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ANEMIAS Mohammad Abu-Fara. MD ANEMIA Anemia: Is defined as a reduction in one or more of major RBC measurements. HGB. HTC. RBC count . Anemia is not a disease by itself but is one of the major signs of disease. May be the first manifestation of a systemic disease, along with other nonspecific complaints such as fever, weight loss, anorexia. HGB Concentration: measures the major oxygen-carrying pigment in whole blood. Values are expressed as grams of HGB per dL of whole blood (g/dL). The normal ranges for HB. Varies in men and women and in different age group. Normal range: M 13-16,5 g/dL F 12-15,5 g/dL Hematocrit (HTC): Is the percent of a volume of whole blood occupied by intact RBCs. Values are expressed as a percentage. Normal range: M 41-51%. F 37-47%. RBC Count: Is the number of RBCs contained in a unit of whole blood. Values are expressed as millions of cells per uL of whole blood. Normal range: M 4,5-6,5 F 3,8-5,8 VOLUME STATUS The three measurements are all concentrations. As such they are dependent upon both the RBC mass and the plasma volume. 1.In acute bleeding anemia develops only after 36-48 hours. 2.Pregnancy:RBC mass is increased by 25% and plasma is increased by 50%.Normal values in pregnancy are different. 3.Dehydration. SPECIAL POPULATIONS 1.Living at high altitude. 2.Smoking and air pollution. 3.African-Americans—lower values. 4.Populations with a high incidence of ch. diseases. 5.Athletes. 6.The elderly: should not have a lower normal range for fear of missing a serious underlying disorder. ERYTHROPOESIS The rate of RBC production equals the rate of RBC destruction. Approximately 1% of RBCs is removed from the circulation daily. The rate of RBC production can increase markedly under the influence of high levels of EPO.5-7 folds. CLINICAL CONSEQUENCES OF ANEMIA The signs and symptoms induced by anemia are dependent upon the degree of anemia as well as the rate at which the anemia has evolved. Symptoms of anemia can result from two factors: 1.Decreased O2 delivery to tissues. 2.Hypovolemia/acute blood. loss/. COMPENSATORY MECHANISMS Signs and symptoms depend also on the compensatory mechanisms. 1.Extraction of O2 by the tissues can increase from 25% to 60%. 2.Cardiac compensation :stroke volume and heart rate/cardiac output/. Thus normal O2 delivery can be maintained by 1 and 2 at rest at HBG as low as 5g/dL,assuming that the intravascular. volume is maintained. Thus symptoms will develop when HBG falls below this level at rest or at higher HBG during exertion or when cardiac compensation is impaired. SYMPTOM AND SIGNS Symptom :is a sensation or change in health function experienced by the patient. It is a subjective report. Dyspnea /S.O.B. :on exertion/at rest. . Fatigue/tiredness. Signs and symptoms of hyperkinetic state: 1.bounding pulses. 2.palpitations. 3.roaring in ears. In more severe anemia: Lethargy, confusion, CHF, angina, MI., Pallor. Headache. Visual impairment, syncope Complications of extra cellular volume depletion/in acute bleeding/ Symptoms and sign due to the underlying cause of anemia . Iron deficiency Most cases are caused by menstrual loss and increased iron requirements of pregnancy. GI bleeding is the presumed etiology in most patient Decreased iron absorption (celiac disease, postgastrectomy, or increase iron requirement as in lactation. History of pica (consmption of substances such as ice, starsh or clay ) can be obtained . Signs : splenomegaly, kiolonychia (spoon nail ) and plummer- vinson syndrome (glossitis, dysphagia, and esophageal webs) are rare finding. Vitamin B12 and Folate deficiency Glossitis, angular stomatitis, juandice, splenomegaly and neurological syndrome of pernicious anemia ( subacute combined degeneration-demylination of dorsal and lateral columns of spinal cord. unsteady gait and progress to irreversible damage and bladder disturbance (only in VB12 def.) Sign: is an objective evidence of the presence of a disease or disorder .Signs are discovered and reported by the physician, not by the patient. Elevated BP. Skin rash. Tachypnea. CAUSES OF ANEMIA There are 2 interrelated approaches one can use to help identify the cause of anemia. 1.Kinetic approach. 2.Morphologic approach. KINETIC APPROACH Anemia can be caused by one or more of 3 independent mechanisms. 1.Decreased RBC production. 2.Increased RBC destruction. 3.RBC loss. MORPHOLOGIC APPROACH According to RBC size. Mean Corpuscular Volume /MCV/. RBC size/MCV/ is 80-96 femtoliters(fL). Microcyte. Macrocyte. Normocyte. ANEMIAS ACCORDING TO THE RBC SIZE 1.Microcytic anemia. 