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HEMOSTASIS & BLEEDING Professor Anwar Sheikha MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP Senior Consultant Clinical & Lab. Hematologist Clinical Professor of Hematology University of Mississippi Medical Center, Jackson, Mississippi Professor of Hematology, University of Salahaddin, Erbil, Kurdistan, IRAQ HEMOSTASIS ARREST OF BLEEDING Hemostasis is a highly integrated process involving Blood Vessels, Platelets and a number of plasma proteins that are collectively responsible for Coagulation and Fibrinolysis HEMOSTASIS ARREST OF BLEEDING Hemostasis is a highly integrated process involving Blood Vessels, Platelets and a number of plasma proteins that are collectively responsible for Coagulation and Fibrinolysis DEFECT IN ANY OF THESE COMPONENTS BLEEDING TRIGGERING OF ANY OF THESE COMPONENTS THROMBOSIS HEMOSTASIS ARREST OF BLEEDING Hemostasis is a highly integrated process involving Blood Vessels, Platelets and a number of plasma proteins that are collectively responsible for Coagulation and Fibrinolysis HEMOSTASIS Hemostasis is a highly integrated process involving Blood Vessels, Platelets and a number of plasma proteins that are collectively responsible for Coagulation and Fibrinolysis HEMOSTASIS BRICKS “Platelets” CEMENT “Clotting” HEMOSTASIS HEMOSTASIS Blood Vessel Platelet ﮔﻪﺭﻩﻻﻮﮊﻩ Clotting BLOOD VESSEL Collagen Microfibrils Nitric Oxide von Willebrand Factor BLEEDING PURPURIC BLEEDING ﻛﻪﭘﺮ DEEP SEATED BLEEDING ﻛﯚﺷﻚ BLEEDING PURPURIC BLEEDING ﻛﻪﭘﺮ DEEP SEATED BLEEDING ﻛﯚﺷﻚ How to do Bleeding Time? Simplate BLEEDING DUE TO VESSEL WALL ABNORMALITIES HEREDITARY HEMORRHAGIC TELENGIECTASIA EHLERSDANLOS SYNDROME SENILE PURPURA SCURVEY MULTIPLE MYELOMA HENOCH-SCHONLEIN PURPURA ALLOPURINOL INDUCED PURPURA SLE SYSTEMIC LUPUS ERYTHEMATOSUS WISKOTT-ALDRICH SYNDROME PURPURA PETICHAE ECCHYMOSIS BRUISES HEMATOMA The old practice of Bleeding Time & Clotting Time! Do Platelet count If Low Do Bleeding Time If Prolonged, give Platelets Do Platelet count If Low Do Bleeding Time If Prolonged, give Platelets BLEEDING DUE TO PLATELET ABNORMALITIES Megakaryocytes Largest hemopoietic marrow cells (~100 um) Multi-lobulated nuclei; no mitosis but nuclear duplication Abundant cytoplasm with azurophilic granules Each Produces 3000 platelets SHEIKHA The committed platelet progenitor cells Megakaryocytes do not undergo classical mitosis; instead they will develop nuclear duplications & cytoplasmic expansion. The rapid increase in cytoplasm is accommodated by progressive folding, or invaginations, of megakaryocytic membrane. These demarcation membranes will eventually produce individual platelet membranes. MK pseudopodia penetrates marrow sinusoids. Blood flow breaks off large platelets that are finally fragmented to individual platelets in the pulmonary microcirculation. SHEIKHA Megakaryocytes In stressed thrombopoiesis, cytoplasm matures quicker than nucleus so that low ploidy MK start to produce platelets that are larger, denser and metabolically more active EACH MK CAN PRODUCE 3000 PALETLETS SHEIKHA THROMBOCYTOPENIA ↓ PRODUCTION APLASTIC ANEMIA LEUKEMIAS CHEMOTHERAPY MARROW INFILTRATION THROMBOCYTOPENIA ↓ PRODUCTION APLASTIC ANEMIA LEUKEMIAS CHEMOTHERAPY