.
    OTHER DISORDERS (ACQUIRED) ORAL ANTICOAGULANTS COUMARIN HEPARIN LIVER DISEASE  MALABSORPTION  BROAD-SPECTRUM ANTIBIOTICS
  • 59.
    INHIBITORS 30% of peoplewith haemophilia develop an antibody to the clotting factor they are receiving for treatment. These antibodies are known as inhibitors. These patients are treated with high does of FVIIa for bleeds or surgery. This overrides defect in FVIII or FIX deficiency. Longterm management involves attempting to eradicate inhibitors by administering high dose FVIII (or FIX) in a process called immune tolerance
  • 60.
    Dosing guidelines forhemophilia A • General measures: avoid trauma, traumatic sports and IM injections • Local measures: local pressure, ICE application • Surgical: Joint replacement in case of joint deformity • Factor VIII concentrate: • Major surgery – Target: 80-100% q8h; 7-14 days (or until wound healing) – Dose: Desired level/2 x BW (kg) • Minor surgery – Target: 30-60% q12h; 3-5 days (or until wound healing) – Dose: Desired level/2 x BW (kg) • Prophylaxis: – Dose is the same as in minor surgery but twice weekly • Adjunctive therapy – aminocaproic acid or DDAVP (for mild – mod disease
  • 61.
    Treatment of hemophiliaB • Dose –Dose: Desired level x BW (kg) –The frequency in major and Minor surgery as in Factor VIII –Prophylaxis = 50 IU/kg once weekly –No role for DDAVP in hemophilia B
  • 62.
    This is themost common hereditary coagulopathy in humans. It can be congenital or acquired. Pathophysiology • Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF). • vWF is a multimeric glycoprotein encoded for by gene map locus 12p13. • It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions: • It assists in platelet plug formation by attracting circulating platelets to the site of damage. • It binds to coagulation factor VIII preventing its clearance from the plasma. Von Willebrand's Disease
  • 63.
    Von Willebrand factor Von Willebrand factoris a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic including thrombotic thrombocyto penic purpura, Heyde's syndrome, and possibly
  • 64.
    Etiology I. Hereditary -three types • vWD Type I, vWD Type II, and vWD Type III • Within the three inherited types of vWD there are various subtypes. II. Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in: • Lymphoproliferative • Myeloproliferative disorders • Solid tumors • Immunological disorders • Cardiovascular disorders e.g., aortic stenosis, • Wilms'tumor, • Hypothyroidism. Von Willebrand's Disease
  • 65.
    Laboratory evaluation of vonWillebrand 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
  • 66.
    Types of hereditaryvon Willebrand's disease (vWD) Type 1 60-80% Quantitative defect (19-45% of enzyme level present) • Heterozygous for defective gene • Inherited as AD • Normal lifespan • Occasionally easy bruising and/or menorrhagia • Bleeding after dental work, major surgery Type 2 20-30% Qualitative defect - multimers abnormal or subgroups absent Usually AD inheritance (rarely AR) Bleeding tendency varies Four subtypes: 2A, 2B, 2M, 2N Type 3 Rare - the most severe form; 1- Quantitative - levels very low or undetectable • Homozygous for defective gene • AR inheritance • Severe mucosal bleeding • May have haemarthrosis (as Von Willebrand's Disease
  • 67.
    Treatment of vonWillebrand Disease • Cryoprecipitate – Source of fibrinogen, factor VIII and VWF – Only plasma fraction that consistently contains VWF multimers – 1 unit / 10 kg • 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
  • 68.
    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
  • 69.
    Common clinical conditionsassociated with Disseminated 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
  • 70.
    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
  • 71.
    Pathogenesis of DIC CoagulationFibrinolysis 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
  • 72.
    Disseminated Intravascular Coagulation Treatmentapproaches • Treatment of underlying disorder • Anticoagulation with heparin • Platelet transfusion • Fresh frozen plasma • Coagulation inhibitor concentrate (ATIII)
  • 73.
    Liver Disease andHemostasis 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
  • 74.
    Management of Hemostatic Defectsin 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
  • 75.
    Treatment Approaches to theBleeding Patient • Red blood cells • Platelet transfusions • Fresh frozen plasma • Cryoprecipitate • Aminocaproic acid • DDAVP • Recombinant Human factor VIIa
  • 76.
    RBC transfusion therapy Indications •Improve oxygen carrying capacity of blood –Bleeding –Chronic anemia that is symptomatic –Peri-operative management
  • 77.
    Transfusion-transmitted disease Infectious agentRisk 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
  • 78.
    Platelet transfusions • Source –Plateletconcentrate (Random donor) –Pheresis platelets (Single donor) • Target level –Bone marrow suppressed patient (>10-20,000/µl) –Bleeding/surgical patient (>50,000/µl)
  • 79.
    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,
  • 80.
    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
  • 81.
    Cryoprecipitate • Prepared fromFFP • 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
  • 82.
    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
  • 83.
    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
  • 84.
    Recombinant human factorVIIa (rhVIIa; • 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”
  • 85.
    Approach to bleedingdisorders Summary • 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
  • 86.