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Hemostasis and Bleeding disorders Dr Mustapha Alfallah Pediatric Hematologist-Oncologist Definitions • Hemostasis is traditionally defined as a physiological response to blood vessel injury and bleeding, which entails a co-ordinated process involving the blood vessel, platelets, and blood clotting proteins (i.e. coagulation factors). Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Hemostasis can be divided into primary and secondary components. • The former is characterized by vascular contraction, platelet adhesion, and formation of a soft aggregate plug. • The latter is initiated following the release of tissue factor and involves a complex sequence of events known as the blood coagulation cascade, encompassing serial steps where each coagulation factor activates another in a chain reaction that culminates in the conversion of fibrinogen to fibrin. Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Mechanism of Hemostasis During Hemostasis three steps occur in a rapid sequence. 1. Vascular spasm - Vascular spasm is the blood vessels first response to injury. 2. Platelet plug formation - Platelets adhere to damaged endothelium to form platelet plug and then degranulate. As platelets adhere to the collagen fibers of a wound they become spiked and much stickier. They then release chemical messengers such as adenosine diphosphate , serotonin and thromboxane A2. These chemicals are released to cause more platelets to stick to the area and release their contents and enhance vascular spasms. The platelet plug formation is activated by the Von Willebrand factor (VWF), 3. Coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a “molecular glue”. Once the platelet plug has been formed by the platelets, the clotting factors begin to form a collagen fiber called fibrin. Once this begins, red and white blood cells become caught up in the fibrin mesh which causes the clot to become even stronger Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Number and/or name Associated genetic disorders I (fibrinogen) Congenital afibrinogenemia, Familial renal amyloidosis II (prothrombin) Hypoprothrombinemia, Thrombophilia III Tissue factor V (proaccelerin, labile factor) Activated protein C resistance VII (stable factor, proconvertin) congenital factor VII deficiency VIII (Antihemophilic factor A) Haemophilia A IX (Antihemophilic factor B or Christmas factor) Haemophilia B X (Stuart-Prower factor) Congenital Factor X deficiency XI (plasma thromboplastin antecedent) Haemophilia C XII (Hageman factor) Hereditary angioedema type III XIII (fibrin-stabilizing factor) von Willebrand factor von Willebrand disease Approach to a patient with bleeding disorder Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist History. The clinical history provides the most useful information and should determine - Site or sites of bleeding, - Severity and duration of hemorrhage, - Age at symptom onset. - Was the bleeding spontaneous or after trauma? - Was there a previous personal or family history of similar problems - If there has been previous surgery or significant dental procedures, or circumcision, - Delayed or slow healing of superficial injuries may suggest a hereditary bleeding disorder. - In postpubertal females, it is important to take a careful menstrual history.. - Medications such as aspirin and other nonsteroidal anti-inflammatory. Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Physical Examination • The physical examination should focus on whether symptoms are primarily associated with the mucous membranes or skin (mucocutaneous bleeding) or the muscles and joints (deep bleeding). • Patients with defects in platelet/blood vessel wall interaction usually have mucous membrane bleeding); petechiae on the skin and mucous membranes; and small, ecchymotic lesions of the skin • Individuals with a clotting factor deficiency have symptoms of deep bleeding into muscles and joints with much more extensive ecchymoses and hematoma formation. • Patients with mild bleeding disorders may have no abnormal findings on physical examination. Laboratory Tests First step evaluation Platelet count, Bleeding time, The bleeding time assesses the function of platelets and their interaction with the vascular wall. PLATELET FUNCTION ANALYZER. PTT, and PT. ACTIVATED" PARTIAL THROMBOPLASTIN TIME (PTT) measures the intrinsic clotting system PROTHROMBIN TIME (PT) measures the extrinsic clotting system The PT has been standardized using the International Normalized Ratio (INR) so that values can be compared from one laboratory or instrument to another. Thrombin Time (TT) detects the rate of fibrin clot formation after a fixed concentration of thrombin is added to a sample, CLOTTING FACTOR ASSAYS. For most clotting factors the normal range is between 50-150 U/dL (50-150%). PLATELET AGGREGATION. When a qualitative platelet function defect is suspected, platelet aggregation testing is usually ordered. Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Defects in Primary Homeostasis A) Vascular phase :Ex:Henoch Schonlein purpura B) Platelets phase: -Quantitative abnormalities of platelets (Thrombocytopenia) Ex I.T.P -Qualitative abnormalities of platelets (Thrombopathies) Ex:Glanzmann thromboasthenia Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Defect Coagulation or Plasma Phase Ex : Hemophilia Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Henoch Schonlein Purpura 1 Definition Vascular damage occurs from immune complex deposition within the blood vessel walls following a viral or bacterial infection Peak age 2 - 8 years Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Henoch Schonlein Purpura 2 Clinically : various combinations of symptoms and signs may occur 1- Skin rash : Maculopapular ,erythematous, and petechial, over legs buttocks, and arms 2- Migratory arthritis 3- Abdominal pain, diarrhea, and GI bleeding 4- Nephritis (Proteinurea, hematurea, azotemia, hypertension ) 5- Others Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Henoch Schonlein Purpura 3 Laboratory findings show no change with normal platelet count Treatment : No specific therapy : Aspirin for arthritis : Prednisone for GI manifestations Prognosis : Usually good (but 50% of patients with nephritis may have persistent abnormal urinary findings Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Immune Thrombocytopenic Purpura (I.T.P) 1 -The most common bleeding disorder of childhood -The most common age of diagnosis is between 2 and 10 years of age, with peak age of 4 – 8 years • There is an equal incidence of ITP in both males and females • -Frequently follows viral infections(rubella, varicella, rubeola) Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Immune Thrombocytopenic Purpura ( ITP ) Clinically : Usually acute onset with -Spontaneous small hemorrhages into the skin and mucous membrane (Petechiæ) -Echymosis -Epistaxis Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist 2 21 Immune Thrombocytopenic Purpura (ITP) 3 Diagnosis -Presenting platelet count < 20,000/µL, - The morphology of platelets is typically normal, with varying numbers of large platelets reflecting the early release of megakaryocytic fragments into the circulation. - The typical finding in the bone marrow of patients with ITP is normal or elevated number of megakaryocytes. The most serious complication is intracranial hemorrhage (in less than 1 % ) Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Immune Thrombocytopenic Purpura (ITP) 4 Treatment If mild disease = No treatment In severe cases = Prednisone or High dose methyl prednisolone, IVIG or Anti-Rh immunoglobulin ("anti-D") Only for Rh positive patients In chronic cases = Splenectomy = immunosuppressive drugs (Vincristine,Azathioprine, Rutiximab?) Prognosis : Remission in 90% of cases Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Hemophilia Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Definition Hemophilia is caused by a deficiency of coagulation factor VIII (FVIII) (hemophilia A) or factor IX (FIX) (hemophilia B) • No ethnic or geographic predisposition has been defined • Hemophilia A is more common than hemophilia B, representing 80-85% of the total • It is inherited in an X-linked recessive manner meaning that males are affected and females are carriers (mutations of the clotting factor gene on X chromosome (FVIII=Xq28) (FIX=Xq27)) • Approximately 30% of cases occur because of spontaneous mutations Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Clinical presentation Spontaneous and post-traumatic hemarthroses and muscle hematomas are the most frequent injuries that affect hemophiliac patients • Hemarthroses most commonly occur in the knees, ankles, and elbows, (bleeding into the shoulder or hip joint are more rare, spinal and wrist joints are very seldom affected) • Joint becomes stiff, swollen, warm, and tender • In acute joint bleeds, once the blood has been reabsorbed and the swelling has diminished, normal joint mobility and function are restored • If repeated bleeding episodes there may be damage to joint component which lead almost inevitably to severe joint damage and disability Other sites of bleeding are • - mouth, gum, nose • - Hematuria • - CNS bleeding • - GIT bleeding Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Diagnosis When the diagnosis is suspected from clinical grounds or family history the laboratory tests will include: 1) Complete Blood Count including Hb level and platelet count, these parameters are normal in hemophilia (If anemia is not present due to bleeding) 2) Normal prothrombin time (PT) 3) Prolonged activated Partial Thromboplastin Time (aPTT) however in mild hemophilia this prolongation may be discrete 4) Factor assays for factor level must be done to differentiate between hemophilia A and B and to classify the hemophilia according to factor level as - Severe hemophilia if factor level ……...< 1% - Moderate hemophilia if factor level …..1-5% - Mild hemophilia if factor level ………..5-25% Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Treatment (General measures): -Prevention of trauma -No IM injection -Aspirin and other drugs that affect platelets function must be avoided Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Treatment of acute bleeding 1) Factor Replacement - Fresh Frozen Plasma (FFP) - Cryoprecipitate (For hemophilia A only) - Prothrombin complex concentrates (PCC) for Hemophilia B - Clotting factor concentrates = Plasma derived or recombinant FVIII or FIX concentrate *Factor VIII or IX concentration must be increased to at least 25-30% of normal. * In the case of severe bleeding, or as cover for surgery, it is necessary to increase the plasma factor concentration to 100% Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Hemophilia Replacement therapy for hemophilia A : Every 1unit / Kg increase factor VIII level in the blood by about 2 % Repeated every 8 hours if necessary Replacement therapy for hemophilia B : Every 1 IU/kg infused, the plasma level of FIX raise by 11.4 %, Repeated every 12 hours if necessary Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Treatment of acute bleeding 3) Adjuvant therapy I) Antifibrinolytic drugs 1) Tranexamic (NA in USA) Cyklokapron® 2) Epsilon Aminocaproic acid (EACA) Amicar ® II) Fibrin sealants • Can be used for: Dental extraction Bleeding from mucous membranes Circumcision Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist Primary prophylactic treatment Although prophylaxis treatment strategies vary greatly, the typical regimen (Malmö regimen) requires FVIII infused at a dose of 25-40 IU/Kg three time per week in hemophilia A and 25-40 IU/Kg twice weekly in hemophilia B • Today the goal is that the child should be able to live as normal live as possible • Primary prophylaxis is both very demanding (on patients and families) and expensive. Dr Mustapha Alfallah – Pediatric Hematologist-Oncologist