MARROW INFILTRATION ↓ SURVIVAL ITP EVANS’ SLE DIC TTP/HUS SEPSIS THROMBOCYTOPENIA ↓ PRODUCTION APLASTIC ANEMIA LEUKEMIAS CHEMOTHERAPY MARROW INFILTRATION ↓ SURVIVAL ITP EVANS’ SLE DIC TTP/HUS SEPSIS LOSS FROM CIRCULATION SPLENOMEGALY MASSIVE TRANSFUSION ITP IMMUNE THROMBOCYTOPENIC PURPURA Old View: Increased Platelet Production with High Platelet Turnover New Concept: Decreased Platelet Production!! Spleen in ITP ITP ACUTE CHRONIC “Childhood” “Adult” Preceding Infection 2–6 1:1 Acute Common 20 – 40 1:3 Chronic Unusual Platelet Count Often <20,000/uL Often >20,000/uL Spontaneous Remission > 80% 2 – 4 weeks < 20% Peak Age “Years” Sex “M/F” Onset Usual Duration Months/ Years EVANS’ SYNDROME MANAGEMENT OF ITP STEROID IV IMMUNOGLOBULIN Anti-D SPLENECTOMY ?Platelet Transfusion Rituximab “Anti CD20” WAS DRUG-INDUCED THROMBOCYTOPENIA TTP/HUS THROMBOTIC THROMBOCYTOPENIC PURPURA HEMOLYTIC UREMIC SYNDROME FEVER ICU TP BROKEN RBCs MAHA A PHONE CALL CNS SAVE A LIFE RENAL Mortality Rate 85% Mortality Rate Recovery Rate 85% 85% BERNARD-SOULIER SYNDROME Advise your Bleeding Patients to avoid Aspirin, NSAID & intramuscular injections BLEEDING DUE TO COAGULATION DISORDERS WORLD HEMOPHILIA DAY HEMOPHILIA Legg, in 1872, defined Hemophilia as “A congenital and lifelong tendency to hemorrhage into muscles and joints”. This is still one of the best definitions for the disease SEXLINKED 1/10,000 BIRTHS 1/5000 MALE BIRHTS A QUARTER OF PATIENTS HAVE FRESH MUTATIONS SEVERE <1% MODERATE 1-5% MILD 5-20% Upward of 1/3 of NEONATAL males with severe Hemophilia will not bleed at circumcision Black or White, Royal or Beggar, it does not matter, as long as you are A MAN! Inhibitor Novo7 CHRISTMAS DISEASE HEMOPHILIA B Factor IX Deficiency Patients with FIX Leyden have severe hemophilia until Puberty, when FIX levels spontaneously increase, suggesting that abnormal gene is androgen sensitive HEMOPHILIA “A” or “B” SEVERE MODERATE MILD Neonatal VIII, IX Level % all Hph A % all Hph. B < 1% 70 % 50 % 15% 15 % > 5% 15 % CNS Bleed Symptoms Tooth Extra M.&J. Bleed Onset AGE <1 yr PCB+++ ICH+ - Spont. High Usual 30 % Minor Trauma Mod. Common 1-2 yr PCB+++ ICH+/- 20 % 2adult PCB ICH -+ Major Trauma Rare Often PCB: Post-circumcision Bleeding ICH: Intra-cranial Hemorrhage Upward of one third of hemophiliacs do not have excessive post-circumcision bleeding. MANAGEMENT OF HEMOPHILIAS AND ALL OTHER BLEEDING DISORDERS IS BY A NEW MAGIC UNIVERSAL HEMOSTATIC AGENT CALLED MANAGEMENT OF HEMOPHILIAS AND ALL OTHER BLEEDING DISORDERS IS BY A NEW MAGIC UNIVERSAL HEMOSTATIC AGENT CALLED NovoNordiscHawlerBayar MANAGEMENT OF HEMOPHILIAS AND ALL OTHER BLEEDING DISORDERS IS BY A NEW UNIVERSAL HEMOSTATIC AGENT CALLED Novo7 “rVIIa” FACTOR VIII:C CONCENTRATE DDAVP TREATMENT OF HEMOPHILIA A ANTIFIBRINOLYTICS Tranexamic Acid EACA Gene Therapy Novo7 or FEIBA “Inhibitors” Factor VIII SA (U/mg Protein) LOW PURITY INTER. PURITY HIGH PURITY ULTRA PURITY <5 1-10 50-100 3000 (Specific Activity) Product CRYOPRECIPITATE Humate-P Profilate -OSD FACTOR VIII Alphanate Koate-HP *Plasma-derived, MoAb-purified *Recombinant F VIII WE BLED, BUT THANK GOD NOW OUR HEMOSTASIS IS INTACT LET US WISH THE SAME FOR THE REST OF OUR BELOVED IRAQ THANK YOU von Willebrand Disease von