2.Macrocytic anemia. 3.Normocytic anemia. MICROCYTIC ANEMIAS Are associated with an MCV below 80 fL. IDA ACD Thalassemias. MACROCYTIC ANEMIAS Are characterized by an MCV above 100 fL. Reticulocytosis. Vit.B12 def. Folate def. MDS. Liver disease Hypothyroidism NORMOCYTIC ANEMIAS By definition the MCV is normal. ACD. MDS. EVALUATION OF THE PATIENT WITH ANEMIA-1 Anemia is one of the major signs of disease. It is never normal and it's cause should be always be sought. History. Physical examination. Simple lab. tests. Are all useful in evaluating the anemic patient. EVALUATION OF THE ANEMIC PATIENT-2 The workup should be directed towards answering the following questions: 1.Is the patient bleeding (now or in the past) ?. 2.Is there evidence of increased RBC destruction? 3.Is the BM suppressed?. 4.Is the patient iron deficient?if so,why?. Anemia associated with red blood cell loss or destruction Sickle cell disease G6PD deficiency Hemolytic anemia BLEEDING DISORDERS HEMOSTASIS-1 In health hemostasis ensures that the blood remains fluid and contained in the vascular system. If a vessel wall is damaged,a number of mechanisms are activated promptly to limit bleeding, involving 1-Endothelial cells. 2-Plasma coagulation factors. 3-Platelets. 4-Fibrinolytic system. HEMOASTASIS-2 These activities are finely balanced between keeping the blood fluid and preventing intravascular thrombosis. 1-Pimary hemostasis: immediate but temporary response to vessel injury . Platelets and von willebrand interact to form a primary plug , after which platelet activation occurs and blood vessels constrict, limiting flow. 2-Secondary hemostasis: (coagulation) :is slower process that results in the formation of a fibrin clot . Coagulation is initiated when vascular damage exposes extravascular tissue factor initiating activation of factor V11, factor X and prothrombin with subsequent activation of factor V,V111,1X,X1,and X111,leading to accelerated and sustained generation of fibrinogen to fibrin and formation of durable clot. 3-Fibrinolysis: activation of fibrin-bound plasminogen resulting in clot lysis. ROLE OF ENDOTHELIAL CELLS IN HEMOSTASIS Blood vessels are lined with endothelial cells,which synthesize and secrete various agents,that regulate hemostasis. 1-Procoagulant(prothrombotic) agents: tissue factor, von Willebrand factor, F V ,F VIII. 2-Anticoagulant(antithrombotic) agents: prostacyclin,Nitric oxide,endothelin-1. ROLE OF PLATELETS IN HEMOSTASIS 1. 2. 3. 4. 5. Each megacaryocyte produces 10002000 platelets,which remain in the circulation for about 10 days. Releasing of hemostatic proteins. Platelet adhesion. Platelet aggregation. COAGULATION SYSTEM Coagulation factors: are plasma proteins synthesized in the liver which ,when activated lead to the deposition of fibrin. 1-Initiation phase: leads to the formation of the complex TF-VIIa. 2-Amplification phase: leads to the formation of a small amount of thrombin from prothrombin. 3-Propagation phase: leads to the formation of much larger amounts of fibrin. INHIBITORS OF COAGULATION Are proteins that inhibit activated procaogulation enzymes and prevent excessive intravascular coagulation Raised levels are not associated with bleeding. Reduced levels may predispose to thrombosis. Antithrombin. Protein C, Protein S. Tissue Factor Pathway Inhibitor (TFPI). FIBRINOLYSIS Small amouns of fibrin are constantly deposited within the vascular system and are removed by the fibrinolytic system Plasminogen Plasmin Fibrin FDPs ASSESSMENT OF BLEEDING SYMPTOMS 1-Careful and full clinical history and examination. (determining whether a bleeding is present or likely congenital or acquired, mild or severe and involving primary or secondary hemostasis ) 2-Appropriate lab. investigations. 3-Other investigations. HISTORY 1. 2. 3. 4. 5. 6. 7. 1-Site of bleeding( dental extractions, circumcision, menstration, labor or delivery and trauma or surgery. Or easy bruising 2-Duration of bleeding and severity. 3-Precipitating cause. 4-Surgery. 5-Family history. 6-Systemic illnesses (acquired bleeding disorders). 7-Drugs. Clinical Features of Bleeding Disorders Platelet disorders Coagulation factor disorders Site of bleeding Skin Mucous membranes (epistaxis, gum, vaginal, GI tract) Deep in soft tissues (joints, muscles) 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, usually mild Delayed (1-2 days), often severe LABORATORY STUDIES Initial studies should include a platelet count, prothrombin time (Pt ), activated partial thromboplastic time (aPtt) and peripheral blood smear review. 