Willebrand Disease 1% 10,000 PATIENTS IN HAWLER of the POPULATION 10,000 PATIENTS IN SULY If I were a surgeon I will be quite cautious, knowing that most of these patients only bleed when challenged surgically von Willebrand Disease Von Willebrand Disease Type 1 Partial Quantitative ↓ of VWF Type 2 Qualitative ↓ of VWF Type 3 Total ↓ of VWF + ↓ ↓ VIII:C Von Willebrand Disease Type 1: Quantitative ↓ of VWF Autosomal dominant >70% of all vWD ~ 1% of Population Von Willebrand Disease Type 3 Total ↓ of VWF & ↓ ↓ VIII:C Autosomal recessive CF: vWD + Hemophilia ↓VWF:Ag ↓VWF:RCo ↑APTT Parents may be Type 1 with normal APTT Von Willebrand Disease Type 1: Quantitative ↓ of VWF Type 2: Qualitative ↓ of VWF Type 3: Total ↓ of VWF + ↓ ↓ VIII:C Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B ↑ binding of VWF & Platelets Depletion of High Multimers & Platelets LOVE AFFAIR ﺣﺐ Von Willebrand Disease Type 2M “Multimers” ↓ binding of VWF & Platelets Normal Multimers HATE AFFAIR ﻁﻼﻖ Von Willebrand Disease Von Willebrand Disease Pseudo-vWD “Platelet type vWD” ↑ binding of Platelet GP Ib-IX-V & Large Multimer VWF Indistinguishable from Type 2B Treat with Platelet Transfusion Von Willebrand Disease Von Willebrand Disease BLOOD GROUP “O” PEOPLE HAS 25% LOWER THAN OTHER BLOOD GROUPS COULD THAT BE TRANSLATED TO A LONGER SURVIVAL WITH LESS ISCHEMIC EFFECTS? TESTING for vWD EVALUATION APTT & FVIII Level ?BLEEDING TIME VWF:Ag VWF:RCo VWF Multimers Analysis RIPA “Ristocetin-induced Platelet Aggregation” FVIII binding assay DNA sequencing of the Gene Management of Von Willebrand Disease DDAVP Treatment of choice for Type 1 vWD Favorable also for Type 2A & 2M but duration of response is shorter In Type 2B it releases the abnormal VWF Thrombocytopenia Dose: 0.3 ug/kg (maximum 20 ug) over 20 minutes Because of tachyphylaxis repeat dose only after 24 to 48 hours Restrict fluids; monitor blood pressure and serum sodium Management of Von Willebrand Disease VWF-containing Factor VIII concentrate Treatment of choice for most bleeds, especially when severe Purified VWF is available in Europe but not USA No monoclonal or recombinant VWF FVIII:C concentrate used for hemophilia is not effective Management of Von Willebrand Disease FFP & Cryoprecipitate should not be considered for treatment of vWD because FFP cannot contain enough VWF & Cryo cannot be virally inactivated Local therapy like antifibrinolytic mouth washes for oropharyngeal bleeds Tranexamic acid 1 gm q6h EACA 2-3 gm q6h Von Willebrand Disease Q4. Type 2B von Willebrand disease is due to: A. Partial Quantitative deficiency of von Willebrand Factor “VWF” B. Deficiency of the high molecular weight VWF multimers C Increased binding of VWF to platelets causing depletion of high molecular weight VWF and thrombocytopenia D. Decreased binding of VWF to platelets, but with normal VWF multimer distribution E. Decreased binding of VWF to Factor VIII causing low plasma Factor VIII:c THANK YOU ENJOY YOUR NOVO7 MEAL Von Willebrand Disease Von Willebrand Disease Q1. Type 2N “N = Normandy” von Willebrand disease is due to: A. Partial Quantitative deficiency of von Willebrand Factor “VWF” B. Deficiency of the high molecular weight VWF multimers C. Increased binding of VWF to