1. platelet count low : manual slide review to rule out a platelet clumping artifact. 2. Bleeding time (BT) : may detect quantitative or qualitative disorder of platelets or vWF or abnormalities of capillary integrity. prolonged after medication as aspirin. In vitro platelet aggregation Von Willebrand factor antigen von Willebrand factor activity , ristocetin cofactor (vWF :RCo ) Von Willbrand factor multimer analysis. Secondary hemostasis Prothrombin time (Pt) : extrinsic pathway (factor V11,and common pathway factor X,V ,prothrombin ) coagulation factors and fibrinogen. INR : (patient PT/ mean normal PT)ISI Activated partial thromboplastin times (aPTT): intrinsic pathway (kininogen, prekallikrein, factor X11, factor 1X,factor X1 and factor V111) and common pathway (factor V,facter X ,prothrombin and fibrinogen. Thrombin time (TT) Fibrinogin Clot urea stability Mixing studies coagulation plasma activity . Coagulation factor disorders 1. Inherited bleeding disorders 1. 2. 3. Hemophilia A and B Von Willebrand disease Other factor deficiencies Acquired bleeding disorders 1. 2. 3. Liver disease Vitamin K deficiency/warfarin overdose DIC Hemophilia A and B Coagulation factor deficiency Inheritance Incidence Severity Hemophilia A Hemophilia B Factor VIII Factor IX X-linked recessive X-linked recessive 1/10,000 males 1/50,000 males 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 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) Treatment of hemophilia A Intermediate purity plasma products High purity (monoclonal) plasma products Virucidally treated No functional von Willebrand factor Recombinant factor VIII Virucidally treated May contain von Willebrand factor 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 Tranexemic acid or DDAVP (for mild disease only) 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 Hepatitis C HIV Human parvovirus Hepatitis A Other RITUXIMAB AND ACQUIRED HEMOPHILIA(F VIII INHIBITORS) STUDY # OF PATS Stasi R,Bld 10 103:4424,2004 acquired,titer 4-96BU Mazj S,Bld 4 acquired 102,03,abs295 5 Wiestner A,Bld 4(3 acquired,1 100,02,3426 hemophilia) OUTCOME 80% CR FW 28.5m 100% CR 100% CR FW 7-12m 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 factor Synthesis in endothelium and megakaryocytes Forms large multimer Carrier of factor VIII Anchors platelets to sub endothelium Bridge between platelets Inheritance - autosomal dominant Incidence - 1/10,000 Clinical features - mucocutaneous bleeding Laboratory evaluation of von Willebrand disease Classification Type 1 Type 2 Type 3 Partial quantitative deficiency Qualitative deficiency Total quantitative deficiency Diagnostic tests: vonWillebrand type 2 Assay 3 1 vWF antigen vWF activity Multimer analysis Absent Normal Normal Normal VWF Multimers plt NP 1 2A 2A 2B Proteolysis 3 Treatment of von Willebrand Disease Cryoprecipitate DDAVP (deamino-8-arginine vasopressin) Source of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF multimers 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 Pathogenesis of DIC Release of thromboplastic material into circulation Coagulation Fibrinolysis Fibrinogen Plasmin Thrombin Fibrin Monomers Fibrin Clot (intravascular) Consumption of coagulation factors; presence of FDPs aPTT PT TT Fibrinogen Presence of plasmin FDP Fibrin(ogen) Degradation Products Plasmin Intravascular clot Platelets Schistocytes Disseminated Intravascular Coagulation (DIC) Mechanism Systemic activation of coagulation Intravascular deposition of fibrin Thrombosis of small and midsize vessels with organ failure Depletion of platelets and coagulation factors Bleeding Common clinical conditions associated with Disseminated Intravascular Coagulation Activation of both coagulation and fibrinolysis Triggered by Sepsis Trauma Head injury Fat embolism Malignancy Obstetrical complications Amniotic fluid embolism Abruptio placentae Vascular disorders Reaction to toxin (e.g. snake venom, drugs) Immunologic disorders Severe allergic reaction Transplant rejection Disseminated Intravascular Coagulation Treatment approaches Treatment of underlying disorder Anticoagulation with heparin Platelet transfusion Fresh frozen plasma Coagulation inhibitor concentrate (ATIII) 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 Platelet interaction Thrombocytopenia Immune-mediated Idioapthic Drug-induced Collagen vascular disease Lymphoproliferative disease Sarcoidosis Non-immune mediated DIC Microangiopathic hemolytic anemia Incidence of adult ITP increases with age Incidence (per 105 / year) Age (yrs) Female Male Total 15-39 40-59 60+ 2.3 3.2 4.6 1.3 1.1 4.4 3.6 4.3 9.0 Total 3.2 2.0 2.6 Frederiksen and Schmidt, Blood 1999:94;909 Initial Treatment of ITP Platelet count (per µl) Symptoms >50,000 None 20-50,000 Not bleeding Bleeding Treatment None Steroids IVIG <20,000 Not bleeding Steroids Bleeding IVIG Hospitalization 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-2antiplasmin) 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 Laboratory Evaluation of Bleeding Overview CBC and smear Platelet count RBC and platelet morphology Thrombocytopenia TTP, DIC, etc. Coagulation Prothrombin time Partial thromboplastin time Coagulation factor assays 50:50 mix Fibrinogen assay Thrombin time Extrinsic/common pathways Intrinsic/common pathways Specific factor deficiencies Inhibitors (e.g., antibodies) Decreased fibrinogen Qualitative/quantitative fibrinogen defects Fibrinolysis (DIC) FDPs or D-dimer Platelet function von Willebrand factor Bleeding time Platelet function analyzer (PFA) Platelet function tests vWD In vivo test (non-specific) Qualitative platelet disorders and vWD Qualitative platelet disorders Coagulation cascade Intrinsic system (surface contact) XII Extrinsic system (tissue damage XIIa Tissue factor XIa XI IX IXa VIII VIIa VIIIa X Vitamin K dependant factors VII Xa V Va II Fibrinogen IIa (Thrombin) Fibrin Laboratory Evaluation of the Coagulation Pathways Partial thromboplastin time (PTT) Prothrombin time (PT) Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium Thromboplastin Tissue factor Phospholipid Calcium Intrinsic pathway Extrinsic pathway Thrombin time Common pathway Thrombin Fibrin clot Initial Evaluation of a Bleeding Patient - 1 Normal PT Normal PTT Abnormal Urea solubility Factor XIII deficiency Normal Consider evaluating for: Mild factor deficiency gammopathy Abnormal fibrinolysis (a2 anti-plasmin def) Monoclonal Platelet disorder Vascular disorder Initial Evaluation of a Bleeding Patient - 2 Normal PT Abnormal PTT Repeat with 50:50 mix 50:50 mix is abnormal Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare) Initial Evaluation of a Bleeding Patient 3 Abnormal PT Normal PTT Repeat with 50:50 mix 50:50 mix is abnormal Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare) 50:50 mix is normal Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC) Initial Evaluation of a Bleeding Patient 4 Abnormal PT Abnormal PTT Repeat with 50:50 mix 50:50 mix is abnormal Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, Coagulation factor deficiencies Summary 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 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 Heparin Hypofibrinogenemia Dysfibrinogenemia Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies 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 Treatment Approaches to the Bleeding Patient Red blood cells Platelet transfusions Fresh frozen plasma Cryoprecipitate Cyclokapron DDAVP Recombinant Human factor VIIa Red blood cell transfusions Adverse reactions Immunologic reactions Hemolysis Anaphylaxis Febrile reaction Urticaria Non-cardiogenic pulmonary edema RBC incompatibility Usually unknown; rarely against IgA Antibody to neutrophils Antibody to donor plasma proteins Donor antibody to leukocytes 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, Interferons) Fresh frozen plasma Content - plasma (decreased factor V and VIII) Indications Dose (225 ml/unit) Multiple coagulation deficiencies (liver disease, trauma) DIC Warfarin reversal Coagulation deficiency (factor XI or VII) 10-15 ml/kg Note Viral screened product ABO compatible Cryoprecipitate Prepared from FFP Content Indications Factor VIII, von Willebrand factor, fibrinogen Fibrinogen deficiency Uremia von Willebrand disease Dose (1 unit = 1 bag) 1-2 units/10 kg body weight Hemostatic drugs Tranexemic acid (Cyclokapron) Mechanism Prevent activation plaminogen -> plasmin Dose 1g iv q6-8hrs Uses Primary menorrhagia Oral bleeding Bleeding in patients with thrombocytopenia Blood loss during cardiac surgery Side effects Optic atrophy Hemostatic drugs Desmopressin (DDAVP) Mechanism Dose 0.3µg/kg IV q12 hrs 150mg intranasal q12hrs Uses Increased release of VWF from endothelium 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) Mechanism Use Factor VIII inhibitors Bleeding with other clotting disorders Warfarin overdose with bleeding CNS bleeding with or without warfarin Dose 100 µg/kg IV q 2 hrX2 “Adjust as clinically indicated” Direct activation of common pathway Cost (70 kg person) - JD0.66per µg 4,800/dose 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 THANK YOU