platelets causing depletion of high molecular weight VWF and thrombocytopenia D. Decreased binding of VWF to platelets, but with normal VWF multimer distribution E Decreased binding of VWF to Factor VIII causing low plasma Factor VIII:C Von Willebrand Disease Q2. A Type 1 von Willebrand disease is due to: Partial Quantitative deficiency of von Willebrand Factor “VWF” B. Deficiency of the high molecular weight VWF multimers C. Increased binding of VWF to platelets causing depletion of high molecular weight VWF and thrombocytopenia D. Decreased binding of VWF to platelets, but with normal VWF multimers E. Decreased binding of VWF to Factor VIII causing low plasma Factor VIII:c Von Willebrand Disease Q3. Type 2M “M = Multimers” von Willebrand disease is due to: A. Partial Quantitative deficiency of von Willebrand Factor “VWF” B. Deficiency of the high molecular weight VWF multimers C. Increased binding of VWF to platelets causing depletion of high molecular weight VWF and thrombocytopenia D Decreased binding of VWF to platelets, but with normal VWF multimers E. Decreased binding of VWF to Factor VIII causing low plasma Factor VIII:c Von Willebrand Disease Q4. Type 2B von Willebrand disease is due to: A. Partial Quantitative deficiency of von Willebrand Factor “VWF” B. Deficiency of the high molecular weight VWF multimers C Increased binding of VWF to platelets causing depletion of high molecular weight VWF and thrombocytopenia D. Decreased binding of VWF to platelets, but with normal VWF multimer distribution E. Decreased binding of VWF to Factor VIII causing low plasma Factor VIII:c Von Willebrand Disease Q5. One of the following types of von Willebrand disease is autosomal recessive: A. Type 1 von Willebrand disease B. Type 2A von Willebrand disease C. Type 2B von Willebrand disease D Type 2N von Willebrand disease E. Type 2M von Willebrand disease Von Willebrand Disease Q6. One of the following types of von Willebrand disease is associated with thrombocytopenia: A. Type 1 von Willebrand disease B. Type 2A von Willebrand disease C Type 2B von Willebrand disease D. Type 2N von Willebrand disease E. Type 2M von Willebrand disease Von Willebrand Disease Q7. Type 2A von Willebrand disease is due to: A. Partial Quantitative deficiency of von Willebrand Factor “VWF” B Deficiency of the high molecular weight VWF multimers C. Increased binding of VWF to platelets causing depletion of high molecular weight VWF and thrombocytopenia D. Decreased binding of VWF to platelets, but with normal VWF multimers E. Decreased binding of VWF to Factor VIII causing low plasma Factor VIII:c Von Willebrand Disease Q8. One of the following features does not relate to Type 3 von Willebrand disease: A It is autosomal dominant B. There is virtual absence of von Willebrand Factor C. There is profound deficiency of Factor VIII:c with prolonged APTT D. Screening assays show absent VWF:RCo and VWF:Ag E. Parents of these patients may have Type 1 von Willebrand disease with bleeding Von Willebrand Disease Q9. One of the following features is not true about Type 2N “N = Normandy” von Willebrand disease: A It is autosomal dominant B. Mutations selectively inactivate FVIII:C binding site on VWF C. The platelet-dependent functions of VWF is intact D. Factor VIII:C is usually <10% and APTT is prolonged E. Patients usually behave like hemophilia but with autosomal style of inheritance Von Willebrand Disease Q10. Type 2N “N = Normandy” von Willebrand disease should be suspected in: A. Any patient with low FVIII:C in whom a Factor VIII inhibitor is ruled out B. Any patient with low FVIII:C in whom X-linked inheritance is not clear C. Any patient with low FVIII:C in whom therapy with recombinant or monoclonal FVIII concentrate gives poor results D All of the above E. None of the above Von Willebrand Disease Von Willebrand Disease Von Willebrand Disease Von Willebrand Disease Von Willebrand Disease Von Willebrand Disease von Willebrand Factor DIC DISSEMINATED INTRAVASCULAR COAGULATION DIC DIC Diagnostic Algorithm 1. Risk Assessment: Does patient have underlying disorder known to be ~ DIC? If Yes proceed. If No, do not use algorithm. 2. Order global coagulation tests? Platelet; PT; Fibrinogen; SFM or FDP, etc 3. Score Global Coagulation Test results: Score 0 Platelet 1 >100 <100 No ↑Fibrin-related 2 3 Total <50 Moder Strong markers (SFM?FDP) <3 sec >1 g/L ↑ P.T. Fibrinogen >3 to < 6 sec >1 g/L >6 sec Calculate Score; If = or > 5 Compatible with overt DIC Repeat scoring daily If < 5 Suggestive (not affirmative) for non-overt DIC; Repeat next 1-2 days. BLEEDING IN DENTAL SURGERY PRACTICE vWD 1% HEMOSTASIS ARREST OF BLEEDING Hemostasis is a highly integrated process involving Blood Vessels, Platelets and a number of plasma proteins that are collectively responsible for Coagulation and Fibrinolysis HEMOSTASIS ARREST OF BLEEDING Hemostasis is a highly integrated process involving Blood Vessels, Platelets and a number of plasma proteins that are collectively responsible for Coagulation and Fibrinolysis DEFECT IN ANY OF THESE COMPONENTS BLEEDING TRIGGERING OF ANY OF THESE COMPONENTS THROMBOSIS DENTAL PROCEDURES IN HEMOPHILIA PATIENTS * Routine examination and cleaning generally can be performed without raising F VIII level DENTAL PROCEDURES IN HEMOPHILIA PATIENTS * Routine examination and cleaning generally can be performed without raising F VIII level * Adequate coverage (FVIII +/- Antifibrinolytics) SHOULD be given before & possibly after the dental appointment in the following situations: # Deep cleaning or scaling because of heavy plaque &/or calculus accumulation in which bleeding would be induced Block local anesthesia or mandibular block Dental extraction, especially multiple or other surgical procedures # # DENTAL PROCEDURES IN HEMOPHILIA PATIENTS SUGGESTED THERAPY Multiple dental extractions or other surgery: Loading dose:Raise to 50%; Give 1 hr before surgery Maintenance dose:? / repeat before bleeding + Tranexamic Acid / EACA for 7 days DENTAL SURGEON INR Hemophilia & vWD HEMATOLOGIST Dental Hygiene ITP Leukemias Conclusions: Prior to any dental procedure, ask the following questions: * Do you have any past problem with bleeding? * Do you get bruised easily? * Have you done any operation in the past and whether you had any bleeding problem? * Ask about circumcision in male patients * Any family history of bleeding. * Any drug history, especially Warfarin. On the slightest suspicion, referral to a hematologist is justified.